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A 14-year-old female attends the paediatric Emergency Department with noticeable palpitations, tremor and debilitating headache. On observations, she was found to have a heart rate of 112 bpm and a blood pressure of 149/56 mm Hg. She had presented 3 years prior and diagnosed with juvenile Graves’ hyperthyroidism and started on methimazole to achieve euthyroidism. Two months ago, she began a gradual reduction of her antithyroid medication. Her most recent thyroid function tests show a low Thyroid Stimulating Hormone (TSH) and a significantly raised free T3 and T4. You suspect recurrent Graves’ disease but are unsure what definitive treatment to achieve remission should be given. Her parents are reluctant to restart her antithyroid medication. They have read about radioiodine online and ask for your opinion on which treatment has the best evidence of achieving remission in the long term.
In children with Graves’ hyperthyroidism (population), should radioiodine or antithyroid drugs (intervention) be used to achieve remission (outcome)?
MEDLINE (2000-present via PubMed), Embase (2000-present via Ovid) and the Cochrane Library were used for the search. Search terms were (Paediatric OR Juvenile OR Child) AND (Grave* OR Hyperthyroid*) AND (Radioiod* OR Thyroid* OR Anti*). Embase revealed 206 hits, Medline had 304 hits and Cochrane had one hit. A further search was conducted to include Graves’ disease in adults to ensure none excluded contained data on juvenile Graves’ disease. Inclusion criteria: English language, publications in the last 20 years (when modern biochemical criteria were established), articles looking at thyroid function in children under 18 years of age and articles reporting on treatment of juvenile Graves’ disease. Articles were excluded on the basis of paediatric or adult adrenal function research, but with no mention of thyroid disease or Graves’ disease. Articles including no children in the analysis were also excluded at this stage.
Of the 511 hits, 504 were excluded after reading the title and/or abstract. The remaining seven articles were read in full, with five ultimately deemed to meet inclusion criteria (table 1). Studies were graded with reference to the Oxford Levels of Evidence.1
Juvenile Graves’ hyperthyroidism is a common cause of thyroid pathology, accounting for 95% of children presenting with thyrotoxicosis.2 It is an autoimmune condition resulting in an overactive thyroid and supraphysiological production of thyroid hormones, T3 and T4. Even though there has been limited studies on the epidemiology of Graves’ disease, it is notable that the incidence is on the rise.3 Clinical presentations are non-specific and include asthaenia, irritability and sleep disorders and clinical signs such as tachycardia, appetite changes and weight loss. Current treatments that are available for patients include antithyroid drugs (ATDs), radioactive iodine therapy (RAI) and surgical removal of part (subtotal thyroidectomy), or complete thyroid (total thyroidectomy).4 However, these treatments have been found to induce varying rates of remission among patients.5 Hence, it is important to evaluate past research to aid clinical decisions. In this article, the use of antithyroid drugs and radioiodine will be analysed.
Five research papers were shortlisted during the search. Four of them were retrospective observational studies, while the study by Wang et al 6 was a meta-analysis of 17 randomised controlled trials (RCTs). The meta-analysis done by Wang et al compared the clinical outcomes of RAI and ATD, with specific reference to remission of Graves’s hyperthyroidism, rates of subsequent hypothyroidism, relapse rate and incidence of adverse events. The long-term follow-up study by Song et al 7 and Cury et al evaluated similar clinical outcomes for ATD and RAI, respectively. Azizi et al 8 compared additional clinical outcomes for both interventions by analysing the difference in goitre rate, thyroid peroxidase antibody level and serum TSH concentration. Lastly, Cohen et al 9 investigated the outcomes of patients who have received ATD prior to RAI.
Generally, the findings on remission rates suggest that patients treated with RAI have a higher cure rate than ATD. Wang et al determined the risk ratio to be 1.66, while Azizi et al identified a higher percentage of those treated with RAI becoming euthyroid. However, RAI has been found to be associated with higher rates of hypothyroidism than ATD, and this is consistent with the research by Wang et al and Azizi et al.
The meta-analysis indicated that the risk of hypothyroidism after RAI is 1.99 times that after ATD. Furthermore, Azizi et al found that 66.2% of the patients treated with RAI became hypothyroid compared with only 2.7% treated with ATD. Adverse events were also reported to be less common among those treated with RAI. The risk ratio calculated by Wang et al was 0.22 and in fact, this was consistent with the three other studies that analysed the rates of adverse events. Both Cohen et al and Cury et al mentioned that there were no adverse events due to RAI therapy, while Song et al mentioned that a small percentage of those treated with ATD experienced adverse events, with the most common event being rash, followed by haematologic abnormalities and elevated liver enzymes.
Though these findings are convincing, it is notable that the findings from the four retrospective observational studies should be taken with caution. Only associative conclusions can be drawn from them since there could be confounding variables that were unaccounted for. With regards to the meta-analysis, 16 out of the 17 RCTs consist of adult patients. However, excluding the RCT with paediatric patients did not have any significant impact on the findings. Hence, it is reasonable to include it and compared with the four other retrospective observational studies, this is the only paper that looked at RCTs. With minimum confounding factors, the findings are more conclusive. Nonetheless, one has to be cautious when generalising the findings to other countries since the majority of the RCTs were based in China. Also, the retrospective studies mentioned that some patients were lost to follow-up. In particular, the 20-year study by Song et al 7 lost nearly 28% of the study population. However, it was noted that the patients who were lost to follow-up had ‘similar baseline clinical and biochemical characteristics’ and hence, the results should not be misleading. It is also worth noting that RAI administration was not standardised across studies, with some individuals requiring higher doses to achieve remission. Therefore, for RAI to become a first-line method of treating Graves’ disease, a standardised dosing regimen must be established to achieve optimum therapeutic benefit.
In summary, the five studies that were shortlisted suggest that the remission rate is possibly higher when treated with RAI with fewer adverse events and lower rates of relapse. However, it might be associated with higher rates of hypothyroidism. Figure 1 highlights the clinical scenarios indicating each possible treatment based on evidence detailed in table 1.
Clinical bottom line
Radioiodine therapy has the potential to become a popular first-line treatment option for juvenile Graves’ hyperthyroidism (Grade B).
Those treated with radioiodine achieve euthyroidism more frequently than those treated with antithyroid drugs (Grade B).
Long-term findings of radioiodine induced neoplasms are rare (Grade C).
Patient consent for publication
Contributors JT developed the manuscript concept. JT and KS completed the literature review and critical appraisal.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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