Hyperthyroidism is a state of excess production and secretion of endogenous thyroid hormone resulting in the clinical symptomatology of thyrotoxicosis.1 The typical clinical manifestations of thyrotoxicosis in children and adolescents are similar to those seen in adults, such as diffuse thyroid enlargement or goiter, tachycardia, tremor, palpitations, weight loss, increased appetite, changes in mood or behavior, and heat intolerance (Table 1).1–4 These symptoms are often insidious in onset, subtle in presentation, or attributed to other clinical conditions, which may delay the evaluation and diagnosis of thyroid dysfunction in young patients.1 This article highlights hyperthyroidism in a pediatric patient and reviews the current treatment options.
Clinical Signs and Symptoms of Thyrotoxicosis in Children and Adolescents
A 12-year-old girl was referred to a pediatric endocrinology clinic for evaluation of an enlarged thyroid gland and abnormal thyroid function test results. The patient initially presented to her pediatrician for routine evaluation 6 months prior, at which time it was noted that the patient was significantly overweight for age and had a prominent thyroid gland. Follow-up laboratory evaluation at that time revealed an elevated thyroid-stimulating hormone (TSH) level.
On presentation to the pediatric endocrinologist, the patient and her parents reported a preceding history of excessive weight gain over many years, which had been attributed to excess “junk food” intake and a sedentary lifestyle. More recently, she had noticed occasional palpitations and restlessness; however, there was no reported cold or heat intolerance, changes in the appearance of her skin or hair, hyperactivity, sleep disturbance, fatigue, drastic changes in mood, difficulty with concentration, or poor performance in school. Additionally, she reported no difficulty with breathing, changes in her voice, or difficulty with swallowing. Her past medical history was otherwise unremarkable, although her mother did report a history of autoimmune thyroid disease in the family.
On examination, the patient was obese but well appearing. Her eyes were normal in appearance, without evidence of proptosis or lid lag. Her thyroid gland was full and diffusely enlarged, but no nodules, bruits, or tenderness were appreciated. No cervical lymphadenopathy was noted.
Repeat thyroid function tests were obtained; this time revealing a markedly decreased TSH level (<.015 mcU/mL; normal 0.34–5.60 mcU/mL), elevated triiodothyronine (T3) level (4.50 ng/mL; normal 0.80–2.13 ng/mL), elevated free thyroxine (free T4) level (2.84 ng/dL; normal 0.61–1.81 ng/dL), and elevated thyroid-stimulating immunoglobulin (TSI) index (4.9; normal ≤1.3). Thyroid ultrasound showed evidence of a diffusely enlarged and heterogenous thyroid gland without discrete nodules.
The pediatric endocrinologist diagnosed the patient with Graves' disease. After a thorough discussion of Graves' disease as well as the relative risks and benefits of available treatment options, the specialist recommended initial medical management with methimazole 30 mg daily with the goal of maintaining a euthyroid state and possibly achieving remission. He also prescribed atenolol 100 mg daily to control her associated symptom of palpitations. The endocrinologist continued to observe the patient closely throughout the course of treatment.
At her 6-month follow-up examination, the patient was asymptomatic. Her parents reported that she had continued to take the methimazole as prescribed, although she missed a dose approximately once per week. Despite reported adherence to medical management, her TSH level remained depressed (<.015 mcU/mL), her T3 and free T4 levels remained elevated (3.60 ng/mL and 2.11 ng/dL, respectively), and her TSI index remained high (6). The pediatric endocrinologist provided additional instruction regarding medical therapy and encouraged medication compliance, while advising that definitive therapy with either radioactive iodine or surgery be considered if the patient was not able to maintain an euthyroid state on antithyroid medication.
After 12 months of medical therapy, the patient remained asymptomatic but biochemically hyperthyroid (TSH: .019 mcU/mL, T3: 3.20 ng/mL, free T4: 1.84 ng/dL). The pediatric endocrinologist determined that the patient was either refractory to medical therapy or a failure of medical therapy due to medication noncompliance, and he referred the patient for surgical consultation.
The patient was evaluated in a multidisciplinary clinic by a pediatric otolaryngologist and a head and neck surgeon in a high-volume thyroid surgery practice. Total thyroidectomy was recommended, and the benefits, risks, and alternatives to surgery were discussed with the patient and her parents. Preoperatively, the patient was instructed to continue methimazole and atenolol, and she was prescribed 250 mg of saturated solution of potassium iodide three times per day for 1 week prior to the operation.
