Are you sure the infant or child has Graves' Disease?

Serum thyroid function tests confirming hyperthyroidism

Total and free thyroxine (T4): Elevated
Total and free triiodothyronine (T3): Elevated
Thyroid stimulating hormone (TSH): Suppressed

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Serum TSH receptor stimulating antibody (TRS-Ab) tests confirming Graves' disease as the etiology

Thyroid stimulating immunoglobulin (TSI): Elevated
TSH receptor antibody (TRAb): positive (elevated)
Thyroid peroxidase (TPO) antibody: Usually elevated

Neonatal Graves' disease

Symptoms of neonatal Graves' disease

Pre-term birth
Increased appetite
Hyperactive
Irritable
Difficult to console
Restless sleep

Signs of neonatal Graves' disease

Low birth weight
Tachycardia
Stare
Goiter
Hepatosplenomegaly
Tremor
Microcephaly
Premature closure of skull fontanelles

These clinical symptoms and signs of thyrotoxicosis occur in the setting of an infant born to a mother with Graves’ disease whose serum thyroid receptor stimulating antibodies (TRS-Ab) are markedly elevated.

Graves' disease in Children

Symptoms of Graves' disease in children

Emotional lability
Hyperactivity
Decreased attention span
Worsening school performance
Difficulty falling asleep, restless sleep
Increase in appetite
Frequent bowel movements
Heat intolerance
Poor weight gain (or even loss)
Secondary amenorrhea in adolescent females

Signs of Graves' disease in children

Goiter
Tachycardia
Wide pulse pressure
Modest increase in linear growth rate
Eye signs, including lid lag, stare, and exopthalamos
Warm, moist palms
Tremor with fingers outstretched
Brisk return of Achilles reflex
Decreased performance in school

What else could the patient have?

Differential diagnoses of neonatal Graves' disease

Drug withdrawal: irritable, hyperactive, restless sleep
Sepsis: irritable, tachycardia, hepatosplenomegaly
Primary cardiac disorder: tachycardia, hepatomegaly, poor weight gain

Differential diagnoses of Graves' disease in children

Attention-deficit hyperactivity disorder (ADHD): hyperactive, decreased attention span, worsening school performance.
Hyperthyroidism due to causes other than Graves’ disease: hyperfunctioning adenoma, toxic multinodular goiter, hyperthyroid phase of Hashimoto’s thyroiditis (“Hashitoxicosis”), hyperthyroid phase of subacute thyroiditis (de Quervain’s disease); TSH-secreting pituitary adenoma (serum TSH levels normal or elevated)
Resistance to thyroid hormone, pituitary > peripheral
Excess levothyroxine ingestion

Key laboratory and imaging tests

Thyroid function should be evaluated by measuring serum free T4, total T3 (or free T3), and TSH levels. Hyperthyroidism is confirmed with elevated serum total and free T4 and total T3 (or free T3) levels and suppressed TSH values. In infants, it is important to compare results to age-normal reference ranges. Serum T4 and T3 ranges (total and free) are higher in the first few weeks of life (serum free T3 could be measured in place of total T3, although there is less information about normal reference ranges in children and the assay is frequently unreliable). See Table I for selected thyroid function test reference ranges.

Table In

Once thyroid function tests confirm hyperthyroidism, serum TRS-Ab should be determined to confirm that hyperthyroidism is caused by Graves’ disease. TRS-Ab can be evaluated by measuring either a thyroid stimulating immunoglobulin (TSI) level or a thyrotropin binding inhibitor immunoglobulin (TBII) level. TSI, a bioassay, is more specific for Graves’ disease. TBII, a competitive inhibition assay, needs to be correlated with thyroid function. Hyperthyroid babies born to mothers with positive TRS-Ab can be assumed to have neonatal Graves’ disease.

Other tests that may prove helpful diagnostically

In infants and children with positive TRS-Ab testing, Graves’ disease is confirmed. In such patients, imaging tests such as radioactive iodine (RAI) uptake and scan are not necessary for the diagnosis. In patients with negative TRS-Ab testing, Graves’ disease may still be the cause of hyperthyroidism. In such patients, a RAI uptake and scan is the next best study. 123-I is the radionuclide of choice, though 131-I is an acceptable alternative. If the RAI uptake is elevated and the scan shows diffuse uptake, the diagnosis most likely is Graves’ disease. If the scan shows uptake only in a “hot nodule”, with suppressed uptake in the remainder of the gland, the diagnosis is a hyperfunctioning adenoma. Patients with toxic multinodular goiter manifest increased uptake present in the multiple “hot nodules”.

