1. Introduction
Graves’ disease (GD) is an autoimmune disorder in which hyperthyroidism and thyroid enlargement are caused by TSH receptor antibodies stimulation. It is the most common cause of hyperthyroidism in iodine-replete populations with prevalence between 0.5% and 2%, and ten times more common in women than in men. GD is typically diagnosed in middle-aged persons with the peak age-specific incidence between 20 and 49 years, but the first clinical presentation is possible also in elder patients as well as in children, especially during adolescence. As in adults, GD is the major cause of hyperthyroidism in children, much more frequent in girls than in boys, although it is a rare clinical problem among pediatric patients who constitute only 1–5% of all patients with GD. In pediatric population, the frequency of GD is higher when associated with coexisting autoimmune diseases or genetic ones like Down syndrome, Turner syndrome or Di George syndrome as well as in families with a history of autoimmune thyroid disorders. Some environmental factors like iodine excess (for example mandatory salt iodination), infectious diseases, smoking, alcohol, stress, selenium status, dioxins, or radiation exposure are discussed as associated with increased risk of GD in children [Citation1–Citation4].
While discussing important considerations when choosing optimum treatment option for GD in children, one should realize the differences referring to course of GD and response to treatment in pediatric population as detailed below.
2. Specificity of Graves’ disease in children
There are some important features of GD in pediatric population. Thyrotoxicosis is less common but more severe than in adults, with tremor, excessive sweating, weight loss, muscle weakness, sleep disturbances, irritability, lack of energy, tachycardia, and palpable goiter. Specific signs such as accelerated growth and an increased bone age may be observed. Some disturbances like weight loss, impaired educational outcomes, subtle changes in behavior, menstrual irregularities, or anxiety may have been present for years before the proper diagnosis.
Thyroid-associated ophthalmopathy (TAO) is quite often in this population (38%), especially in adolescents (11–18 years old – 68.2%), usually mild with proptosis and soft tissue involvement as main manifestations.
The outcome of pharmacological treatment of children with GD is disappointing, as compared to the results in adults with much lower remission rate not exceeding 25–30% and with higher prevalence of adverse reactions to antithyroid drugs (ATD).
Both hyperthyroidism and hypothyroidism (as a consequence of treatment or natural disease course) result in educational and social difficulties of young patient and this factor must be taken into account in each decision making [Citation5–Citation7].
3. Current therapeutic choice for Graves’ disease
As in adult population we have three main treatment options for a child diagnosed with GD – ATD therapy, surgical treatment, and radioiodine therapy.
The profits of ATD therapy include no risk of radioactive iodine exposure and no surgical procedure potentially connected with complications and hospitalization but on the other hand, longer treatment duration and possibility of adverse drug reactions.
Surgical treatment of GD in children is effective but requires an invasive procedure and is connected with the necessity of thyroid hormone replacement therapy. In such cases, total or near total thyroidectomy is recommended and it must be performed by a high-volume surgeon.
Radioiodine therapy (131I therapy) is considered as a safe and reliable treatment but associated with a high risk of future hypothyroidism development. 131I therapy should be considered in children without remission after ATD therapy, in children who experienced severe adverse events, refused to have surgical treatment or in case of lack of compliance. According to ATA guidelines, 131I therapy should be avoided in children younger than 5 years due to potentially increased risk for thyroid neoplasm development in case of low administered activities of 131I. RAI is acceptable in children aged 5–10 years if less than 10 mCi of 131I is administered. In children older than 10 years of age, the activity of 131I should be more than 150 μCi/g of thyroid tissue.
The ATA recommendation authors emphasize that these principles are based on theoretical concerns, like total-body radiation dose assessment using phantom modeling, and further direct study of this issue is needed [Citation8,Citation9].
The primary definitive therapy of GD could be the best option for children with chronic comorbidities (especially cardiac failure or diabetes).
As a general rule, ATD therapy is the primary treatment option in pediatric population [Citation5,Citation8–Citation11].
4. Pharmacotherapy for Graves’ disease in children – profits and threats
Two types of ATD are available – thiamazole (as methimazole (MMI) or carbimazole (CBZ), which is metabolized to MMI in the liver) and propylthiouracil (PTU).
MMI is preferred because of its once-daily dosing regimen and rapid normalization of thyroid function with fewer adverse drug reactions comparing with PTU.
Whereas PTU was used in the past in pediatric patients, nowadays only MMI should be used, as PTU is associated with an unacceptable risk of side effects, especially liver failure and antineutrophil cytoplasmic antibody (ANCA) – associated vasculitis syndrome.
