Pediatric Graves Disease Treatment & Management

The adverse effects of all treatments for Graves disease, but particularly antithyroid drug therapy, are considerable, and obtaining true collaborative informed consent is important. ^[15]

Neonatal thyrotoxicosis caused by transplacental passage of maternal TSI is transient but leads to prenatal deaths due to arrhythmia and cardiac failure. Postnatally, poor weight gain, rapid heart rate, and jaundice may indicate the severity of the disorder. These children require special attention after treatment of thyrotoxicosis and remission, because TSI have been attenuated and long-term TSH suppression may render the patients hypothyroid for variable periods.

Management of Graves disease during pregnancy requires careful therapy with PTU and maintenance of thyroid hormone levels in the high range typical of pregnancy. Overtreatment can lead to fetal hypothyroidism and goiter, with concomitant poor intellectual outcome. Undertreatment can lead to fetal loss. Surgery also can lead to fetal loss and should be carried out only if absolutely necessary.

Assess adolescent girls treated for Graves disease for pregnancy risk and start contraception if indicated. Do not administer RAI therapy to a sexually active adolescent girl until she is known to have a negative pregnancy test result. Destruction of the fetal thyroid by RAI produces severe in utero hypothyroidism.

None of the treatments presently available for Graves disease is fully satisfactory. All are aimed at the thyroid, which is simply the target of potent autoantibodies rather than the cause of the disorder. Two medical therapies (antithyroid drugs and RAI ablation) and one surgical therapy (subtotal thyroidectomy) are acceptable approaches to treatment. These therapeutic options reduce thyroid gland mass or action and, as a limited side benefit, may reduce the mass or activity of the mononuclear cells producing the TSH receptor–stimulating antibodies etiologic in the disorder.

Antithyroid drugs of the thiourea class have been available since the late 1940s, and their uses and limitations have been well defined. The 2 agents available for use in the United States are methimazole (Tapazole) and PTU. ^[16] These drugs inhibit the synthesis of thyroid hormone by inhibition of the organification of iodide and by inhibition of the coupling of iodotyrosines (inhibition of thyroperoxidase). In addition, PTU specifically inhibits the peripheral conversion of T₄ to T₃, making the use of this drug advantageous when a rapid reduction in active thyroid hormone is indicated, as in thyroid storm.

Some evidence suggests that both drugs inhibit the production of TSI. This immunosuppressive effect may explain the reduction in thyroid gland size often observed during therapy with the thioamide drugs. Methimazole has a longer half-life in serum than PTU and, therefore, can be administered as a once- or twice-daily dose. PTU is usually administered three times daily.

Both agents have a rather significant array of adverse effects, but complete overlap does not occur. The most common adverse effect is a pruritic skin rash. Both agents can induce autoimmune or allergic responses ranging from skin rashes and fever to arthralgia, arthritis, and frank lupus-like findings with positive ANAs and vasculitis. Leukopenia may be induced by both drugs and may be dose related. Arthralgia, urticaria, rash, and fever may occur in 5% of patients treated with these drugs.

Other complications are much less common. Idiosyncratic agranulocytosis is reported in less than 1% of individuals and appears more common in elderly persons. Liver disease is a rare complication of both agents, but methimazole administration leads to cholestatic jaundice. Fulminant hepatic failure leading to death, liver transplantation, or both has been reported with PTU, and prompted a label warning by the US Food and Drug Administration (FDA) since May 2010. Less significant adverse effects include ageusia or dysgeusia.

PTU is the drug of choice in pregnant women with Graves disease. Methimazole has been associated with fetal scalp aplasia cutis. Methimazole also crosses to the fetus much more easily than PTU and, therefore, is more likely to be a fetal goitrogen, even when cautiously used.

The FDA had added a boxed warning, the strongest warning issued by the FDA, to the prescribing information for PTU. The boxed warning emphasizes the risk for severe liver injury and acute liver failure, some cases of which have been fatal. The boxed warning also states that PTU should be reserved for use in patients who cannot tolerate other treatments, such as methimazole, RAI, or surgery.