Patients with a low or absent RAI uptake may have some form of destructive thyroiditis, such as silent lymphocytic thyroiditis or painful subacute thyroiditis, or they may have thyrotoxicosis resulting from excess levothyroxine ingestion. A serum thyroglobulin measurement usually will separate these possibilities. Serum thyroglobulin levels are elevated in any form of destructive thyroiditis, but values are decreased with levothyroxine ingestion. In the presence of thyroglobulin antibodies, serum thyroglobulin usually cannot be accurately measured.

Infants and children with elevated serum free T4 and T3 but normal or slightly elevated serum TSH levels most likely have resistance to thyroid hormone (RTH). A rare cause of these laboratory findings is a TSH pituitary adenoma. A serum alpha subunit measurement will separate these two possibilities. Serum alpha subunit is normal with RTH, while it is elevated with TSH-secreting pituitary adenomas. Patients with findings consistent with a TSH-secreting pituitary adenoma should undergo magnetic resonance imaging (MRI) with gadolinium contrast to confirm the presence of a pituitary tumor.

Management and treatment of the disease

Recommendations for the management and treatment of neonatal Graves’ disease and Grave’s disease in children are discussed below.

Neonatal Grave's disease

Neonatal Graves’ disease is most commonly treated by a combination of an anti-thyroid drug and a beta adrenergic antagonist. In severe cases, some clinicians add iodine for the first few weeks of treatment. In extremely ill infants (in particular, those with signs of cardiac or circulatory compromise), glucocorticoids are added to the treatment regimen. Since the etiology of neonatal Graves’ disease is the transplacental passage of the TSI from the mother, the disease is self-limiting and usually disappears in about 4 months, when the infant’s TSI from the mother disappears.

1. Anti-thyroid drugs (ATDs) – These work by inhibiting further production of thyroid hormone from the thyroid gland.

Methimazole (MMI) 0.25-1.0 mg/kg/24 hrs by mouth, divided every 8 to 12 hr (or once daily)
Propylthiouracil (PTU) 5-10 mg/kg/24 hrs by mouth divided every 6 to 8 hrs

PTU has the slight advantage of decreasing the conversion of T4 to T3. However, PTU is not recommended as a first line anti-thyroid drug in children with hyperthyroidism, as there are rare reports of severe hepatic toxicity, resulting in either liver transplantation or death. MMI is the preferred anti-thyroid drug.

In patients who are unable to take medications orally, both MMI and PTU can be made into a suspension and temporarily administered via nasogastric tube. MMI is water soluble, while PTU is not. Thus, MMI could be administered as a rectal solution.

2. Beta adrenergic antagonists- Beta blockers control the excess adrenergic nervous system symptoms and signs associated with hyperthyroidism.

Propranolol 1-2 mg/kg/24 hr by mouth divided every 8 hrs
Propranolol .01-.10 mg/kg IV every 6 to 8 hrs (if unable to take by mouth)
Atenolol 1-2 mg/kg by mouth once daily (if a cardioselective beta blocker is preferred)

Once patients are euthyroid, beta blockers can be discontinued.

3. Iodine – Iodine will inhibit secretion of thyroid hormone and may help to block some thyroidal synthesis of T4 and T3.

Lugol’s solution (8 mg/drop, 20 drops per mL) 1 drop by mouth 3 times daily
SSKI (35-50 mg/drop) 1 drop by mouth daily

Iodine can be toxic to esophageal and intestinal mucosa and should be diluted in another liquid. Iodine should not be given for longer than 10-14 days, as patients “escape” from its inhibitory effect after that time.

4. Glucocorticoids- Steroids readily decrease the peripheral tissue conversion of T4 to T3, the bioactive hormone. In addition, in pharmacological doses, steroids optimize cardiovascular function.

