THYROID DISEASE IN CHILDREN
During embryogenesis, epithelial cells on the pharyngeal floor
thicken to form a diverticulum. This diverticulum elongates, and
the primordial thyroid cells migrate caudally until they fuse with
the ventral aspect of the fourth pharyngeal pouch, at about the
fourth gestational week.
Two lobes connected by an isthmus are typically located
approximately anterior to the third tracheal cartilage. The
thyroglossal duct that results from the migration normally
involutes. Retention and growth of thyroid tissue at the lower end
of the duct occasionally results in a pyramidal lobe.
Thyroglobulin is produced by the eighth gestational week;
trapping of iodine occurs by week 10, followed by iodination of
tyrosine. Colloid formation and pituitary thyroid-stimulating
hormone (TSH) secretion occur by week 12. Fetal thyroid
development is completely independent of the mother's
pituitary-thyroid axis, since negligible amounts of maternal
thyroid-stimulating hormone or thyroxine ([T.sub.4]) cross the
placenta.
Normal Thyroid Physiology
Secretion of [T.sub.4] is controlled by TSH secreted by the
pituitary gland. TSH secretion, in turn, is controlled by
thyrotropin-releasing hormone (TRH) produced in the hypothalamus.
Both TSH and TRH secretion are moderated by serum [T.sub.4]
levels, by means of a negative feedback loop.
Circulating [T.sub.4] is predominantly bound by
thyroxine-binding globulin (TBG) and thyroxine-binding prealbumin.
[T.sub.4] is deiodinated in peripheral tissues to the more
bioactive hormone triiodothyronine ([T.sub.3]). [T.sub.3] affects
almost every tissue in the body. [T.sub.3] binds to its receptors
in the nucleus, and this complex then alters gene transcription,
leading to increased oxygen consumption and adenosine triphosphate
(ATP) formation, and cellular cyclic adenosine monophosphate (AMP)
concentration.
Within 30 minutes after delivery, TSH levels in the normal
neonate rapidly rise to about 80 [micro] U per mL (80 mU per L)
and then slowly decline over the next three days. In response,
[T.sub.4] and [T.sub.3] levels rise dramatically by 24 hours of
age, then slowly decline over the next few weeks.
Congenital Hypothyroidism
It has long been known that mental development of children
with congenital hypothyroidism is related to adequacy of
treatment.2 Beginning treatment before three months of age
improves the prognosis for mental development in these children.3
However, early diagnosis and treatment were often delayed because
of the paucity of early signs and symptoms in infants (Table 1).
TABLE 1
Signs and Symptoms of Congenital Hypothyroidism at Age Five
Weeks
Sign or symptom Percentage of patients
Prolonged
jaundice 31
Umbilical hernia 23
Constipation 21
Macroglossia 21
Feeding problems 19
Distended abdomen 16
Hypotonia 16
Hoarse cry 16
Large posterior fontanelle 13
Dry skin 10
Hypothermia 5
Goiter 2
In Quebec, population screening for congenital
hypothyroidism began in 1974, using a newly developed technique,
[T.sub.4] radioimmunoassay of blood spots on filter paper. This
screening was combined with screening for phenylketonuria.[4]
Refinements in the Quebec screening program developed rapidly, and
most industrialized nations now have such screening programs.
Newborn screening programs in North America measure total
[T.sub.4] levels in all newborns. Generally, in neonates whose
[T.sub.4] level falls within the lowest 10th percentile, both
[T.sub.4] and TSH are reassayed.
Newborn screening programs detect about one infant with
congenital hypothyroidism for every 4,000 five births. Up to five
false-positive screenings may occur for every one confirmed case
of congenital hypothyroidism. However, statistically, congenital
hypothyroidism may be missed by newborn screening programs in
about three infants for every 100,000 live births (about 12
percent of an infants with congenital hypothyroidism).
Of infants with congenital hypothyroidism, 75 percent have
sporadic thyroid dysgenesis, 10 percent have thyroid enzyme
defects, 5 percent have hypothalamic-pituitary hypothyroidism and
10 percent have transient hypothyroidism. Thyroid enzyme defects
are inherited in an autosomal recessive pattern.
