Delbert A. Fisher
JUVENILE GRAVES DISEASE
Graves disease is a multisystem autoimmune disease involving hyperthyroidism, eye manifestations, and dermopathy.1-12In children, in contrast to adults, the latter manifestation are absent or mild.
The disease occurs in preschool children; rarely, it may begin in infancy. However, the incidence increases sharply as children approach adolescence. Girls are affected six to eight times more often than boys. Graves disease, like Hashimoto thyroiditis, has a genetic basis; a high proportion of patients have a family history positive for goiter, hyperthyroidism, or hypothyroidism. It is believed that both Graves disease and Hashimoto thyroiditis arise randomly in a genetically predisposed population. The concordance rate for Graves disease in monozygotic twins has been reported as 30% to 60%; in dizygotic twins, it is only 3% to 9%. Family studies have disclosed a high percentage of circulating antithyroid antibodies in near relatives. Furthermore, certain HLA haplotypes, such as HLA B8 and Dr3 in Caucasians, and linkage to genetic determinants on the X chromosome and chromosomes 14 and 20 have been reported in affected families.
The hyperthyroidism is due to the production of thyroid-stimulating autoantibody, which, like thyroid-stimulating hormone (TSH), stimulates the TSH receptor. The three principal autoantigens in Graves disease (the TSH receptor, thyroid peroxidase, and thyroglobulin) have been cloned. The TSH receptor autoantibodies have the major pathogenetic role in Graves disease.
The onset of thyrotoxicosis is usually insidious, with a period of increasing nervousness, palpitation, increased appetite, and muscle weakness.8-11 Marked weight loss occurs in some patients, usually in association with a voracious appetite. Occasionally, children and especially adolescents show a weight increase with the onset of the disease. Except for exophthalmos and other eye signs, the symptoms of thyrotoxicosis are non-specific and, for prolonged periods, may be mistaken for some other condition. Behavioral abnormalities, declining school performance, and emotional instability frequently dominate the clinical picture. In other patients, cardiovascular signs are most prominent, and attention is focused on a cardiac murmur or decreased exercise tolerance. Fatigability and objective muscle weakness are observed in 60% to 70% of patients. The pulse pressure widens, and the precordium may be overactive. Other signs of sympathetic overactivity are tremor, excessive perspiration, rapid tendon reflex relaxation times, and emotional liability.
The size of the thyroid gland is highly variable, and the goiter may escape notice in a patient whose gland is only slightly enlarged. The eye findings are those due to sympathetic hyperactivity and those due to specific pathologic changes in the orbit.12The latter are rarely seen in childhood and adolescence. Those due to sympathetic hyperactivity give the appearance of stare, owing to retraction of the upper lid and a wide palpebral aperture with a lag in the descent of the upper lid on looking downward (lid lag).
The initial laboratory tests should include serum thyroid-stimulating hormone (TSH), free T4, and total T3 determinations. The serum TSH level is suppressed, usually below 0.04 mU/L. A serum TSH level above 1.0 mU/L (1.0 μU/mL) suggests TSH-dependent hyperthyroidism. A measurement of serum levels of TSH receptor autoantibody, TSH receptor-binding immunoglobulin (TBII) or TSH receptor-stimulating immunoglobulin (TSI), can be confirmatory for the diagnosis. The TSH receptor-stimulating antibodies (TSA or TSI) can be identified by bioassay and receptor assay techniques. Receptor assay methods measuring displacement of radiolabeled TSH from thyroid cell membrane TSH receptor are referred to as TSH binding-inhibiting immunoglobulin (TBII) or TBIA. The TBII assay measures both stimulating and blocking antibodies without differentiation.
