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Acquired hypothyroidism in childhood and adolescence
Author
Stephen LaFranchi, MD
Section Editors
Douglas S Ross, MD
Mitchell Geffner, MD
Deputy Editor
Alison G Hoppin, MD
Disclosures:Stephen LaFranchi, MD Nothing to disclose. Douglas S Ross, MD
Grant/Research/Clinical Trial Support: Genzyme [thyroid cancer (rhTSH)].
Mitchell Geffner, MD Grant/Research/Clinical Trial Support: Genentech; Ipsen;
NovoNordisk; Pfizer; Versartis (for all-growth [somatropin]). Consultant/Advisory
Boards: Daiichi-Sankyo (T2DM [Colesevelam]); Endo (puberty [Histrelin
acetate]); Ipsen (growth [Mecasermin (IGF-I) Increlex]); Pfizer (growth
[Somatropin (GH) Genotropin]). Alison G Hoppin, MD Employee of UpToDate,
Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial
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All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Mar 2014. | This topic last updated: Jun 12,
2013.
INTRODUCTION Hypothyroidism is the most common disturbance of thyroid
function in children; acquired hypothyroidism is most often caused by
autoimmune thyroiditis [1]. As in adults, acquired hypothyroidism can be
caused by both thyroid disease (primary hypothyroidism) and hypothalamicpituitary disease (central hypothyroidism); furthermore, primary

hypothyroidism may be either subclinical (high serum thyroid stimulating


hormone [TSH] and normal serum free thyroxine [T4] concentrations) or overt
(high serum TSH and low serum free T4 concentrations). Whatever its cause,
hypothyroidism in children can have deleterious effects on growth, pubertal
development and school performance.
CLINICAL MANIFESTATIONS The most common manifestation of
hypothyroidism in children is declining growth velocity, often resulting in short
stature. The growth delay tends to be insidious in onset, and it may be present
for several years before other symptoms occur, if they occur at all [2]. Thus,
any child with declining growth velocity should be evaluated for
hypothyroidism. (See "Diagnostic approach to children and adolescents with
short stature".)
Another common feature is altered school performance. Performance often
declines, but it improves in some children, perhaps because they are less
active and, therefore, less easily distracted and better able to concentrate. One
reason for delay in diagnosis is that parents see the latter changes as positive.
Other common symptoms are sluggishness, lethargy, cold intolerance,
constipation, dry skin, brittle hair, facial puffiness, and muscle aches and pains.
If the cause is hypothalamic or pituitary disease, the child may have
headaches, visual symptoms, or manifestations of other pituitary hormone
deficiencies. (See "Clinical manifestations of hypothyroidism".)
The most common physical finding at presentation is a diffusely enlarged
thyroid gland (goiter). In one series from Israel, a noticeable goiter was present
in 39.5 percent of children with autoimmune thyroiditis [3]. Alternatively, the
thyroid gland may be normal in size or not palpable at all. Abnormalities on
physical examination include short stature, apparent overweight (more fluid
retention than obesity), puffy facies with a dull, placid expression, bradycardia,
pseudohypertrophy of the muscles, and delayed deep tendon reflexes.
Pubertal development is delayed in most adolescent hypothyroid children.
However, some children have sexual precocity, characterized by breast
development and vaginal bleeding in girls and macro-orchidism (enlarged
testes) in boys, and slightly increased (for age) serum gonadotropin
concentrations. A few patients have hyperprolactinemia and rarely
galactorrhea. Growth hormone secretion may be normal or decreased, and
serum insulin-like growth factor I (IGF-I) levels are usually decreased [4].
Primary hypothyroidism may be associated with enlargement of the sella
turcica, resulting from secondary hyperplasia of thyrotroph cells [5]. The
enlargement may be discovered when cranial imaging is performed for
evaluation of short stature. Although pituitary enlargement may be rather
pronounced, with the upper convexity of the gland even abutting inferiorly on