Hydrocortisone (solu-cortef) 1-2 mg/kg IV every 8 hrs
Dexamethasone 0.1 mg/kg IV every 12 hrs

With clinical and biochemical improvement, both iodine and glucocorticoids can be discontinued. Once euthyroid, beta adrenergic antagonists can be discontinued.

Graves' disease in children

Graves’ hyperthyroidism in children can be managed by one of the three treatment modalities used in adults: anti-thyroid drugs, radioactive iodine, or surgery. We recommend explaining the benefits and potential adverse effects of each of the three options to parents and patients to involve them in selecting the initial treatment. Most children are initially treated with ATDs.

1. Anti-thyroid drugs (ATDs) – ATDs work by inhibiting further production of thyroid hormone from the thyroid gland. Methimazole (MMI) is the preferred ATD in children. Propylthiouracil (PTU) is also effective and has the slight advantage of decreasing the conversion of T4 to T3, but several society guidelines (including the Endocrine Society, the American Thyroid Association, and the American Association of Clinical Endocrinologists) recommend against the use of PTU as first-drug treatment in children due to a rare risk of severe hepatotoxicity, which may result in liver failure or death.

The initial starting dose of MMI is 0.25-1.0 mg/kg/day, usually as a single daily dose. Patients with milder clinical thyrotoxic features, a smaller goiter, and milder elevations of serum free T4 and T3 are started at the lower end of the dose range, while patients with more severe thyrotoxic features, a larger goiter, and more severe elevations of serum free T4 and T3 are started at the higher end of the dose range. In addition to the thyroid diagnostic tests (see above), prior to starting MMI, we recommend obtaining a baseline CBC and differential and liver function tests (see adverse reactions, below). Most children will become euthyroid within 6 weeks to 3 months after starting ATD treatment. Children with severe Graves’ hyperthyroidism may need an increase in MMI dosing to achieve euthyroidism. Compliance may be an issue with older children and adolescents.

Adding beta adrenergic antagonists: In patients with cardiovascular overactivity (tachycardia, palpitations) or with signs of neuromuscular overactivity (tremor, hyperactivity), addition of a beta blocker will provide symptomatic relief. They provide the most rapid control of clinical thyrotoxicosis. Drug options include:

Propranolol 1-2 mg/kg/day, divided every 8 hrs
Atenolol 1-2 mg/kg/day, given once daily

Once patients are euthyroid, beta blockers can be discontinued.

Monitoring ATD therapy: Patients are followed every 3-4 months, with clinical examination and serum free T4, total T3, and TSH measurements. The ATD dose is titrated so as to maintain normal thyroid function tests, with resulting improvement in clinical features of hyperthyroidism. Consensus guidelines do not recommend “block and replace” treatment (higher dose ATD to “block” thyroid hormone production combined with levothyroxine to treat resultant hypothyroidism). Using the “titration” method, over time one is often able to reduce the ATD dose. If one is able to maintain a euthyroid state on a low dose of MMI (e.g., 5 mg/day), this often predicts that the patient may achieve a remission when ATDs are stopped.

Adverse reactions to ATDs: Minor side effects include papular or urticarial skin rashes, arthralgias, nausea, abnormal taste sensation (primarily with PTU), and transient granulocytopenia. Major side effects include agranulocytosis (<250/mm3), a lupus-like vasculitis associated with positive antinuclear cytoplasmic antibodies (ANCA), arthritis, and nephritis. Hepatitis and resultant severe liver disease are rare side effects of PTU use. With minor adverse reactions, MMI should be discontinued and patient treated with an antihistamine, or, if severe, a short course of steroids.

Once the reaction resolves, MMI may be cautiously restarted, although some patients may prefer (and some clinicians recommend) another mode of treatment. Severe adverse reactions are a contraindication to restarting an ATD. In these circumstances, another mode of treatment, such as radioactive iodine or surgery, should be recommended.

