Thyrotoxicosis during the first two decades of life is uncommon and usually is not a difficult disease to diagnose, but often a challenging one to manage.1·2 With few exceptions, the cause is autoimmune, either as a transient disease in the neonate acquired from the mother or as an acquired disease during childhood and adolescence with either an insidious or rather abrupt clinical presentation. The physician must be aware of the early clinical symptoms and signs of thyrotoxicosis in the child so that the diagnosis is established early and therapy instituted promptly to avoid the chronic disability and potentially life-threatening condition that occurs in the untreated disease. There are controversies in the management of the disease that are dependent on the age of the child, the experience and preferences of the physician, and the attitudes and compliance of the family.
This article focuses on the common cause of thyrotoxicosis, autoimmune thyrotoxicosis, which is usually known as Graves' disease but is also described in the literature as Parry's, Parry-Graves', and Gravesvon Basedow diseases. There are other rare causes of thyrotoxicosis during childhood that are important in the differential diagnosis so that an appropriate, yet not exhaustive, evaluation of the child can enable the physician to select the proper therapy (Tables 1 and 2).
To better understand the pathophysiology of thyrotoxicosis, the distinction between thyrotoxicosis and hyperthyroidism is helpful.3 Neither term refers to any specific disease. Thyrotoxicosis describes the clinical response to excessive amounts of thyroid hormones that reach the tissues and produce an excessive response to cause the clinical symptoms and signs of the disease. The child is not thyrotoxic unless these symptoms and signs are present.
By definition, hyperthyroidism refers to an excessive synthesis and secretion of thyroid hormones specifically by the thyroid gland. Hyperthyroidism is the cause of thyrotoxicosis in more than 90% of children since the most common cause, Graves' disease, results from excessive stimulation of the thyroid gland by antibodies that stimulate the thyrotropin-stimulating hormone (TSH) receptor.4'5 However, Table 1 lists several examples of thyrotoxicosis without hyperthyroidism.3 These include the ingestion of excessive amounts of thyroid hormone, known as thyrotoxtcosis fectitia, that are present in foods, such as contaminated meat products, or in medications, such as diet pills used by adolescents, pills taken intentionally and surreptitiously by patients with psychiatric disorders, or pills ingested accidentally by toddlers.6
Classification of Thyrotoxicosis With and Without Hyperthyroldlsm
In the early transient phase of viral (subacute) thyroiditis or rarely in autoimmune (chronic) thyroiditis, preformed thyroid hormones leak from the gland into the circulation to cause thyrotoxicosis. The thyrotoxic phase of thyroiditis, also known as toxic thyroiditis, is seen infrequently in childhood, not only because it rarely occurs and appears only briefly during the early course of the disease, but also because the clinical symptoms and signs mimic many common childhood diseases.1 Hyperthyroidism in patients with autoimmune thyroiditis usually results from coexisting Graves' disease with the presence of antibodies in serum, which stimulates the thyroid. Hyperthyroxinemia must be differentiated from hyperthyroidism in the asymptomatic child (Table 2).
Hyperthyroxinemia Without Thyrotoxicosis
ETIOLOGY AND PATHOGENESIS
The pathogenesis of Graves' disease in adults and children has been explained by the presence of antibodies that stimulate the receptor on the thyroid that mediates the action of ?5??5 This stimulating antibody, known as the thyrotropin receptor antibody (TRAb),4'5'7 is an immunoglobulin G (IgG), and recently was identified in the IgG1 subclass.8
The etiology of the disease is poorly understood and very likely multifactorial.9 Evidence supports the presence of a genetic predisposition to an abnormality in immune surveillance, with environmental factors precipitating the development of the disease.9 There are specific human lymphocyte antigen (HLA) types found in association with Graves' and other autoimmune diseases.
Viral infections and psychologic stresses are reported to precede and possibly precipitate the immunopathologic processes that result in the production of TRAb and the onset of thyrotoxicosis. In a genetically predisposed individual, the immune response after an infection, for example, may persist if the normal suppressive factors of the response are not mobilized. An antigen on surface of Yersinia resembles the TSH receptor and may initiate an immune response by the production of an antibody to the TSH receptor which, in Graves' disease, would stimulate the thyroid. The disease persists as a result of suppressor cell dysfunction and continued secretion of TRAb by IgG-producing B lymphocytes. However, in some patients, the activity of the disease is interrupted and reduced during therapy with antithyroid drugs that have an immunosuppressive effect. Several recent reviews discuss this complex, but fascinating process, in depth.*9·10
Patients with thyrotoxicosis and Graves' disease usually experience a gradual development of clinical symptoms and signs over a period of weeks (Table 3). Often the disease initially is mistaken for behavioral or psychological problems, particularly since these are frequent in children, and emotional stress has been associated with the onset of Graves' disease. During the early phase, parents may observe an unexplained deterioration in school performance, and the teacher reports that the child is restless, has a shortened attention span, has difficulty in concentration, and often asks to leave the classroom to urinate.