Treatment of thyrotoxicosis is directed toward reducing the secretory rate of thyroid hormones and, if possible, blunting the toxic effects produced by high circulating levels. Three methods are available for reducing thyroid hormone secretion: subtotal or total ablation of the thyroid gland with radioactive iodine, subtotal surgical thyroidectomy, and blocking thyroid hormone biosynthesis by means of drugs. The choice of therapy in thyrotoxicosis must be individualized, taking into consideration any illnesses, the quality of thyroid surgery available, and the socioeconomic factors that play such a large role in determining the success of a prolonged medical regimen. In most instances, treatment is begun with antithyroid drugs, and a decision regarding surgery or radioiodine is made when the patient becomes euthyroid. In severely toxic patients, the adrenergic blocking agent, propranolol, is of value in controlling many of the manifestations of Graves disease in the interval before specific antithyroid drugs become effective and has proved effective in the preoperative preparation for subtotal thyroidectomy.
The antithyroid drugs inhibit oxidation of iodide and thereby block synthesis of thyroid hormone. Of the commonly used drugs, carbimazole and methimazole have a longer half-life than propylthiouracil, and maintenance therapy with these drugs can sometimes be accomplished with a single daily dose. The rapidity of response to therapy correlates best with the initial size of the thyroid gland. Patients with weight loss and decreased body mass index (BMI), a large goiter, or a high iodine intake are more resistant to drug therapy.13-17
The initial dose of propylthiouracil varies from 300 to 600 mg daily (175 mg/m2 or 2–6 mg/kg) in dosages spaced at 6- or 8-hour intervals. Skin rashes occur in about 2% of patients treated with propylthiouracil or carbimazole, and in 5% of patients treated with methimazole early in the course of therapy; they disappear when the drug is withheld. Often these rashes are mild and can be controlled with antihistamines. Severe reactions are rare (0.5–1.4% of patients). Granulocytopenia, when it occurs, is usually delayed (4–8 weeks of therapy). Protective isolation and antibiotic treatment usually allow recovery. Fatal liver failure has been described in adult patients treated with propylthiouracil (PTU). Usually, it is necessary to continue drug therapy for 1 to 2 years, and, in many instances, treatment must be continued for 3 to 6 years before the gland has lost its hyperplastic character. The best clinical prognostic guide is the size of the thyroid gland. Most patients with continued thyroid enlargement will relapse if antithyroid drugs are discontinued. It is also possible to monitor the levels of circulating thyroid-stimulating activity (TSA) or TSH binding-inhibiting immunoglobulin (TBII) and thyroid-stimulating hormone (TSH). When circulating TSH receptor antibody levels fall and serum TSH increases in a patient in clinical remission on drug treatment, a permanent remission off treatment is more likely.
The use of inorganic iodine is reserved for severely toxic patients and for the immediate preoperative preparation of patients who are about to undergo subtotal thyroidectomy. Iodinated radiographic contrast agents (ipodate or iopanoic acid) have been employed successfully in drug treatment of Graves hyperthyroidism. Doses of 0.01 μg/kg/day or 0.4 to 0.05 μg/kg every 3 days have been employed and may maintain remission a few months. There is only limited experience with their use in children.
Management of Graves disease patients with antithyroid drugs propylthiouracil or methimazole requires a prolonged period of drug therapy (usually 2–5 years), and close supervision by the physician is necessary for years.11,15-17Even in patients treated successfully, no more than 60% to 70% have permanent remission with drug therapy alone.
Treatment with Radioactive Iodine
In terms of ease, cost, efficacy, and short-term safety, treatment with iodine-131 is superior to other treatment approaches. However, it has been used relatively infrequently to date in childhood and adolescence because of the high prevalence of posttreatment hypothyroidism and the potential risks of leukemia, thyroid cancer, and genetic damage.11,13,14 Several children treated with radioiodine have been reported to develop thyroid adenomas. This has been attributed to relatively low radioiodine treatment doses in the past. Such low treatment doses (< 50 microcuries 131 I/g thyroid tissue) are also associated with the need for additional treatment to achieve euthyroidism and with delayed but eventual hypothyroidism. Therefore, when treating children and adolescents with radioiodine, a dose that will achieve thyroid tissue destruction is recommended, and the dosage is calculated to optimize the thyroid radiation dose while minimizing total body radiation exposure, particularly in young children. Radioiodine has now been used to treat more than 1000 reported children and adolescents since 1950, and there have been no reports of thyroid neoplasia or other untoward effects.11,14 Hypothyroidism is expected and requires lifelong management. Most physicians still reserve the use of radioiodine for treatment of thyrotoxicosis in older adolescents who fail to follow a medical regimen and who cannot be adequately prepared for surgical thyroidectomy. Current evidence suggests that this approach may be safe enough to consider as initial treatment in selected patients, particularly those 10 years of age or older.