The decision to include a boxed warning was based on the FDA's review of postmarketing safety reports and meetings held with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community.

The FDA has identified 32 cases (22 adult and 10 pediatric) of serious liver injury associated with PTU. Among the adults, 12 deaths and 5 liver transplants occurred; among the pediatric patients, 1 death and 6 liver transplants occurred. PTU remains available for select cases of hyperthyroidism (ie, true thyroid storm, during pregnancy, or unamenable to other medical and surgical interventions).

These reports suggest an increased risk for liver toxicity with PTU compared with methimazole. Serious liver injury has been identified with methimazole in 5 cases (3 resulting in death). PTU is considered to be a second-line drug therapy, except in patients who are allergic or have an intolerance to methimazole or in women who are in the first trimester of pregnancy. Rare cases of embryopathy, including aplasia cutis, have been reported with methimazole during pregnancy.

The FDA recommends the following criteria be considered for prescribing PTU (for more information, see the FDA Safety Alert) ^[17] :

• Reserve PTU for use during first trimester of pregnancy or in patients who are allergic or have an intolerance to methimazole (as stated above)

• Closely monitor PTU therapy for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy

• For suspected liver injury, promptly discontinue PTU therapy, evaluate for evidence of liver injury, and provide supportive care

• PTU should not be used in pediatric patients unless the patient is allergic or has an intolerance to methimazole and no other treatment options are available

• Counsel patients to promptly contact their health care provider if the following signs or symptoms occur: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin

Antithyroid drugs are often administered with a beta-blocking agent during the initial weeks of treatment. The rate of remission while taking these agents is much higher in adults than in children. Remission rates are enhanced if drug withdrawal is not completed until the thyroid gland is essentially of normal size. Nonetheless, remission figures in childhood and adolescence are rather poor, ranging from 25% for each year of therapy in one series to much lower remission figures in prepubertal children.

RAI treatment of thyrotoxicosis has proved efficacious for 50 years. Nonetheless, the concern has been that this therapy carries increased risk of malignancy in children. Meta-analyses and long-term follow-up (over 35 y) suggest that if increased risk is observed, it is very small compared with the real and serious risks of other forms of therapy. ^[18]

Some consider RAI the treatment of choice for all nonpregnant patients with Graves disease who are older than age 10 years. If possible, younger children are maintained on antithyroid drugs until they enter into remission or reach this age. This practice is not based on strong data, suggesting that younger children might be at greater risk of malignancy.

The idea that the outcome of RAI treatment should be thyroid ablation is fairly well accepted. Therefore, thyroid hormone replacement therapy is generally required after the RAI has exerted its full effect. This treatment may take 3-4 months or more to be effective. During the first month, treatment with iodine drops or a return to antithyroid drugs may restore euthyroidism. Do not start iodine drops or antithyroid medication for 5-7 days after treatment, so that the full effect of the RAI on the thyroid can be realized.

Adjunctive therapy with a beta-blocking agent can also be useful. Monitor the patient closely so that thyroid hormone can be instituted as soon as hypothyroidism is detected. In rare instances, more than 1 treatment with RAI is necessary.

Subtotal thyroidectomy was the treatment of choice for Graves disease before experience with RAI developed. In the hands of an experienced thyroid surgeon, subtotal thyroidectomy carries little risk; however, do not forget the risks of surgery and anesthesia, hypoparathyroidism, and injury to the recurrent laryngeal nerve. The thyroid surgeon must weigh the risk of recurrence against that of hypothyroidism when the thyroidectomy is carried out. Hypothyroidism is usually considered a suitable outcome today, because this greatly reduces the risk of later recurrence. ^[19]

Medical management of the candidate for subtotal thyroidectomy preoperatively and postoperatively is very important. Although anesthetic management of the thyrotoxic patient has been made easier with the availability of newer anesthetic agents and short-acting beta-blocking drugs, most surgeons prefer to operate on a euthyroid patient with a small, minimally vascular gland. Therefore, pretreatment with antithyroid thioureylene drugs until a euthyroid state is reached and 10 days to 2 weeks of treatment with daily iodide drops (eg, a saturated solution of potassium iodide [SSKI]) is considered the standard of care at most institutions.