Total thyroidectomy was completed without complication. The four parathyroid glands and bilateral recurrent laryngeal nerves were identified and noted to be intact, and the estimated blood loss was minimal. The final pathologic specimen was a 58-g thyroid gland (normal range in adults: 25–30 g) with diffuse hyperplasia and changes consistent with Graves' disease (ie, prominent in-foldings of hyperplastic follicular epithelium with scalloping out of the colloid in the follicle). There was no evidence of malignant changes.
Postoperatively, the patient was admitted for clinical observation and routine checks of serum calcium and parathyroid hormone (PTH) levels. During the first postoperative day, the patient reported a tingling sensation around her lips. The corresponding serum calcium was 6.8 mg/dL (normal 8.5–10.3 mg/dL) and PTH was <6 pg/mL (normal 12–88 pg/mL). Supplementation with calcium carbonate and calcitriol was initiated and titrated to improvement in clinical symptoms and elevation of serum calcium levels. Hypoparathyroidism resolved after 2 weeks. Otherwise, the patient tolerated the surgery and recovered well. Antithyroid medication was discontinued, and thyroid replacement with levothyroxine was started. She was ultimately discharged home in stable condition on postoperative day 2, with routine outpatient follow-up requirements with the pediatric endocrinologist.
This illustrative case describes the symptom complex and workup associated with thyrotoxicosis refractory to medical therapy that was cured by surgery. The differential diagnosis of thyrotoxicosis in this patient population is broad and includes various etiologies of hyperthyroidism as well as diseases associated with excess secretion of preformed endogenous thyroid hormone or excess intake of exogenous thyroid hormone (Table 2).1,4,5 Graves' disease is the most common cause of thyrotoxicosis in children and adolescents,2,4,5 representing more than 90% of cases.1 The incidence of Graves' disease in the pediatric population is approximately .02%,1 although it's more commonly seen in adolescence and more frequently diagnosed in girls as compared to boys (a ratio of 5:1).2
Differential Diagnosis of Thyrotoxicosis in Children and Adolescents
Graves' disease is an autoimmune disorder characterized by the presence of TSH-receptor stimulating antibodies, which induce increased synthesis and secretion of endogenous thyroid hormone.3,4 The diagnosis of Graves' disease is made by the presentation of symptoms of thyrotoxicosis, presence of diffuse thyroid enlargement, depressed TSH levels in the setting of elevated total T3 and free T4 levels, and presence of TSH-receptor stimulating antibodies.4
Three therapeutic options are commonly employed for the treatment of Graves' disease in children and adolescents: antithyroid drugs (ATDs), radioactive iodine therapy, and thyroidectomy.4–7 The choice of treatment modality is guided by patient age and medical condition and determined by the preferences of the patient, family, and physician given the relative advantages and disadvantages of each option.3,4,7 Regardless of the treatment modality chosen, there is great impetus for a multidisciplinary approach to evaluation, treatment, and follow-up plans for these patients.
