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
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 production of thyroid stimulating antibodies
by B lymphocytes is probably a secondary response to a cell-mediated
immune reaction requiring involvement of T lymphocytes in a manner
similar to that postulated for Hashimoto thyroiditis. Cell cultures
of lymphocytes from patients with Graves disease produce immunoglobulins
only after stimulation with phytohemagglutinin. Because the latter
substance stimulates only T cells (which are incapable of secreting
immunoglobulins), it may be inferred that both cell-mediated and humoral
immune mechanisms are involved in the genesis of the thyrotoxic
state. This is supported by more recent studies indicating that thyrocytes
can be activated by TSA + insulinlike growth factor 1 (IGF-1)
to express powerful T-cell chemoattractants that stimulate T-cell
infiltration independently of the TSH receptor.
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 nonspecific
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). Severe
Graves ophthalmopathy is uncommon in children, and malignant exophthalmos
is virtually unknown. Rarely, there are changes in the orbit due to
infiltration of mucopolysaccharides, lymphocytes, and edema fluid
within the ocular muscles, lacrimal glands, and retroorbital fat.8,9These
changes can lead to exophthalmos, ophthalmoplegia, chemosis of the
conjunctiva, pain, swelling, and irritation. Although the inflammatory
changes usually improve with treatment of the hyperthyroid state,
the course of the thyroid and eye manifestations may differ. Some
degree of exophthalmos tends to remain after recovery from the thyrotoxicosis
in such patients. The accumulation of mucopolysaccharides in skin
and subcutaneous tissues, referred to as Graves dermopathy or pretibial
myxedema, is also rare in children. Graves disease and Hashimoto
thyroiditis are occasionally encountered in the same patient. These
children have clinical and laboratory features of Hashimoto thyroiditis,
and also exhibit thyrotoxicosis and resistance to thyroidal suppression
by T3. The somewhat whimsical term Hashitoxicosis has
been applied to these patients. Rarely, juvenile Graves disease
may occur in association with myasthenia gravis, or another autoimmune
disorder such as lupus erythematosus.
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
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.11,15-17 Even in patients
treated successfully, no more than 60% to 70% have
permanent remission with drug therapy alone.
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 The thyroid glands of young animals
are much more susceptible to induction of thyroid carcinoma by ionizing
radiation than are those of older animals. Radiation to the neck
in infancy has been incriminated as an important cause of thyroid
cancer in children, whereas this is infrequent in adults. 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