Radioactive iodine therapy in the management of pediatric Graves’ disease

CASE SCENARIO

A 9-year-old girl presented to the outpatient department with a visible neck swelling and symptoms of diaphoresis and tremors. Her height was 137 cm (+0.85 standard deviation score [SDS]) and weight 28.5 kg (+0.22 SDS) with a body mass index SDS of −0.27. Parents reported a weight of approximately 31 kg, 5 months prior, suggesting significant weight loss despite increased appetite. Physical examination revealed a soft, World Health Organization (WHO) grade 2 goiter with a bruit, lid retraction, and lid lag, suggesting mild Graves’ orbitopathy. Biochemical evaluation confirmed overt thyrotoxicosis with high thyroxine (T4) 17 mg/dL (normal: 4.8–12.7 mg/dL), high triiodothyronine (T3) 2.5 ng/mL (normal: 0.8–2.0 ng/mL), suppressed thyroid-stimulating hormone (TSH) 0.0029 mIU/L (normal: 0.27–4.2 mIU/L), and elevated TSH receptor antibody (TSHRAb) titer at 18 IU/L (reference: <1.75 IU/L). Antithyroid peroxidase antibody was also positive. Complete blood counts and liver function tests were normal at baseline. Thyroid ultrasonography demonstrated diffuse enlargement of both lobes with marked hypervascularity (“thyroid inferno” pattern) on Doppler imaging. A diagnosis of Graves’ disease (GD) was established. The treatment was initiated with methimazole (MMI) at 0.5 mg/kg/day (15 mg/ day) in divided doses along with propranolol for symptomatic control. She had symptomatic improvement over the next 6–8 weeks. At 6 months following initiation of MMI therapy, she achieved biochemical euthyroidism with serum T4 8.9 mg/dL, T3 1.4 ng/mL, and TSH 0.82 mIU/L.

The MMI dose was subsequently tapered cautiously, with periodic monitoring of thyroid function tests. However, at 18 months of therapy, the child developed biochemical relapse during dose reduction (while at a dose of 5 mg/day), with recurrence of elevated T4 and T3 and suppressed TSH. TSHRAb titres remained persistently elevated at 15 IU/L. Escalation of the MMI dose again achieved temporary biochemical control; however, a second relapse occurred during subsequent tapering attempts over the next year. Given the young age at presentation, large diffuse goiter, persistently elevated TSHRAb titres, and recurrent relapses despite prolonged antithyroid drug (ATD) therapy, the likelihood of sustained remission was considered low. This case reflects the typical clinical course of many pediatric patients, where the limitations of medical therapy drive the need for radioactive iodine (RAI) or surgery as definitive options. The above case scenario highlights the need for a definitive therapy after failed attempts to taper the ATDs when remission is achieved. This review addresses the options available in such a scenario. The pros and cons of RAI therapy and thyroidectomy are reviewed along with the available treatment guidelines from the scientific societies.

INTRODUCTION

Graves’ disease (GD) represents an overwhelming majority of hyperthyroidism cases in children, accounting for approximately 95–99% of pediatric thyrotoxicosis.^[1] The disease results from a failure of immune tolerance, leading to the production of thyrotropin receptor antibodies (TSHRAb) that bind to and activate the thyroid-stimulating hormone (TSH) receptor on thyroid follicular cells. This activation stimulates the synthesis and release of thyroid hormones independent of the normal pituitary–thyroid feedback loop, leading to systemic hypermetabolism.

In children, the consequences of untreated thyrotoxicosis are profound. Beyond the typical symptoms of weight loss, palpitations, and heat intolerance seen in adults, pediatric patients face certain unique risks. Chronic thyroid hormone excess accelerates bone maturation, potentially leading to premature epiphyseal closure and reduced final stature. Furthermore, the neuropsychiatric manifestations, including attention-deficit symptoms, declining academic performance, and severe emotional lability, can have long-lasting effects on a child’s development.