the optic chiasm, it rarely causes symptoms or signs (in contrast to a pituitary
tumor or craniopharyngioma), and it is reversible with T4 therapy. Thus,
primary hypothyroidism must be excluded in any child with an enlarged sella
turcica.
ETIOLOGY The causes of hypothyroidism in children are listed in the table
(table 1). They are similar to those in adults, but iatrogenic hypothyroidism is
relatively less common. Most can be identified from the history and physical
examination. (See "Disorders that cause hypothyroidism".)
Chronic autoimmune (Hashimotos) thyroiditis The most common cause of
hypothyroidism in children is chronic autoimmune (Hashimoto's) thyroiditis,
resulting in either thyroid atrophy or goiter. It is more common in girls than
boys and in whites than blacks. Among all children with this disorder, euthyroid
goiter is more common than hypothyroidism [3,6,7]. The changes in the thyroid
gland may not be detectable on physical examination. (See "Congenital and
acquired goiter in children", section on 'Chronic autoimmune (Hashimoto's)
thyroiditis'.)
In the National Health and Nutrition Examination Survey (NHANES III) from
1988 to 1994, 6.3 percent of adolescents (12 to 19 years of age) had positive
anti-thyroglobulin antibodies (Tg Ab) and 4.8 percent had positive anti-thyroid
peroxidase antibodies (TPO Ab) [8]. The likelihood of detecting Tg Ab and TPO
Ab was two times greater in female versus male adolescents. The incidence of
antithyroid antibodies was highest in Hispanic-American adolescents and
lowest in black non-Hispanic adolescents; non-Hispanic whites had an
incidence between these two groups. Approximately 2 percent of surveyed
adolescents had a serum TSH >4.5 mU/L, a value indicating hypothyroidism.
The natural history of euthyroid autoimmune thyroiditis was illustrated in a
report of 160 children (mean age 9.1 years) [9]. Among 105 children with
elevated thyroid antibodies and normal thyroid stimulating hormone (TSH)
followed for five years, 65 percent remained euthyroid, 10 percent developed
mild elevation in serum TSH concentrations (typically 5 to 10 mU/L), and 26
percent developed serum TSH levels twofold above the upper limit of normal
(usually >10 mU/L). In a subsequent study of 87 children with elevated thyroid
antibodies and mild TSH elevation (5 to 10 mU/L) followed for three years, 41
percent reverted to euthyroidism (TSH <5 mU/L), 20 percent had persistent
mild TSH elevation (5 to 10 mU/L), while 39 percent developed more overt
hypothyroidism (TSH >10 mU/L) [10].
Pathogenesis Different mechanisms can be responsible for thyroid atrophy or
goiter formation in these patients [11]. (See "Pathogenesis of Hashimoto's
thyroiditis (chronic autoimmune thyroiditis)".)

Atrophic thyroiditis is primarily the result of cell-mediated cytotoxicity leading