Nocturia and occasionally unexplained enuresis occur as a result of the increased glomerular filtration rate and free water clearance that persist during sleep in thyrotoxic patients. Parents may notice sleep disturbances such as restlessness, inappropriate perspiration, sleepwalking, and nightmares; occasionally, the child may fall out of bed. In addition, the child may have difficulty in falling asleep that cannot be attributed to ingestion of beverages with caffeine or other stimulants, or the child may be a light sleeper who is easily aroused. However, during the day in school, the child may appear drowsy and fatigued because of inadequate sleep and the muscle weakness and fatigue associated with thyrotoxicosis. Often these children cannot sit still to do anything, are known to have trouble with fine motor movements, and always want the environment cooler.
Clinical signs are important. In contrast to adults, children almost invariably have an enlarged thyroid gland by the time symptoms appear. In our patient population of more than 60 children with thyrotoxicosis, only one female referred with unilateral exophthalmos had a normal thyroid gland on palpation that was confirmed by ultrasound unpublished data). In the absence of thyromegaly, the diagnosis of thyrotoxicosis with hyperthyroidism is very unlikely, and causes of thyrotoxicosis without hyperthyroidism should be investigated if initial laboratory tests confirm the presence of thyrotoxicosis.6
Symptoms and Signs of Pediatrie Thyrotoxicosis
The texture of the thyroid is usually soft and spongy, but may be firm and crenated if coexisting thyroiditis is present. The pyramidal lobe extending superiorly from the isthmus may be enlarged and mistaken for nodular thyroid disease. A bruit may be heard on auscultation of a large, vascular gland. Table 3 summarizes symptoms and signs involving other organ systems that are present when clinical thyrotoxicosis is evident.
Eye signs and symptoms are fortunately mild in children and are often limited to signs of upper eyelid retraction, stare, and eyelid lag. Periorbital and conjunctival edema, conjunctival injection, and proptosis occur less often. Symptoms of pain, lacrimation, diplopia, photophobia, and blurring of vision occur when proptosis is prominent. Severe ophthalmopathy is rare during childhood and adolescence.
Thyrotoxicosis in the neonate usually presents shortly after birth, although the disease may be delayed for several days to as long as 4 to 6 weeks in rare cases of infants born to mothers on antithyroid medication.1'2·11 An enlarged thyroid is invariably present in clinically symptomatic infants with neonatal Graves' disease, the physical finding that distinguishes the thyrotoxic infant from infants with other diseases with similar clinical presentations such as narcotic withdrawal and sepsis. In addition, a history of autoimmune thyroid disease in the mother - usually treated or untreated Graves' disease - is another important differential diagnostic finding.12 Symptoms and signs of neonatal thyrotoxicosis include a restless, anxious, irritable, preterm, or low birthweight infant with poor weight gain or excessive weight loss despite a voracious appetite. Often the skin is flushed and warm, and tachycardia is an expected sign. Less often present, and limited to severely affected infants, are signs of reticuloendothelial involvement such as hepatosplenomegaly, jaundice, lymphadenopathy, thrombocytopenia, petechiae, and hyperviscosity syndrome.
Figure. The patterns of uptake by the thyroid gland of 123l-iodide in children and adolescents with thyrotoxicosis of different etiologoies are compared. In children with Graves' disease, early (2-, 4-, and 6-hour) and 24-hour uptakes are elevated. The 24-hour uptake is rarely normal in children with Graves' disease when there is a very rapid turnover of iodine; however, the early uptake is elevated and it should be measured whenever the uptake of radioiodine is determined. In ihyrotoxicosis without hyperthyroidism, the uptake is lower than in most patients with hypothyroidism and may be indistinguishable from the background uptake of the isotope. The normal range varies throughout the world, depending on the dietary content of iodine in a geographic region.