The management of pediatric GD is complicated by the fact that children are less likely than adults to achieve remission with antithyroid drugs (ATDs). While the remission rate among adults after 12–18 months of ATDs ranges from 40% to 60%, children often show rates as low as 20–30%.^[2] This aggressive disease course necessitates the use of definitive therapy. Radioactive iodine (RAI) therapy serves as a key option that balances efficacy with a minimally invasive profile.

Q1: WHAT IS THE BURDEN AND NATURAL HISTORY OF PEDIATRIC GD?

GD is the most common cause of pediatric thyrotoxicosis. However, it accounts for only 5% of all GD cases. The overall incidence in children and adolescents is around 4.58/100,000/ year, but it is lower: 1–2.91/100,000/year before 15 years of age.^[3] GD is 3.4 times more common in girls than in boys.^[1] ATDs, particularly methimazole (MMI)/carbimazole (CBZ), remain the recommended first-line treatment for pediatric GD. After commencing standard treatment with ATDs, most of the patients become biochemically euthyroid within 4–6 weeks, although this timeline is variable and will depend on the disease severity, ATD dosages, and compliance. Patients with higher baseline thyroid hormone concentrations may take a longer time to normalize. As ATDs take a few weeks to build up in the thyroid, symptom improvement may not be immediate. Around 15% of pediatric patients with GD on ATD, mainly MMI/CBZ, develop at least one side effect or adverse event.^[4] The most frequent minor side effects include cutaneous reactions such as pruritic rash or urticaria. Hepatitis or liver dysfunction with MMI/CBZ is cholestatic and usually resolves after ATD is stopped. Major side effects, including agranulocytosis, are also rarely reported in pediatric GD patients.^[5] The rate of side effects is higher in younger children, and most occur within the first 3 months of treatment. Severe adverse events may be dose-dependent.^[6]

The overall remission rate with ATD treatment in pediatric GD patients is only 20–30% after 2 years of therapy.^[2] Remission rates have been shown to increase with longer treatment duration. Remission rates of 24.1, 31.0, and 43.7% have been reported with treatment durations of 1.5–2.5, 2.5–5, and 5–6 years, respectively.^[2,6] Only one study with a 9-year treatment duration reported a remission rate of 75%.^[7]

Q2: WHEN SHOULD DEFINITIVE THERAPY BE CONSIDERED IN A CHILD/ADOLESCENT WITH GD?

Determining when to transition from medical management to definitive therapy requires careful assessment of clinical predictors and patient-specific factors. However, the probability of achieving a drug-free remission remains low.

Definitive therapy is generally recommended in the following scenarios:^[8]

1. Relapse after ATD therapy: If hyperthyroidism recurs after a course of ATDs (typically 1.5–2.5 years), the likelihood of achieving remission with a second course of medication is significantly reduced

2. Severe ATD toxicity: Life-threatening side effects, such as agranulocytosis or severe hepatotoxicity, are absolute indications to discontinue thionamides and need definitive alternatives

3. Refractory compliance issues: Adolescents, in particular, may struggle with the daily multiple-dose requirements of ATD therapy, leading to unstable thyroid hormone levels and increased morbidity

4. Failure to achieve euthyroidism: Some patients require exceptionally high doses of MMI to control symptoms, increasing the risk of dose-dependent side effects

5. Patient and family preference: In selected cases, the desire for a definitive solution to avoid long-term medical monitoring is a valid consideration in shared decision-making.

The presence of high TSHRAb levels, large goiter, and young age at diagnosis are consistent predictors of a low remission probability.^[7]

Q3: WHAT ARE THE SPECIFIC INDICATIONS AND CONTRAINDICATIONS FOR RAI IN CHILDREN?

The selection of RAI over surgery or continued ATD therapy depends on the patient’s age, clinical status, and the presence of extrathyroidal manifestations. RAI is most frequently indicated for adolescents over 10 years of age who have failed medical therapy. The non-invasive nature of RAI is a significant advantage, particularly in patients who wish to avoid the risks of general anesthesia or surgical scarring.

Q4: WHAT ARE THE GLOBAL CONSENSUS GUIDELINES REGARDING RAI USE IN PEDIATRIC GD?