2. Radioactive iodine (RAI) – RAI is an effective alternate treatment option for children with Graves’ hyperthyroidism. Due to evidence that thyroid glands in young children are more sensitive to radiation (manifested by an increased risk of thyroid nodules and cancer), current guidelines by the American Thyroid Association recommend that administration of RAI be reserved for children >10 years of age. RAI may be considered in children between 5- 10 years of age if the dose of I-131 is <10 mCi. The dose of I-131 may be calculated using a formula or by fixed dose:

Formula dose: 100-300 μCi x thyroid weight (grams) / fractional 24 hr I-131 uptake

Fixed dose: 12-15 mCi

The goal is to select a high enough I-131 dose to produce ablation of the thyroid gland to result in hypothyroidism. Ablation of the thyroid gland will eliminate future risk of thyroid nodules or cancer, and it will likely obviate the need for additional RAI treatment doses. If a patient has been pre-treated with ATD, the drug should be discontinued 5 days before administration of RAI. In patients with large glands or severe hyperthyroidism, there may be some benefit to restarting ATD after RAI treatment until the RAI has had enough time to reduce thyroid hormone production. After administration of RAI, serum total and free T4 and TSH should be monitored at periodic intervals, anticipating the development of hypothyroidism and to start thyroid hormone replacement.

3. Surgery – The recommended surgical treatment of Graves’ disease in children is a near-total thyroidectomy. Guidelines from the American Thyroid Association recommend that surgery be performed by a high-volume thyroid surgeon. The risk of surgery and associated anesthesia are reduced if patients are treated with an ATD for 6-12 weeks to result in euthyroidism or near-euthyroidism. If this is not possible, patients should be treated with a beta adrenergic antagonist (see above). In addition, treatment with iodine for 7-10 days prior to surgery reduces thyroid blood flow and blood loss during surgery. Surgery may be the eventual approach in children with large goiters, those resistant or noncompliant with ATD, and children with ophthalmopathy, since RAI may worsen Graves’ eye disease.

Of the 3 options presented above, most patients and parents select ATDs as the initial treatment. Most children with Graves’ hyperthyroidism treated with ATDs are treated for a longer period of time than adults. Studies in children and adults agree that approximately 25-30% will achieve a remission after 18-24 months of ATD treatment (remission defined as remaining euthyroid for at least one year after discontinuation of ATD treatment). There is disagreement about whether longer-term ATD treatment results in a better remission rate. One study (Lippe et al) reports a 25% remission rate for every 2 years of ATD treatment, with a 50% remission rate after 4.5 years. If, at some point, a patient prefers a more definitive treatment, either RAI or surgery is recommended. In children >10 years of age, RAI is probably the second form of treatment selected by patient and parents (and by some clinicians, who prefer RAI as the first-line treatment in adolescents with Graves’ disease). In children <10 years of age, and particularly children <5 years of age, surgery is the preferred second form of treatment.

ATDs may be contraindicated in patients with underlying liver disease. It should be noted, however, that hyperthyroidism itself appears to result in mild elevation of liver enzymes. This mild elevation is not a contraindication to ATD treatment and usually resolves when patients become euthyroid. In patients with a co-existing autoimmune vasculitis (e.g. glomerulonephritis) or significant granulocytopenia, treatment with ATDs also is usually contraindicated.

What’s the Evidence?/References

Neonatal Graves' Disease

Hamada, N, Momotani, N, Ishikawa, N. “Persistent high TRAb values during pregnancy predict increased risk of neonatal hyperthyroidism following radioiodine therapy for refractory hyperthyroidism”. Endocr J. vol. 58. 2011. pp. 55-58. (A reminder that, while maternal TRAb levels decrease after RAI treatment, some women still have positive levels 5 years after RAI.)

Zakarija, M, McKenzie, JM, Hoffman, WH. “Prediction and therapy of intrauterine and late-onset neonatal hyperthyroidism”. J Clin Endocrinol Metab. vol. 62. 1986. pp. 368-371. (Excellent study demonstrating that maternal TR-Ab levels predict onset of neonatal Graves' disease.)

Abalovich, M, Amino, N, Barbour, LA. “Management of thyroid dysfunction during pregnancy and postpartum: An Endocrine Society Clinical Practice Guideline”. vol. 92. 2007. pp. S1-S47. (Guidelines from the Endocrine Society emphasizing that maternal thyroid dysfunction impacts the fetus.)

Daneman, D, Howard, NJ. “Neonatal thyrotoxicosis: intellectual impairment and craniosynostosis in later years”. J Pediatr. vol. 97. 1980. pp. 257-259. (Report of long-term adverse effects of neonatal Graves' hyperthyroidism [and likely fetal hyperthyroidism] in a relatively large number of patients.)