Important initial laboratory tests include thyroid function tests (total and free T4, T3 and TSH)1 thyroid antibodies that include TRAb, and complete blood and differential counts. Other tests may be necessary if the diagnosis of Graves' disease is uncertain. Serum T3 is the first thyroid function test to become abnormal in hyperthyroidism unless the euthyroid sick syndrome is present. Serum TSH should be undetectable when one of the newer TSH assays is used where sensitivity is .05 µ,p?/L or lower.13
If the serum TSH is measurable or mildly elevated, either the diagnosis of thyrotoxicosis is incorrect, or the patient has one of the causes of inappropriate pituitary secretion of TSH; these include a TSHsecreting adenoma or isolated pituitary resistance to thyroid hormone (PRTH).14'15 In the latter two diseases, the free alpha subunit should be measured in serum since its molar concentration usually is increased and greater than the molar concentration for TSH when a pituitary TSH-secreting adenoma is present. A thyrotyrpin-releasing hormone (TRH) test will help in the differential diagnosis: in PRTH, the TSH response is normal even though the basal TSH level is inappropriately high for the serum free T4 value. The TSH response to TRH in patients with a TSH-secreting pituitary adenoma is abnormal (no response or a high baseline TSH with little or no TSH response to TRH).14 In other causes of thyrotoxicosis, the basal TSH value is undetectable and there is no TSH response to TRH, since the elevated concentrations of free T4 and T3 completely inhibit pituitary TSH secretion.
Prior to the routine availability of TRAb tests, the definitive test for Graves' disease was the T3 suppression test. This test is rarely needed except in cases of mild thyrotoxicosis with diffuse thyromegaly of unknown etiology with negative TRAb values.5 Because the thyroid in Graves' disease is stimulated by an antibody (TRAb) instead of TSH, the administration of thyroid hormones in excess (either T4 or, as usually employed, T3) will not suppress the increased uptake of radioiodide that is found in patients with Graves' disease (Figure). In normal subjects, however, the uptake is suppressed by greater than -50% of the basal uptake. A similar failure to suppress an elevated uptake also would occur in a patient with an autonomously secreting thyroid adenoma, but this diagnosis is established when a nodule is present on physical examination and there is increased uptake of isotope by the nodule (hot nodule) on thyroid imaging.
Radionuclide uptake and image studies are rarely required in the evaluation of thyrotoxicosis during childhood and adolescence. If there is a nodular thyroid on examination, the image, or scan, with 123I-iodide or "mTc pertechnetate is important to define a hyperfunctioning thyroid nodule. When the thyroid is tender; a radioiodine uptake with 123Iiodide will be very low if subacute or viral thyroiditis is present (Figure). This disease is rare (or rarely detected) during the first two decades of life, and the silent, nontender form of the disease seems to occur only in adults. The radioiodine uptake is also low in other forms of thyrotoxicosis without hyperthyroidism such as in thyrotoxicosis factitia6 (Figure).
Transient thyrotoxicosis rarely occurs during the early phase of chronic lymphocytic (Hashimoto's) thyroiditis. There are two possible mechanisms to explain this phenomenon. Children may have coexisting Graves' disease and chronic lymphocytic thyroiditis. When both diseases present at the same time and thyroiditis is only mild to moderate in severity, TRAb can stimulate the thyroid to cause thyrotoxicosis. The thyrotoxicosis lasts only a few weeks to a few months for two theoretical reasons: either there is diminution in the antigenic stimulus that causes the production of TRAb and levels decline, or the immune process of thyroiditis damages thyroid follicular cells to the extent that they are no longer capable of responding to TRAb. A second possible cause of transient thyrotoxicosis is a mechanism analogous to that seen in subacute thyroiditis. Instead of viral damage to follicular cells, they are acutely damaged by the immune-mediated cytotoxic mechanisms,10 and preformed thyroid hormones are released into the circulation to cause transient thyrotoxicosis. These two mechanisms can be differentiated during the thyrotoxic phase of the disease by the measurement of TRAb in serum and a radioiodine uptake test (Figure).
Side Effects of Antithyroid Drugs
Once the diagnosis of Graves' disease is established clinically and confirmed with laboratory tests, therapy for symptomatic control in moderately to severely affected patients needs to be initiated promptly with beta-adrenergic blocking drugs such as propranolol. The recommended dose in neonates is 2 mg/kg/day in six hourly divided doses, and 10 mg every 6 to 8 hours initially in children and adolescents. ]·2 If there is poor clinical response within a few days, the dose should be gradually increased until the resting pulse rate is normal. The drug should not be used when there are contraindications, such as asthma and congestive heart failure. As soon as thyroid function is normal, usually within 3 to 6 weeks, propranolol should be discontinued.