to follicular cell apoptosis; complement-dependent antibody-mediated
cytotoxicity may contribute to thyroid damage. TSH receptor blocking
antibodies result in loss of thyroid morphological integrity, which may be
reversible.
Goitrous thyroiditis may be induced by one of three mechanisms: lymphocytic
and plasma cell infiltration (and lymphoid germinal centers), the production of
antibodies that stimulate thyroid growth, or excess TSH secretion.
Disorders with associated autoimmune thyroid disease Children with some
chromosomal disorders or other autoimmune disorders are at increased risk for
chronic autoimmune thyroiditis and, to a lesser extent, hypothyroidism. These
include Down syndrome (trisomy 21), Turner syndrome, type 1 (autoimmune)
diabetes mellitus, celiac disease, and possibly Klinefelter syndrome [12-17].
Down syndrome In one report of children with Down syndrome, 28 percent
had positive serum thyroid antibody concentrations (mostly TPO Ab), 14
percent had subclinical hypothyroidism, 7 percent overt hypothyroidism, and 5
percent hyperthyroidism [12]. In another cross-sectional study of 70 children,
24 percent were hypothyroid; the percentage increased with age in those with
positive serum antithyroid antibody concentrations [18]. In a longitudinal
series, the cumulative incidence of hypothyroidism up to age 25 years was 35
percent [19]. Because of the high rate of congenital hypothyroidism, a
randomized trial was performed to determine the effects of universal treatment
of all Down syndrome neonates with levothyroxine. Treatment reduced delays
in motor development and possibly mental development and was associated
with greater gains in length and weight [20]. Until these results are confirmed
in other randomized clinical trials, however, routine treatment of all Down
syndrome neonates should NOT be considered standard of care.
Turner syndrome In a study of girls with Turner syndrome, 41 percent had
high serum antithyroid antibody concentrations (again predominantly TPO Ab),
18 percent had a goiter, and 8 percent had subclinical or overt hypothyroidism
[13]. In another series of 75 girls and women with Turner syndrome, the
frequency of chronic autoimmune thyroiditis increased from 15 percent in the
first decade of life to 30 percent in the third decade [14]. A study from Sweden
confirmed that hypothyroidism becomes more common over time [21]. At the
beginning of the study, 23 of 91 adult women (mean age 37.7 11 years) with
Turner syndrome had hypothyroidism [21]. At the end of a five-year follow-up,
an additional 11 had developed hypothyroidism, resulting in an annual
incidence of 3.2 percent. In one study, there was a higher prevalence of
autoimmune hypothyroidism in those with an isochromosome X karyotype as
compared with those with a 45 XO karyotype [22].

Klinefelter syndrome There is limited information on the risk of thyroid


disease; one study reported hypothyroidism in one of eight boys with
Klinefelter syndrome [16]. However, another study found a general shift toward
lower values in serum free T4 concentrations but no compensatory increase in
serum TSH, changes more consistent with central hypothyroidism [17].
Type 1 diabetes mellitus Similar findings have been noted among children
with type 1 diabetes mellitus. Approximately 20 percent have high serum
antithyroid antibody concentrations, and 5 percent have abnormalities in
thyroid function, usually subclinical hypothyroidism [23].
Celiac disease In a study of 135 children with celiac disease, 31 (23 percent)
had positive antithyroid antibodies [24]. During long-term follow up, 26 percent
of the patients with positive antibodies developed subclinical hypothyroidism,
while 74 percent remained euthyroid. Another study examined the
development of celiac disease in 302 children with autoimmune thyroid
disease, in whom 4.6 percent had positive tissue transglutaminase antibodies,
and half of whom had confirmed celiac disease on biopsy [25]. Excluding
children with Down syndrome and type 1 diabetes mellitus, the incidence of
celiac disease fell to 1.3 percent, similar to the general population. (See
"Clinical manifestations and diagnosis of celiac disease in children", section on
'Autoimmune thyroiditis'.)
Thus, children with Down, Turner, or Klinefelter syndrome, type 1 diabetes
mellitus, or celiac disease should be screened annually for hypothyroidism by
measuring serum TSH. Thyroid screening starts when the syndrome or disease
is diagnosed. In the case of Down syndrome this is typically in infancy. Children
discovered to have autoimmune thyroiditis by screening present at an earlier
stage of the disease, and so have fewer clinical symptoms and signs of
hypothyroidism [26].
Autoimmune polyglandular syndrome A few children with chronic
autoimmune thyroiditis have or later develop other autoimmune
endocrinopathies, and, therefore, have an autoimmune polyglandular
syndrome [27]. Chronic autoimmune thyroiditis occurs in about 10 percent of
children with type I autoimmune polyglandular syndrome (APECED or Whitaker
syndrome); the more common manifestations of this syndrome are
hypoparathyroidism, adrenal insufficiency, and mucocutaneous candidiasis.
Chronic autoimmune thyroiditis also occurs in about 70 percent of children with
type II autoimmune polyglandular syndrome (Schmidt syndrome), which has as
its other major manifestations adrenal insufficiency and autoimmune diabetes.
In one study, autoimmune gastritis with antibodies to gastric parietal cells was
found in 30 percent of children with autoimmune thyroiditis [28]. (See "Causes
of primary adrenal insufficiency (Addison's disease)", section on 'Autoimmune
adrenalitis'.)