Once an infant with congenital hypothyroidism has been
identified by a state screening program, the physician should
immediately examine that infant for signs of congenital
hypothyroidism and obtain serum free and TSH levels for
confirmation Infants who have TBG deficiency are also identified
by state screening programs but, on confirmation testing, their
free [T.sub.4] levels are found to be normal. Infants of mothers
receiving antithyroid medication may have abnormal screening test
results.
Therapy with levothyroxine (Levothroid, Levoxine,
Synthroid) should begin without delay after the confirmatory blood
tests, before results are obtained. If confirmatory tests show
normal thyroid function, therapy is discontinued.The starting
daily dosage of levothyroxine is 10 [micro] g per kg, which is
usually the equivalent of 0.025 mg, 0.0325 mg or 0.05 mg per day.
Once treatment has been initiated, [T.sub.4] and TSH levels
should be followed monthly during the first year of life, every
other month during the second year, quarterly during the third
year and biannually thereafter.
Dosage increases of 0.0125 mg (one-half of a 0.025 mg
tablet) should be initiated when indicated, and repeat
measurements of [T.sub.4] and TSH should be obtained one month
after the increase. The tablets are easily crushed and can be
added to formula or stirred into cereal.
Since the half-life of [T.sub.4] is about six days, four
weeks are required for serum [T.sub.4] values to reach a steady
state. Suppression of elevated TSH levels may take even longer.
Even with adequate diagnosis and therapy, some children
with congenital hypothyroidism have IQ values that are lower than
predicted. Factors that may contribute to this lower IQ include a
markedly low [T.sub.4] value at birth, a markedly delayed bone age
at birth, a delay in treatment, or a serum [T.sub.4] value less
than 8 [micro] g per dL (103 nmol per L) during the first year of
therapy.
Sometimes infants are identified by a state screening
program as having congenital hypothyroidism, but the confirmatory
test shows a normal [T.sub.4] value and a TSH value greater than
20 [micro] U per ML (20 mU per L). In these cases, a thyroid scan
may show an ectopic gland. A normal thyroid scan in such an infant
indicates the presence of impaired thyroid hormone synthesis,
which may be caused by an enzyme defect. A cautious approach is to
treat these infants with levothyroxine until after two years of
age. At this time, therapy may be stopped for six weeks and repeat
[T.sub.4] and TSH levels obtained. Some pediatric endocrinologists
may choose to follow these infants carefully and treat them if the
TSH levels increase over time.
Acquired Hypothyroidism
A common cause of acquired hypothyroidism in children is
autoimmune thyroiditis, which occurs in genetically predisposed
persons. Clinical disease is triggered or aggravated by
unidentified factors. The thyroid gland becomes enlarged, but is
usually not painful. Histologic changes include lymphocytic
infiltration, formation of lymphoid follicles and follicular cell
hyperplasia. Antibodies to thyroid peroxidase (so-called
microsomal antibodies) are characteristic of Hashimoto's (chronic
lymphocytic) thyroiditis. However, these antibodies are not
responsible for the actual thyroid cell destruction, which is
probably caused by cytotoxic lymphocytes.
Other causes of primary hypothyroidism in children include
drug-induced hypothyroidism (e.g., lithium, amiodarone
[Cordarone]), endemic goiter due to nutritional iodide deficiency,
irradiation of the thyroid and surgical excision of the thyroid.
Hypothyroid children may have weakness, lethargy, decreased
appetite, cold intolerance, constipation, dry skin and mild
obesity. Common signs of childhood hypothyroidism are listed in
Table 2.
TABLE 2
Signs of Acquired Hypothyroidism in Children
Goiter
Growth retardation
Delayed dentition
Delayed or precocious puberty
Galactorrhea
Carotenemia
Pale, dry skin
Myopathy and muscular hypertrophy
Derived from Dallas and Foley.
Once hypothyroidism is suspected in a child, serum
[T.sub.4] and TSH levels should be measured. If the [T.sub.4]
level is low and the TSH level is high, the diagnosis of
hypothyroidism is confirmed, and levothyroxine therapy should be
started. Measuring thyroid antibodies is unnecessary since the
result of this test does not alter the treatment regimen.
In children with goiter and normal [T.sub.4] and TSH
levels, positive titers of microsomal thyroid antibodies confirm a
diagnosis of Hashimoto's thyroiditis, explaining the thyromegaly.