The availability of an experienced thyroid surgeon is an important criterion for successful surgical treatment. The incidences of permanent hypoparathyroidism and recurrent laryngeal nerve damage following subtotal thyroidectomy are still appreciable, and these serious complications will persist and may require lifelong treatment. The surgeon attempts to leave enough thyroid tissue that the patient is euthyroid postoperatively. With proper surgical management, most patients achieve a rapid and satisfactory remission, and requirements for intensive medical follow-up are less rigorous than in those patients treated exclusively with drugs.8,9,15,16 The patient may, however, have recurrence of the thyrotoxicosis or, conversely, may develop later hypothyroidism.
Neonatal thyrotoxicosis is usually caused by thyroid-stimulating antibodies acquired from the mother through placental transport (neonatal Graves disease).11,18-20The disease is uncommon because of the low incidence of thyrotoxicosis in pregnancy (1–2 cases per 1000 pregnancies) and because the neonatal disease occurs in only about 1 in 70 thyrotoxic pregnancies. Most cases are characterized by maternal Graves disease and high titers of TSH receptor-stimulating immunoglobulin (TSI) or TSH binding-inhibiting immunoglobulin (TBII). However, rare cases can occur in pregnant women with inactive Graves disease or Hashimoto thyroiditis. Rare cases of neonatal hyperthyroidism caused by activating mutations of the thyroid-stimulating hormone (TSH) receptor have been reported. A familial history and absence of maternal thyroid-stimulating activity (TSA) should arouse suspicion.
Graves disease among newborns manifests as irritability, flushing, tachycardia, hypertension, poor weight gain or excessive weight loss, thyroid enlargement, and exophthalmos.19,20Thrombocytopenia with hepatosplenomegaly, jaundice, and hypoprothrombinemia have been observed. Arrhythmia, cardiac failure, and death can occur if the thyrotoxicity is severe and treatment is inadequate. Although neonatal Graves disease can manifest at birth, the onset of symptoms and signs can usually be delayed as long as 8 to 9 days due to the postnatal depletion of transplacentally acquired blocking doses of antithyroid drugs and the increase in newborn T3 concentration normally associated with birth.
The diagnosis is confirmed with high levels of T4, free T4, and T3 and low thyroid-stimulating hormone (TSH) in postnatal blood. The disease usually resolves as maternal thyroid-stimulating antibodies in the newborn are degraded; the half-life approximates 12 days. The usual clinical course of neonatal Graves disease extends 3 to 12 weeks.
Management includes sedatives and digitalization as necessary. Iodide or thionamide drugs are administered to decrease secretion of thyroid hormone. Lugol solution (5% iodine and 10% potassium iodide; 126 mg of iodine per milliliter) is given in doses of 1 drop (about 8 mg) three times a day. Methimazole is administered in a dosage of 0.5 to 1 mg/kg/day in divided doses at 8-hour intervals. The dosage of propylthiouracil is 5 to 10 mg/kg/day in divided doses every 8 hours. A therapeutic response should be observed within 24 to 36 hours. If not, the dose of antithyroid drug and iodide can be increased by 50%. Adrenal glucocorticoids in anti-inflammatory dosage and propranolol (1–2 mg/kg/day) can also be helpful. Radiographic contrast agents can be useful because the disease is transient. Sodium ipodate, 100 mg daily, or 0.3 to 0.5 g every 2 to 3 days, either alone or in conjunction with antithyroid drugs, has been effective.18
OTHER CAUSES OF HYPERTHYROIDISM
Thyroid-stimulating hormone (TSH)-secreting pituitary tumors associated with clinical hyper-thyroidism have been reported among adults and children.21 Among children, the local manifestations of the tumor are prominent. These included visual changes, optic atrophy, hydrocephalus, and amaurosis. Children with hyperthyroidism and measurable serum TSH concentrations need to be examined for neurologic dysfunction and visual abnormalities; brain MRI for careful evaluation of the sella turcica is indicated if this evaluation arouses suspicion or if the serum concentration of TSH is normal or elevated.