IPEX syndrome Autoimmune thyroiditis may present in infancy as part of the


rare x-linked disorder characterized by autoimmune endocrinopathy,
enteropathy, and eczema. (See "IPEX: Immune dysregulation,
polyendocrinopathy, enteropathy, X-linked".)
Obesity Moderate elevation of serum TSH concentration occurs in 10 to 23
percent of obese children, associated with normal or slightly elevated T4 and
T3 values [29]. Elevated serum leptin, present in children with obesity,
stimulates increased transcription of thyrotropin releasing hormone (TRH), and
so may be the primary factor increasing serum TSH levels. Thus, the elevated
TSH levels probably are a consequence rather than a cause of obesity. The
elevated TSH levels return to normal after weight loss [30]. Therefore, obese
children with a mild TSH elevation (5 to 10 mU/L) should be managed by
lifestyle changes rather than T4 treatment.
Complications Pericardial and pleural effusions may occur in children with
severe hypothyroidism [31]. These effusions resolve with thyroid hormone
treatment. Hypothyroidism should be considered in any child with unexplained
pericardial or pleural effusions.
Rarely, an encephalopathy may occur in children or adults with autoimmune
thyroiditis. This disorder has been termed Hashimoto's encephalopathy, and is
thought to be immune-mediated but unrelated to thyroid dysfunction [32]. (See
"Hashimoto's encephalopathy".)
Painless thyroiditis or subacute granulomatous thyroiditis Hypothyroidism
also occurs transiently during recovery from painless thyroiditis or subacute
granulomatous thyroiditis. (See "Overview of thyroiditis".)
Iodine deficiency The most common cause of hypothyroidism worldwide is
iodine deficiency (endemic goiter). Although symptomatic iodine deficiency is
uncommon in North America because of fortification of salt and presence of
iodine in dairy products, the most recent National Health and Nutrition
Examination Survey (NHANES) reported that approximately 15 percent of
women of reproductive age in the United States fall into the iodine-deficient
category [33].
Excess iodine ingestion Hypothyroidism that is reversible can occur as a
result of iodine excess (eg, after ingestion of nutritional supplements or iodinerich drugs, such as amiodarone or expectorants). (See "Disorders that cause
hypothyroidism", section on 'Iodine'.)
Antithyroid drugs Hypothyroidism also can occur in patients with
hyperthyroidism treated with antithyroid drugs. (See "Treatment and prognosis
of Graves' disease in children and adolescents".)