Clinical practice is largely guided by the 2016 American Thyroid Association (ATA) and the 2022 ETA guidelines.^[8,12] While both organizations emphasize the importance of achieving permanent ablation rather than euthyroidism, there are some differences in their recommended approaches. Table 1 summarizes the comparison between the two guidelines.

The target outcome across all modern guidelines is the induction of permanent hypothyroidism. This approach is favored because it provides a definitive end to the thyrotoxic state and eliminates the risk of future recurrence. Further, high-dose ablation is believed to be safer from an oncological perspective, as lethal radiation doses prevent the survival of mutated cells that could, in theory, undergo malignant transformation.

Q5: WHAT IS THE MECHANISM OF ACTION AND RADIOBIOLOGY OF RAI IN THYROID TISSUE?

The therapeutic efficacy of I-131 in GD is based on the thyroid gland’s unique ability to concentrate iodine. I-131 is a radioisotope that undergoes beta-minus decay, a process in which a neutron in the unstable nucleus stabilizes by converting into a proton while emitting a high-energy electron (beta particle) and an antineutrino. Gamma radiation is also emitted during its decay process.

Q6: HOW SHOULD THE PEDIATRIC PATIENT BE PREPARED FOR RAI ADMINISTRATION?

Preparation is vital to maximize the therapeutic efficacy of I-131. The primary goal is to ensure that the thyroid gland is highly “avid” for iodine when it’s administered.

Q7: WHAT ARE THE STANDARD PROCEDURAL STEPS FOR RAI ADMINISTRATION?

The administration of RAI in children is typically performed in an outpatient setting, in the Department of Nuclear Medicine under controlled radiation precaution conditions, in accordance with local radiation safety regulations and guidelines.

Q8: WHAT IS THE PREFERRED DOSING STRATEGY FOR PEDIATRIC RAI THERAPY?

The historical approach of giving low doses to achieve euthyroidism resulted in high rates of persistent hyperthyroidism and the need for repeat treatments. Modern practice favors an “ablative” approach.

Q9: WHAT ARE THE RADIATION SAFETY PROTOCOLS FOLLOWING PEDIATRIC RAI THERAPY?

Adherence to safety protocols is essential to protect the family members and the community. These precautions are centered around the principles of time, distance, and hygiene.

Q10: WHAT IS THE EXPECTED TEMPORAL COURSE OF THYROID STATUS POST-RAI THERAPY, AND HOW SHOULD THESE PATIENTS BE MONITORED?

The clinical and biochemical course of pediatric GD following RAI therapy is a dynamic process characterized by distinct physiological phases. Understanding this temporal sequence is critical to avoiding clinical mismanagement and ensuring timely intervention. The expected post-therapeutic course of thyroid status is summarized in Table 3.

During the first phase (1–6 weeks), acute radiation thyroiditis occurs. As the high-energy beta particles induce follicular cell necrosis, the physical integrity of the follicles is compromised. This causes an uncontrolled, passive leakage of preformed T4 and T3 into the systemic circulation. In the second phase (2–3 months), the intraglandular stores of pre-formed thyroid hormone gradually become depleted. Concurrently, the radiation-damaged thyroid follicular cells lose their capacity to capture iodine and synthesize new hormones, leading to a precipitous drop in circulating T4 and T3 levels. It is during this crucial window that pituitary TSH secretion begins its gradual recovery. By 4–6 months post-treatment, thyroid hormone levels fall below the normal reference range, and TSH becomes frequently elevated. This signals that thyroid ablation is biochemically complete. More than 80% of pediatric patients exhibit primary hypothyroidism by this stage, highlighting the success of the ablative intervention. At 12 months, the transition to permanent hypothyroidism is usually complete. The patient’s long-term thyroid status is entirely dependent on exogenous hormone replacement therapy. TSH and free thyroid hormones are maintained within age-appropriate target ranges through daily, weight-based levothyroxine (LT4) dosing.