Hyperthyroidism Due to Pituitary Resistance
Hyperthyroidism with diffuse goiter and elevated serum levels of TSH has been reported in several patients without enlargement of the pituitary gland.8 These patients have pituitary resistance to the feedback effect of thyroid hormones on TSH release because of an activating thyroid hormone TRβ1 receptor mutation. These patients may be misdiagnosed as Graves disease. Pituitary resistance to thyroid hormone should be suspected when any patient has elevated thyroid hormone levels in the presence of normal or elevated TSH concentrations. Therapy is difficult. Dopaminergic drugs, triiodothyroacetic acid, and single morning doses of T3 have been tried. Thyroid ablative therapy may be necessary. (See discussion in Chapter 527.)
Hyperthyroidism Due to Autonomous Thyroid Nodule(s)
Thyroid function of patients with thyroid nodules is variable.8,22 Most patients are euthyroid. Most functioning thyroid nodules occur in association with multinodular goiter. Somatic gain-of-function mutations of the thyroid-stimulating hormone (TSH) receptor have been a major cause of benign toxic thyroid adenoma. Autonomously functioning thyroid nodules are uncommon among children and do not usually produce clinical thyrotoxicosis; large nodules (> 3 cm in diameter) are most likely to do so. Suppressed levels of serum TSH in the presence of euthyroid levels of thyroid hormones indicates a non-TSH thyroid stimulator or thyroid autonomy.
The course of functioning thyroid nodules in euthyroid patients is variable. Most patients remain euthyroid. The nodule often degenerates, presumably through recurrent hemorrhage. Follow-up care is essential because thyrotoxicosis can develop. Functioning nodules that produce clinical and chemical thyrotoxicosis necessitate treatment.
Hyperthyroidism Due to Activating Thyroid-Stimulating Hormone Receptor Mutations
Several families have been reported to have hyperthyroidism segregating as an autosomal-dominant trait in the absence of autoimmune disease of the thyroid. The affected persons have goiter, increased serum total and free levels of T4, and suppressed thyroid-stimulating hormone (TSH).23 Among patients treated surgically, the thyroid glands have diffuse hyperplasia without lymphocytic infiltration. Gain-of-function germline mutations of the TSH receptor have been found in these patients. This form of hyperthyroidism is usually detected during childhood or adolescence, but a few diagnoses have been made before the patient was 2 years of age or in the neonatal period. Treatment of such infants is difficult because the disorder is not transient. Antithyroid drugs for short-term management and partial thyroidectomy seem the best therapies at present.
Hyperthyroidism Due to Activating G-Protein Mutations
Activating mutations of the α-subunit of the stimulatory G protein, Gs, increase formation of cyclic adenosine monophosphate (cAMP) and the associated endocrinopathies of Mc-Cune-Albright syndrome.24The clinical manifestations are related to the tissues involved. They include polyostotic fibrosis dysplasia of bone and hyperfunction of one or more endocrine glands. The latter include ovarian cysts, gonadal hyperfunction and precocious puberty, pituitary adenoma causing adrenal hyperplasia or hypersecretion of growth hormone (GH), and hyperthyroidism. The thyroid hyperplasia and hyperthyroidism resemble those of Graves disease, but without ophthalmologic features and without autoantibodies. Treatment options include antithyroid drugs, surgery, and radioiodine.