In the United States, when PTU was initially less expensive than MMI and was used predominantly in the 1980s, many cases of serious PTU-associated hepatic dysfunction have been reported in children younger than 17 years.
Since the cut of adverse drug reactions is the priority, doses of ATD in children treatment have tended to decrease. Stated starting ATD doses are 0.25–1.0 mg/kg/d for MMI and 2–6 mg/kg/d for PTU, with the upper limit of 30 mg/d for MMI and 300 mg/d for PTU. There are some predictors of poor prognosis like large goiter, high elevated pre-treatment FT4 level or TRAb level, in these cases the start dose should be 1 mg/kg/d MMI, similarly in severe cases with symptoms of heart failure. For mild cases, a starting dose of approximately 0.5 mg/kg/d of MMI is suggested. As a general rule the older children require lower initial ATD dose.
Concomitant use of β-blockers is useful for patients with severe symptoms as an initial treatment to reduce tachycardia.
Most adverse reactions of ATD occur within 3 months after treatment initiation so monitoring should be performed every 2 weeks during this period. White blood cell count, levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutanyl transpeptidase (GGTP), and total bilirubin should be checked [Citation8,Citation10,Citation11].
There are controversial opinions on when to reduce the ATD doses, usually it can be done when serum FT4 and FT3 levels normalize. Then ATD in minimal dose (2,5–10 mg/d) is continued for at least 18–24 months to maintain remission, monitoring the patient every 3–4 months to confirm normal thyroid function (with TSH level within the normal range).
The decision of treatment discontinuation is difficult and requires careful consideration, as there is no established method to state remission in GD. The stable TSH levels, results of TRAb level measurements or clinical features can be used to make such judgments. Pediatric endocrinologists are likely to continue ATD even for years, especially in younger group with poor remission prognosis or in adolescent patients in order to maintain stability in young person’s school life (entrance examinations, sport activity, and so on), when compliance may also be a particularly difficult issue [Citation11–Citation13].
5. Expert opinion
The best treatment of GD in children population is still the matter for discussion. The remission rate during long-term ATD therapy varied from 11% to 49%, even when the time of ATD usage is prolonged over 2 years. In case of relapse long-term low-dose ATD (MMI or CBZ) is recommended. Radioiodine treatment is avoided in children younger than 5 years and limited till the age of 10 years. Thyroidectomy is usually indicated for patients with a high volume of goiter (>80 g). The complications such as hypoparathyroidism, recurrent laryngeal nerve injury, and keloid formation may occur in children population with an estimated whole number of incidences of approximately 15%, so the high-volume surgeon presence is crucial [Citation14,Citation15].
We have no reliable method to state remission and no specific standard for ATD treatment discontinuation, so for children younger than 5 years long-term low-dose MMI (CBZ) therapy is the treatment of choice with surgery in exceptional cases (severe side effects of ATD). In the group of 5–10 years children, ATD is also primary treatment option; the minimal time of therapy is 18–24 months but in case of poor remission prognosis (large goiter, high TRAb level, high required ATD dose, lack of compliance) definitive treatment can be considered. In this group, the option of long-term MMI (CBZ) use should be also considered [Citation11,Citation16,Citation17].
The adolescents should be qualified to radioiodine treatment if the pharmacological treatment option is ineffective or to surgical procedures in cases of thyroid nodules, large goiter, or patient’s preferences.
To sum up, the choice of proper therapy depends on some important factors such as children age, effectiveness of first line ATD treatment, presence of side effects of used drug, clinical features like large goiter, thyroid nodules presence, or concomitant diseases.
In my opinion, long-term ATD therapy can be the optimal, safe, and effective choice in this age group [Citation16,Citation17]. It can be followed by surgery in well-grounded cases or 131I therapy when the child reaches a suitable age (preferably 15 years).
During long-term therapy, MMI is the drug of choice. The block-and-replace therapy (a fixed high dose of ATD combined with levothyroxine) although is not a routine regime may be useful in selected cases of unstable thyroid function. Concomitant β-blockers are useful.
In case of necessary surgical treatment of GD in pediatric patient, thyroidectomy must be performed by a high-volume surgeon.
It is crucial to individualize the therapeutic approach which depends not only on clinical or pharmacological features but also on patient or family preference. Important task for endocrinologist is to explain the possible solutions with their benefits and threats, especially that GD therapy in childhood is the long way for the patient and her/his doctor.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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