The resumption of ATDs/thionamides after RAI therapy, to reduce symptoms of hyperthyroidism till RAI therapy takes its effect, is a controversial topic. Thionamides function as potent chemical radioprotectors. By actively scavenging radiation-induced free radicals and decreasing the effective half-life of I-131 within the thyroid gland, the post-RAI use of MMI/CBZ rescues sub-lethally damaged follicular cells and, hence, theoretically, can significantly reduce the long-term cure rate of the therapy.^[16]

For most pediatric patients, mild to moderate post-ablative hyperthyroidism during the 6–12 week transition can be managed conservatively using beta-adrenergic antagonists (e.g., propranolol or esmolol) to control peripheral symptoms without compromising the success of the ablation. Therefore, thionamides should be resumed post-RAI in select, severe cases where rapid biochemical control is clinically required to prevent cardiovascular or neurological decompensation. Nevertheless, ETA 2022 guidelines recommend restarting thionamides 1–2 days after RAI and continuing for 1–3 months.^[8]

Another critical pitfall in the post-therapeutic monitoring is relying on serum TSH as an early marker of thyroid status. Long-standing, severe thyrotoxicosis causes profound, chronic down-regulation of the hypothalamic–pituitary– thyroid axis, leading to severe functional suppression and pituitary thyrotrope hypoplasia. Following successful RAI ablation, peripheral FT4 and FT3 levels drop rapidly, often falling below the lower limit of normal within 4–8 weeks. However, the suppressed thyrotropes exhibit a marked recovery lag, and TSH secretion can remain completely suppressed for several months despite profound peripheral hypothyroidism.

Relying solely on TSH during the first 3–6 months post-RAI can result in a delay in diagnosing hypothyroidism and initiation of LT4. Consequently, serum TSH is an unreliable guide for early post-ablation monitoring. A comprehensive biochemical assessment, including both TSH and FT4, is needed, starting at 4–6 weeks. Falling FT4 concentration (and not TSH elevation) should be used as the primary biochemical trigger to initiate LT4 replacement. Failure of resolution of hyperthyroid state beyond 12 months is suggestive of treatment failure and warrants repeat therapy.

Q11: HOW EFFECTIVE IS RAI THERAPY, AND WHAT ARE THE MAJOR FACTORS AFFECTING RESPONSE?

RAI therapy is an effective treatment for hyperthyroidism, achieving a long-term cure or remission rate of approximately 80–95% after a single dose, and up to 100% success after multiple courses.^[19] Several key factors directly influence this response and dictate whether a patient is at risk of treatment failure. A large thyroid or goiter volume is a primary independent predictor of failure, as larger glands require higher radiation activities to achieve complete ablation.^[20] Severe baseline thyrotoxicosis (characterized by high free thyroid hormone levels), the presence of active ophthalmopathy, and positive TSHRAb also lower first-dose cure rates.^[21] Pharmacologically, pre-treatment with propylthiouracil (PTU) significantly reduces the efficacy of subsequent I-131 therapy due to a persistent radioprotective effect, whereas MMI pre-treatment does not impair cure rates, provided it is discontinued at least 3–7 days before administration. In addition, treatment failure is more common in males and in cases with low 24-h RAI uptake, whereas the use of adjuvant lithium carbonate can significantly improve efficacy and accelerate recovery by prolonging I-131 retention within the thyroid follicles.^[22]

Q12: WHAT ARE THE SHORT-TERM AND LONG-TERM SAFETY CONCERNS WITH RAI THERAPY?