After surgery, careful assessment of calcium status and of thyroid hormone status permits institution of supplemental calcium as necessary and indicates the appropriate time to begin thyroid hormone therapy. Adolescents with a long history of thyrotoxicosis may have rather depleted calcium stores and develop hungry bone syndrome after surgery, requiring large amounts of calcium intravenously until the calcium stores are replete and the patients’ parathyroid glands return to peak functioning.

Inpatient care is only indicated in the event of thyroid storm or for a few days of the postoperative period after subtotal thyroidectomy.

After subtotal thyroidectomy, assess serum calcium and laryngeal nerves. Damage to these tissues is very unusual in the hands of an experienced thyroid surgeon; nonetheless, having calcium for injection by the bedside is reasonable to treat severe, acute hypocalcemia. If the patient is hypocalcemic because of transient or permanent hypoparathyroidism, commence treatment with calcium and vitamin D as soon as necessary.

Outpatient care is predicated on the treatment option chosen.

Antithyroid drug therapy

Monitor the patient at 6-week to 3-month intervals with TFTs (TSH, total T₃, and free T₄ levels), LFTs, and CBC. Assess other potential adverse effects of the agent by history.

If beta-adrenergic blocking agents have been started, discontinue when the patient is euthyroid.

At each visit, assess thyroid gland size and firmness. Risk of recurrence upon discontinuation of therapy is great unless the thyroid gland is close to normal in size. After 1-2 years of therapy, if the thyroid is still large and the drug dose has not been able to be decreased to relatively low levels (eg, one half to one fourth of the initial dose), consider alternative therapies.

Radioactive iodine treatment

The purpose of this treatment should be to render the patient hypothyroid and, therefore, decrease the risk of recurrence. In severe thyrotoxicosis, adding Lugol solution or SSKI drops to the regimen 5-7 days after treatment may enhance the speed of remission. Antithyroid drugs may also be started or restarted after 5-7 days, and beta-adrenergic blocking agents may be continued until remission, which may take 4-6 months for full effect.

If the patient is not in remission by 6 months, consider a second treatment. Repeat thyroid hormone and TSH levels at about 4- to 6-week intervals and start supplementation with levothyroxine (L-T ₄ ) when indicated by these tests. Long-term follow-up is essential for the adjustment of thyroid hormone.

Subtotal thyroidectomy

TFTs performed after surgery should provide evidence of hypothyroidism. Individuals who are euthyroid have a very high recurrence rate.

Start thyroid hormone treatment as indicated and monitor the appropriate dose at 3-month intervals for several visits and then at 6-month intervals during childhood.

Transfer

An experienced pediatric endocrinologist should care for children with Graves disease. If care involves RAI therapy, transfer of the patient to the temporary care of the treating endocrinologist or nuclear medicine physician is indicated. If care involves surgery, transfer of the patient to the care of an experienced thyroid surgeon is warranted.

Children and adolescents with thyrotoxicosis are often voracious eaters. When they are treated for their condition, if they continue to eat in the same manner, they often gain weight and begin to struggle with obesity.

Anticipatory guidance before and in the early phases of treatment can be very useful. Appropriate food choices can be discussed, and early referral for nutritional counseling can be considered.

Many children with Graves disease self-limit their activity. While they are thyrotoxic, they probably should not compete in stressful competitive sports.

The following consultations may be indicated:

• Endocrinologist - An experienced pediatric endocrinologist can adjust medication and plan medical management, as well as assist the patient and family in decision-making as to appropriate long-term therapy options

• Nuclear medicine specialist or endocrinologist - Certification in the therapeutic use of RAI is required for this form of therapy; few pediatric endocrinologists are certified in this use (most refer to the locally certified individuals who may be specialists in nuclear medicine or endocrinologists)

• Thyroid surgeon - If a family opts for their child to have a subtotal thyroidectomy, having the thyroidectomy performed by an experienced endocrine or pediatric surgeon is important to maintain the lowest possible risk of complications

Novel therapeutic approaches include monoclonal antibody targeting B-cell, TSHR-targeted therapies.