Alfadhli, E, Gianoukakis, AG. “Management of severe thyrotoxicosis when the gastrointestinal tract is compromised”. Thyroid. vol. 21. 2011. pp. 215-220. (When drugs, such as ATDs, beta blockers, iodine, and glucocorticoids, cannot be administered by mouth, this review points out that plasmapheresis may be a temporary treatment modality.)

Graves' Disease in Children

Shulman, DI, Muhar, I, Jorgensen, EV. “Autoimmune hyperthyroidism in prepubertal children and adolescents: comparison of clinical and biochemical features at diagnosis and responses to medical therapy”. Thyroid. vol. 7. 1997. pp. 755-760. (Study reporting that prepubertal children with Graves' disease tend to be more severely affected at diagnosis and take longer to go into remission with ATD treatment.)

Nabhan, ZM, Kreher, NC, Eugster, EA. “Hashitoxicosis in children: clinical features and natural history”. J Pediatr. vol. 146. 2005. pp. 533-536. (Study comparing clinical and diagnostic features that separate children with "Hashitoxicosis" vs. Graves' disease.)

Bahn, RS, Burch, HB, Cooper, DS. “Hyperthyroidism and other causes of thyrotoxicosis: Management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists”. Thyroid. vol. 21. 2011. pp. 593-640. (Current guidelines from the ATA & AACE on management of hyperthyroidism; although focused on adults, there is a special section devoted to children with Graves' hyperthyroidism.)

Lippe, BM, Landaw, EM, Kaplan, SA. “Hyperthyroidism in children treated with long term medical therapy: twenty-five percent remission every two years”. J Clin Endocrinol Metab. vol. 64. 1987. pp. 1241-1245. (Using a "survival" mode of analysis, this study followed children with Graves' disease treated with ATDs for up to 10 years.)

Rivkees, SA, Szarfman, A. “Dissimilar hepatotoxicity profiles of propylthiouracil and methimazole in children”. J Clin Endocrinol Metab. vol. 95. 2010. pp. 3260-3267. (Reminder that MMI tends to cause hepatic cholestasis, whereas PTU risks more severe hepatitis and failure.)

Glaser, NS, Styne, DM. “Predictors of early remission of hyperthyroidism in children”. J Clin Endocrinol Metab. vol. 82. 1997. pp. 1719-1726. (Study of features predicting remission during ATD therapy, reporting that smaller goiter size and higher BMI are associated with greater likelihood of remission.)

Kaguelidou, F, Albert, C, Castenet, M. “Predictors of autoimmune hyperthyroidism relapse in children after discontinuation of antithyroid drug treatment”. J Clin Endocrinol Metab. vol. 93. 2008. pp. 3817-3826. (Study of clinical and laboratory findings at diagnosis that predict likelihood of remission on ATD treatment.)

Rivkees, SA, Dinaurer, C. “An optimal treatment for pediatric Graves' disease is radioiodine”. J Clin Endocrinol Metab. vol. 92. 2007. pp. 797-800. (The advantages and disadvantages of the 3 treatment modalities for Graves' disease are compared in this review article.)

Léger, J, Gelwane, G, Kaguelidou, F. “Positive impact of long-term antithyroid drug treatment on the outcome of children with Graves' disease: national long-term cohort study”. J Clin Endocrinol Metab. vol. 97. 2012. pp. 110-119. (This long-term study of anti-thyroid drug treatment in a large number of children with Graves’ disease (n=154) reported a 20% remission rate after 4 yrs, 37% after 6 yrs, 45% after 8 yrs, and 49% after 10 yrs of ATD. Thus, approximately half of the study cohort achieved remission with long-term ATD treatment.)

Rabbiosi, S, Peroni, E, Tronconi, GM. “Asymptomatic thyrotropin-secreting pituitary macroadenoma in a 13-year-old girl: successful first-line treatment with somatostatin analogs”. Thyroid. vol. 22. 2012. pp. 1076-1079. (This patient had a large TSH-secreting pituitary adenoma: 2.8 x 2.5 x 2. cm; treatment with octreotide (100 µg SQ 3 times daily) resulted in significant shrinkage of the tumor and improvement of optic chiasm and nerve compression.)

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