If the child or adolescent with Hashimoto's thyroiditis has a
noticeable goiter, treatment with levothyroxine may cause some
reduction in the size of the goiter but does not usually lead to
complete reduction in size.
Levothyroxine treatment should be started with a dosage of
0.05 mg per day, which is lower than the dosage required to attain
euthyroidism. Initial treatment with larger doses of levothyroxine
may cause headaches and abrupt personality changes.
[T.sub.4] and TSH levels should be determined no sooner
than one month after a dosage change. TSH levels in the normal
range are desirable, while a TSH level below normal indicates
over-treatment.
Parents and teachers should be warned that the previously
quiet, docile child will soon be more active and even
rambunctious. The dramatic change in personality that occurs after
therapy is initiated may be more than teachers, and even some
parents, can readily accommodate.
Euthyroid Sick Syndrome
[T.sub.4] is converted in peripheral tissues to bioactive
[T.sub.3] by the 5'-deiodinase enzyme. This enzyme is also
responsible for clearing the small amounts of inactive reverse
[T.sub.3] that are a byproduct of [T.sub.4] metabolism. During
acute or chronic severe illnesses, surgery, trauma or
malnutrition, activity of the deiodinase enzyme is decreased, thus
decreasing the amount of [T.sub.3] produced and causing a build-up
of reverse [T.sub.3]. TSH secretion is also decreased and does not
respond to falling levels of [T.sub.4]. Low levels of [T.sub.4]
and [T.sub.3], as well as normal to low levels of TSH, are common
in stressed persons. These sick euthyroid patients do not need to
be treated with thyroid hormone replacement.
Hyperthyroidism
Children with hyperthyroidism can be divided into two broad
groups: those with an increased production of thyroid hormone and
those with only an increased release of thyroid hormone (Table 3).
A radioactive iodine uptake scan will clearly differentiate
between these two causes of hyperthyroidism. In cases of excess
thyroid hormone production, the scan shows increased uptake. In
cases of increased release only, the scan reveals decreased
uptake.
TABLE 3
Causes of Hyperthyroidism
Excess production of [T.sub.4]
Graves' disease
Toxic adenoma
McCune-Albright syndrome
TSH-producing pituitary tumor
Pituitary resistance to thyroid hormone
Excess release of [T.sub.4]
Subacute thyroiditis
Hashimoto's toxic thyroiditis
Iodine-induced hyperthyroidism
[T.sub.4] = thyroxine, TSH = thyroid-stimulating
hormone.
Graves' disease is an autoimmune disorder in which the
patient develops antibodies that stimulate the TSH receptor, thus
stimulating the production of [T.sub.4].
Hyperthyroid children may note tiredness or easy
fatigability. Hyperthyroidism in children can easily be mistaken
for an anxiety disorder, anorexia nervosa or a psychiatric
illness. Common symptoms and signs of Graves' disease in
adolescents are presented in Table 4.
TABLE 4
Prevalence of Signs and Symptoms of Graves' Disease in
Adolescents
Sign or symptom Percentage of patients
Goiter 98
Tachycardia 82
Nervousness 82
Increased pulse pressure 80
Proptosis 65
Increased appetite 60
Tremor 52
Weight loss 50
Heat intolerance 30
The diagnosis of Graves' disease can often be made
clinically in the presence of goiter, exophthalmos, weight loss or
tachycardia. The diagnosis may be documented by an elevated free
[T.sub.4] level and a low TSH level. TSH assays are now capable of
differentiating low levels from normal levels. In less obvious
cases, a radioactive iodine uptake scan is helpful in determining
the presence and etiology of hyperthyroidism (increased uptake in
cases of Graves' disease).
Treatment of Graves' disease may be initiated with
antithyroid medications, radioactive iodine ablation or surgical
excision of the thyroid. Administration of beta blockers such as
propranolol (Inderal), 10 to 20 mg every eight hours, stops many
of the symptoms of hyperthyroidism and may make patients more
comfortable.
Propylthiouracil and methimazole (Tapazole) interfere with
several steps in thyroid hormone synthesis. Propylthiouracil also
blocks the peripheral conversion of [T.sub.4] to [T.sub.3].
Propylthiouracil, at a dosage of 5 to 10 mg per kg per day, is
given every eight hours. Methimazole, at a dosage of 0.5 mg per kg
per day, may be given once daily.