There are three acceptable modes of therapy for Graves disease: antithyroid drugs, radioiodide ablation, and subtotal thyroidectomy.1'2'16 Initially, euthyroidism should be achieved by the combined use of antithyroid drugs and, as needed, beta-adrenergic blocking drugs. Methimazole and propylthiouracil are used in the United States, and carbimazole is used in Europe. Initially, the drugs are given three times a day. Studies with methimazole in euthyroid subjects suggest that a once daily dose will maintain intrathyroidal concentrations for more than 24 hours.17 The same should apply to carbimazole since it is converted to methimazole by the body. Similar studies have not been reported for propylthiouracil.
Recent evidence in the treatment of adult patients with Graves' disease supports the usual method for treatment of children and adolescents to add thyroxine to the therapeutic regimen once antithyroid drug therapy alone has blocked thyroid hormone secretion and induced primary hypothyroìdìsm.18 Thyrotropin receptor antibody values, reflecting the activity of the disease, diminish during this so-called combined therapy, and the frequency of recurrence of hyperthyroidism is less when thyroxine therapy, when compared to placebo, is added during antithyroid drug therapy and continued after antithyroid drug therapy is discontinued.18 Whether TSH suppression by thyroxine therapy will be associated with prolonged remission of Graves' disease remains to be determined.
Side effects of antithyroid drugs occur in less than 5% of patients (Table 4) and are usually mild and regress in a few days to 2 weeks after discontinuation of the drug. When the side effects are questionable, such as symptoms similar to a viraMike illness, or mild, a trial with an alternate antithyroid drug may be successful; however, close monitoring of the patient for recurrence of side effects is essential.
The usual course of therapy is 1 to 3 years, or longer in younger children. If thyroid gland size remains large, if TRAb activity persists in serum, if the uptake of radionuclide is not suppressed by exogenous thyroid hormone, or if the patient is not compliant with medication or develops an idiosyncratic reaction to the drugs, a more definitive mode of therapy is advised.1·16
Radioiodide ablative therapy with 13ll-iodide has become the definitive therapy of choice in recent years for older children and adults.1·19 Treatment with radioiodine in the doses needed to ablate the thyroid are approximately tenfold less than required for treatment of thyroid cancer. No long-term sequelae from ablative radioiodine therapy of adolescents with Graves' disease have been reported after more than 40 years of careful follow-up,19 and treatment is welltolerated. Rarely do patients experience local symptoms of tenderness at dysphagia, and progressive ophthalmic disease has not been observed after therapy. Once the patient becomes hypothyroid, usually within 1 to 3 months, replacement therapy with 1-thyroxine (I to 2 ^g/kg/day) will maintain euthyroidism without the possibility of relapse of thyrotoxicosis. This need for life-long therapy is the only negative aspect of this form of therapy.
Subtotal thyroidectomy was the earliest acceptable mode of therapy for Graves' disease. Because of the associated morbidity and the rare, but finite, mortality of surgery, it usually is reserved for failures of the other forms of therapy, or for patients who reject daily medication and the use of radioisotopes. Surgery is indicated when antithyroid drugs do not control the disease after the first trimester of pregnancy and when nodules suspicious of malignancy are present at any age. Occasionally, patients with rapid turnover of iodine cannot be successfully treated with radioiodine unless unacceptably high doses are given, and in this situation, surgery is the preferred method of treatment. The surgeon must be experienced in thyroid surgery, particularly in children, and must try to remove most but not all thyroid tissue with the goal to maintain euthyroidism without relapse or development of hypothyroidism.2 In such situations, the surgeon is careful to visualize and preserve the parathyroid glands and the recurrent laryngeal nerve. However, the incidence of primary hypothyroidism progressively increases during subsequent decades after surgery.
In the future, there will be an effort to identify those individuals who are genetically predisposed to develop autoimmune thyroid disease, correct the defect, or prevent its development. In the meantime, therapeutic modalities that directly block the TSH receptor or interrupt the immune progression of the disease continue to be sought. At the moment, primary care physicians must be able to recognize the disease and be familiar with the various forms of therapy directed toward blocking or ablating the thyroid gland.
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Classification of Thyrotoxicosis With and Without Hyperthyroldlsm
Hyperthyroxinemia Without Thyrotoxicosis
Symptoms and Signs of Pediatrie Thyrotoxicosis
Side Effects of Antithyroid Drugs