Therapeutic administration of RAI can precipitate several acute, short-term complications. Radiation thyroiditis, typically manifesting as localized anterior neck pain and a transient hyperthyroid flare within 1–2 weeks post-treatment, results from follicular necrosis and is managed symptomatically with non-steroidal anti-inflammatory drugs or moderate-dose corticosteroids alongside beta-adrenergic blockers.^[23] A much more severe, life-threatening complication is thyroid storm (thyrotoxic crisis), an endocrine emergency with a mortality rate of approximately 20% that can be triggered by rapid post-ablation thyroid hormone leakage. Thyroid storm is clinically diagnosed using tools such as the Burch–Wartofsky point scale and managed in critical care units with multi-targeted therapies, including high-dose ATDs (preferably PTU to inhibit peripheral conversion), delayed potassium iodide, intravenous glucocorticoids, and carefully titrated, short-acting intravenous beta-blockers such as esmolol to avoid cardiovascular collapse. Patients with severe thyrotoxicosis and very large goiters are at the highest risk of thyroid storm post-RAI therapy. ATDs stopped too soon before treatment increases the risk of thyroid storm. Hence, discontinuing ATDs 5 days before I-131 is administered is sufficient. There are very few pediatric case reports of thyroid storm following RAI therapy. Rohrs et al. reported a rapid onset of thyroid storm and cerebral infarction within 24 h of RAI, resulting in persistent neurological deficits in an 11-year-old girl with severe thyrotoxicosis.^[24] This case underscores the importance of adequate medical management of thyrotoxicosis using ATDs before considering RAI treatment. Furthermore, I-131 therapy can cause the onset or progression of GO due to a post-radiation rise in TRAb titers.^[25] To mitigate this risk, both the ATA 2016 guidelines and the ETA 2022 consensus statement on thyroid eye disease recommend steroids, in accordance with European Group on Graves’ Orbitopathy guidelines, for patients with mild, active GO, whereas active moderate-to-severe GO is an absolute contraindication.^[10]

Although the short-term safety concerns remain important, the more common concern for parents when considering RAI therapy is the long-term safety, specifically the risk of secondary malignancies and effects on future fertility.

Q13: HOW DOES RAI THERAPY COMPARE TO TOTAL THYROIDECTOMY AS A DEFINITIVE OPTION?

Choosing between RAI and surgery (total thyroidectomy) is a difficult decision, as it involves balancing the risks of each option with how quickly it can achieve a cure. Table 4 compares these two treatment options.

MANAGEMENT AND FOLLOW-UP OF THE INDEX CASE (CASE SCENARIO)

The index case underwent RAI therapy after 6 years of MMI treatment at the age of 15 years due to persistent disease activity with elevated TSHRAb. Following optimization of ATD therapy to achieve near-biochemical euthyroidism, MMI was discontinued 7 days before RAI administration, while propranolol was initiated for symptomatic control. She received a single oral dose of I-131 (RAIU-guided), with uptake values of 11.3% at 2 h and 26.3% at 24 h. A dose of 10 mCi of I-131 was administered under direct supervision. Serial thyroid function tests were monitored subsequently, and LT4 replacement therapy was initiated during follow-up, 3 months after RAI therapy. At 1-year post-RAI therapy, she remains in remission on LT4 replacement and is clinically doing well.

CONCLUSION

RAI therapy remains a safe, effective, and indispensable definitive treatment for pediatric GD. Its efficacy depends on appropriate patient selection, thorough pre-treatment preparation, and the use of adequately ablative dosing strategies. In adolescents who do not achieve remission with prolonged ATD therapy, RAI provides a non-invasive alternative that avoids the inherent procedural risks associated with surgery.

Although the use of RAI has declined in favor of extended courses of ATDs, it remains an important definitive treatment option, alongside total thyroidectomy, for children with drug intolerance, poor adherence, or relapse following ATD therapy. Importantly, concerns regarding radiation-induced malignancy have not been substantiated by large retrospective studies at the doses typically employed for the management of hyperthyroidism.

Emerging targeted biological therapies, including FcRn (neonatal Fc receptor) inhibitors and rituximab, represent a promising area of development, with the potential to achieve higher remission rates without necessitating permanent thyroid ablation.^[29] However, until such therapies are validated and approved for use in the pediatric population, RAI remains a key therapeutic option.

Optimal outcomes with RAI therapy require a shared decision-making approach, strict adherence to established safety protocols, and compliance with contemporary clinical guidelines. The principal therapeutic objective remains the prompt restoration of a euthyroid state to preserve the child’s physical health, cognitive function, and emotional well-being.