Medical management with ATDs is well-established and considered first-line therapy for most pediatric patients with Graves' disease.6,7 ATDs inhibit thyroid hormone synthesis by interfering with iodination of thyroglobulin by thyroid peroxidase, effectively rendering patients biochemically euthyroid during use.8 Methimazole is the most commonly prescribed antithyroid medication. Its use is associated with minor side effects in approximately 15% to 25% of pediatric patients, including hives, edema, arthralgias, and neutropenia, as well as rare major side effects, such as lupus-like syndrome, vasculitis, Stevens-Johnson syndrome, and agranulocytosis.4,5,8 Adverse events typically occur within the first 6 months of therapy, although events may occur up to 2 years after beginning therapy in approximately 3% of patients.4 Propylthiouracil is also an effective antithyroid medication; however, its use is not recommended in pediatric patients except in special cases due to the risk of more frequent and more severe side effects, including irreversible hepatotoxicity.6–8
The ultimate aim of treatment with ATDs is to achieve remission with persistence of a euthyroid state for at least 6 months after the medication is discontinued. However, lasting remission is achieved in only 20% to 65% of pediatric patients undergoing prolonged therapy,3–7 and relapse occurs in as many as 40% to 60% after antithyroid medication is withdrawn.4,6,7 The most common cause of treatment failure in pediatric patients is medication noncompliance, due in large part to the need for a prolonged course of therapy.9 Although the optimal duration of therapy is not clearly defined,4 the American Thyroid Association and American Association of Clinical Endocrinologists recommend administration of antithyroid medication for 1 to 2 years prior to discontinuation and assessment for remission. If remission is not achieved after 1 to 2 years, radioactive iodine therapy or thyroidectomy should be considered.7 ATDs drugs may serve as a bridge to definitive therapy in these cases.7,8
Radioactive iodine uptake in the thyroid gland induces destruction of follicular cells by beta-emission and renders the patient permanently hypothyroid.4,5 Thyroid ablation is successful in more than 90% of cases when a single, therapeutic dose is administered. In refractory cases, subsequent doses may be necessary to achieve hypothyroidism.4 Definitive therapy with radioactive iodine is recommended for older children and adolescents in whom Graves' disease persists or recurs despite long-term antithyroid drug therapy, major adverse events associated with ATDs are seen, or compliance and long-term follow up with ATD drug therapy are unlikely.6 The most common side effect of radioactive iodine therapy—mild, transient neck tenderness—is seen in approximately 10% of patients but does not tend to preclude its use.5,7 The effectiveness of radioiodine therapy may be reduced in patients with large thyroid glands (>80 g).5 Additionally, patients with significant ophthalmopathy may have exacerbation of related symptoms with radioactive iodine therapy.4,10,11 Therefore, alternative therapy may be considered in these patient populations.5 Given a theoretical, although never proven, lifetime risk of radiation-induced malignancy in very young children, radioactive iodine therapy is avoided in patients younger than age 5 years.6,7,12
Surgical therapy with thyroidectomy is an effective and safe alternative to radioactive iodine ablation as definitive therapy for Graves' disease in children and adolescents.4,5,7 As with radioactive iodine therapy, thyroidectomy may be recommended for patients in whom hyperthyroidism persists or recurs, major adverse events occur, or compliance and follow-up care are unlikely with ATD therapy. When definitive therapy is required, thyroidectomy is preferred for patients with large thyroid glands due to decreased likelihood of response to radioactive iodine therapy and for patients younger than age 5 years due to theoretic risk of radiation-induced malignancy with radioactive iodine therapy.5,10–12 Additionally, thyroidectomy is indicated in patients with severe thyrotoxicosis, severe ophthalmopathy, obstructive or compressive symptoms associated with large goiter, and coexistent suspicious or malignant thyroid nodules.10–12
When surgical therapy is chosen, total or near-total thyroidectomy should be performed by a high-volume thyroid surgeon to optimize surgical outcome and reduce the likelihood of postoperative complications.7,13,14 In multiple large, single-institution case series, successful completion of total or near-total thyroidectomy by high-volume thyroid surgeons resulted in the expected postoperative outcome of hypothyroidism with low risk (0%–4%) of persistent or recurrent hyperthyroidism requiring additional therapy.10–12 Resultant iatrogenic hypothyroidism is treated with thyroid hormone replacement therapy, which is well-tolerated and associated with few side effects.4,5,10,12
Typical complications of thyroid surgery are related to the risk of injury to adjacent parathyroid glands (resulting in hypocalcemia) and recurrent laryngeal nerves (resulting in vocal cord paresis or paralysis). Although complication rates are higher in children than adults, in the hands of experienced thyroid surgeons, such complications are still rarely encountered in the pediatric population.7 Several reviews of institutional experience of thyroidectomy in children and adolescents with Graves' disease report rates of transient hypocalcemia of 6% to 20%, permanent hypocalcemia of 0% to 3%, transient vocal cord paresis of 0% to 11%, and permanent vocal cord paralysis of 0% to 1%.10–12 Additionally, postoperative hemorrhage and postoperative infection are seen in fewer than 1% of patients.6 No mortalities associated with surgery are reported.10–12
Medical management with ATDs is first-line therapy for children and adolescents with Graves' disease; however, achievement of lasting remission is uncommon, rates of relapse after remission are high, and side effects associated with the medications occur frequently. Definitive therapy with either radioactive iodine ablation or thyroidectomy is therefore required in the majority of pediatric patients with Graves' disease. In general, the indications for radioactive iodine therapy and surgical therapy are similar, and the decision for one or the other is ultimately dependent on patient, family, and physician preference in light of the relative advantages and disadvantages of each. Thyroidectomy is safe and effective, with low rates of surgical complications and high rates of cure without relapse when performed by high-volume thyroid surgeons. Regardless of the therapeutic options pursued, a multidisciplinary approach to evaluation, treatment, and follow-up care is essential.