Both propylthiouracil and methimazole are associated with
side effects, including rash, arthritis, leukopenia and hepatic
toxicity. These side effects require stopping the medication in
about 5 percent of patients. Patients must be warned about these
side effects and instructed to return to their physician for a
complete blood count if they have a sore throat or a fever.
Patients who develop jaundice must stop the medication immediately
and contact their physician.
Forty-five percent of patients taking these drugs may
experience a remission, as evidenced by goiter resolution, and no
longer require antithyroid medication. If remission does not occur
within three years of treatment initiation, radioactive ablation
or subtotal thyroidectomy should be performed.
Radioactive iodine ablation does not increase the risk of
future thyroid neoplasia, nor does it appear to have any
teratogenic effects among the progeny of patients who receive it.
Increased thyroid antibody titers occur after radioactive iodine
ablation and may be responsible for the temporary worsening of
Graves' eye disease that is sometimes observed after radioactive
iodine ablation.[18] Besides leaving a scar, thyroidectomy may
cause damage to the recurrent laryngeal nerve and
hypoparathyroidism.
Neonatal Graves' Disease
Pregnant women with Graves' disease or a history of Graves'
disease may transfer IgG thyroid-stimulating immunoglobulins (TSI)
to the fetus. Affected infants may exhibit any of the signs listed
in Table 5. An elevated free [T.sub.4] level, low TSH level and
positive TSI test confirm the diagnosis.[19] Treatment with
propylthiouracil, 5 to 10 mg per kg per day, or methimazole, 0.5
mg per kg per day, should be initiated in these children.
TABLE 5
Signs and Symptoms of Neonatal Graves' Disease
Premature birth
Low birth weight
Goiter
Restlessness and irritability
Fever, flushing
Tachycardia, cardiomegaly, heart failure
Lid retraction, proptosis, periorbital edema
Poor weight gain or weight loss
Increased gastrointestinal motility frequent, stooling
Derived from Dallas and Foley.[10]
In severely ill neonates, prednisone may be required to
stabilize the infants while they are thyrotoxic. As [T.sub.4]
levels become suppressed, levothyroxine should be given to
maintain normal [T.sub.4] and TSH levels. After six months, the
antithyroid medication and levothyroxine may be discontinued.
Subacute Thyroiditis
Painful enlargement of the thyroid gland that is associated
with signs and symptoms of hyperthyroidism may occur as a
postviral syndrome. The [T.sub.4] level is elevated, while the TSH
level is suppressed. A radioactive iodine uptake scan reveals
little uptake. Although no thyroid hormone production occurs,
there is an increased dysfunctional release of the vast stores of
thyroid hormone from the inflamed gland. Antithyroid medications
such as propylthiouracil have no effect on subacute thyroiditis.
Treatment is limited to administration of beta blockers, aspirin
and, in extreme cases, glucocorticoids.
Thyroid Nodules
Thyroid nodules are uncommon in children, compared with a 5
percent prevalence in adults over 50 years of age. The risk of a
solitary thyroid nodule being malignant in a child or an
adolescent is approximately 33 percent.
In these children and young people, a history of endocrine
tumors indicative of multiple endocrine neoplasia type II in any
family members should be sought, as well as a history of previous
radiation therapy to the head or neck.
Solid thyroid nodules in children should be surgically
excised. Before excision, a l@31 thyroid scan may be obtained.
"Hot" nodules are usually not malignant, but some exceptions have
occurred.] Simple cysts are usually not malignant, but exceptions
are also possible in these cases
Ultrasonographic examination of the thyroid is warranted
for "cold" nodules. A cold nodule that is found to be solid,
complex cystic or mixed on ultrasonography should be regarded as
malignant until proved otherwise. Fine-needle biopsy of solitary
thyroid nodules in adults has proved helpful; however, its
efficacy has not yet been proved in children.
Thyroid surgery in children requires a pediatric
anesthesiologist and a surgeon with ample experience in anterior
neck surgery.
Final Comment
Acquired hypothyroidism in children can be diagnosed and
treated by the family physician. Congenital hypothyroidism,
Graves' disease, subacute thyroiditis and thyroid nodules are
conditions that might best be referred to a pediatric
endocrinologist, after appropriate laboratory evaluation and
confirmation of the diagnosis.