- LaFranchi S. Clinical manifestations and diagnosis of hyperthyroidism in children and adolescents. http://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hyperthyroidism-in-children-and-adolescents. Accessed April 11, 2016.
- D'Souza S, Patel P, Hageman JR, Deplewski D. An adolescent with Graves' disease and thymic hyperplasia. Pediatr Ann. 2014;43(3):e65–68. doi:10.3928/00904481-20140221-10 [CrossRef]
- Ledbetter DJ. Thyroid surgery in children. Semin Pediatr Surg. 2014;23:60–65. doi:10.1053/j.sempedsurg.2014.03.002 [CrossRef]
- Okawa ER, Grant FD, Smith JR. Pediatric Graves' disease: decisions regarding therapy. Curr Opin Pediatr. 2015;27:442–447. doi:10.1097/MOP.0000000000000241 [CrossRef]
- Rivkees SA. Pediatric Graves' disease: management in the post-propylthiouracil era. Int J Pediatr Endocrinol. 2014;2014(1):10. doi:10.1186/1687-9856-2014-10 [CrossRef]
- LaFranchi S. Treatment and prognosis of Graves' disease in children and adolescents. http://www.uptodate.com/contents/treatment-and-prognosis-of-graves-disease-in-children-and-adolescents. Accessed April 16, 2016.
- Bahn Chair RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Associated of Clinical Endocrinologists. Thyroid. 2011;21(6):593–646. doi:10.1089/thy.2010.0417 [CrossRef]
- Cooper DS. Antithyroid drugs. N Engl J Med. 2005;352(9):905–917. doi:10.1056/NEJMra042972 [CrossRef]
- Léger J, Kaguelidou F, Alberti C, Carel JC. Graves' disease in children. Best Pract Res Clin Endocrinol Metabol. 2014;28:233–243. doi:10.1016/j.beem.2013.08.008 [CrossRef]
- Peroni E, Angiolini MR, Vigone MC, et al. Surgical management of pediatric Graves' disease: an effective definitive treatment. Pediatr Surg Int. 2012;28:609–614. doi:10.1007/s00383-012-3095-5 [CrossRef]
- Liu J, Bargren A, Schaefer S, Chen H, Sippel RS. Total thyroidectomy: a safe and effective treatment for Graves' disease. J Surg Res. 2011;168:1–4. doi:10.1016/j.jss.2010.12.038 [CrossRef]
- Sherman J, Thompson GB, Lteif A, et al. Surgical management of Graves' disease in childhood and adolescence: an institutional experience. Surgery. 2006;140(6):1056–1062. doi:10.1016/j.surg.2006.07.040 [CrossRef]
- Tuggle CT, Roman SA, Wang TS, et al. Pediatric endocrine surgery: who is operating on our children?Surgery. 2008;144(6):869–877. doi:10.1016/j.surg.2008.08.033 [CrossRef]
- Sosa JA, Bowman HM, Tielsch JM, Powe NR, Gordon TA, Udelsman R. The importance of surgeon experience for clinical and economic outcomes from thyroidectomy. Ann Surg. 1998; 228(3):320–330. doi:10.1097/00000658-199809000-00005 [CrossRef]
Clinical Signs and Symptoms of Thyrotoxicosis in Children and Adolescents
||Poor school performance
|Advanced bone age
|Hair and skin changes
Differential Diagnosis of Thyrotoxicosis in Children and Adolescents
Toxic multinodular goiter
Thyroid-stimulating hormone producing pituitary adenoma
Pituitary resistance to thyroid hormone
Thyrotoxic phase of thyroiditisb
Chronic lymphocytic thyroiditis (Hashimoto's thyroiditis)
Subacute lymphocytic thyroiditis
Subacute granulomatous thyroiditis (de Quervain's disease)