Thyroid injury Thyroid injury and, therefore, hypothyroidism may be caused


by external radiation or radioactive iodine therapy, after thyroidectomy, or with
infiltrative diseases of the thyroid (eg, Langerhans cell histiocytosis and
cystinosis).
Craniospinal irradiation Approximately 40 percent of children with tumors of
the head and neck region (eg, Hodgkin lymphoma) who are treated with
radiation (5000 rads [50 Gy]) develop hypothyroidism during prolonged followup [34]; the risk is probably life-long. Among children with brain tumors or
leukemia who receive craniospinal radiation, a substantial proportion develops
primary hypothyroidism or central hypothyroidism [35]. In a study of children
with brain or head and neck tumors treated with external radiation,
approximately 30 percent developed primary hypothyroidism, and
approximately 50 percent had evidence of central hypothyroidism [36]. Many of
the latter were identified on the basis of a subnormal serum TSH response to
thyrotropin-releasing hormone or absence of the nocturnal surge in TSH
secretion. Other studies report a lower rate of central hypothyroidism, around
10 to 20 percent. Thyroid ultrasonography will show reduced thyroid volume in
irradiated patients who develop hypothyroidism [37]. Chemotherapy may
increase the risk of hypothyroidism.
Follow-up of 13 to 17 year old adolescents exposed to nuclear fallout from the
Chernobyl accident showed a higher prevalence of TPO Abs (6.4 versus 2.4
percent in controls), but thyroid function remained normal [38].
Transient suppression of the metabolic activity of the thyroid tissue may protect
it from injury induced by external radiation. In a small uncontrolled study,
children undergoing craniospinal irradiation for medulloblastoma or primitive
neuroectodermal tumor were treated with L-thyroxine throughout the radiation
treatment at doses designed to suppress thyroid activity [39]. Children in
whom the metabolic activity of the thyroid was suppressed during the period of
external radiation (as measured by TSH levels of <0.3 mU/L) were less likely to
develop long-term hypothyroidism as compared to those in whom thyroid
suppression was not achieved. Randomized trials of this approach will be
required to fully examine whether concurrent administration of L-thyroxine
reduces the risk for radiation-induced hypothyroidism.
Hypothyroidism after treatment for Graves' disease With low or moderate
doses of radioactive iodine, hypothyroidism develops in approximately 10 to 20
percent in the first year after therapy and in about 3 percent per year
thereafter [40]. With newer recommendations to treat children with higher
doses of radioiodine, hypothyroidism develops by six months after therapy in
essentially all treated patients [41]. Similarly, hypothyroidism often occurs after
subtotal thyroidectomy in children with Graves' hyperthyroidism and invariably
after thyroidectomy for thyroid cancer.

Some children diagnosed with Graves disease who are treated with antithyroid
drugs have relatively rapid resolution of their hyperthyroidism, typically within
six months of diagnosis. After discontinuation of antithyroid drug treatment,
they remain hypothyroid. In hindsight, such children are recognized to have
Hashitoxicosis rather than Graves disease [42]. Other children with Graves
disease who are treated with antithyroid drugs may achieve a true remission,
remaining euthyroid after discontinuation of antithyroid drugs. About 10
percent of such children later become hypothyroid, caused by chronic
autoimmune thyroiditis, either with destruction of the thyroid or due to
production of a TSH receptor blocking antibody [43].
Late-onset congenital hypothyroidism Late-onset congenital hypothyroidism
that develops during childhood may appear to be acquired hypothyroidism.
This may occur with some forms of thyroid dysgenesis, such as an ectopic
gland, or with inborn errors of thyroid hormone synthesis (dyshormonogenesis).
Children with high TSH and normal free T4 during neonatal screening are more
likely to have subclinical hypothyroidism during early childhood [44]. (See
"Clinical features and detection of congenital hypothyroidism", section on
'Etiology' and "Reduced sensitivity to thyroid hormone".)
Williams syndrome Subclinical hypothyroidism is common among young
patients with Williams syndrome (caused by a deletion of genes in the 7q11.23
region, including elastin). In a report of 92 patients with Williams syndrome, 32
percent had subclinical hypothyroidism; none had thyroid autoantibodies [45].
In most cases, thyroid function improves with age. (See "Williams-Beuren
syndrome" and "Microdeletion syndromes (chromosomes 1 to 11)", section on
'7q11.23 deletion syndrome (Williams syndrome)'.)
Hepatitis C infection In a report of 36 children with chronic hepatitis C
infection acquired from their mother, 11.1 percent had subclinical
hypothyroidism [46]. This did not appear to be autoimmune thyroiditis because
antithyroid antibodies were negative.
Hemangiomas Hypothyroidism can occur in young children with large
hemangiomas of the liver [47]. The tumors contain very high levels of type 3
deiodinase activity, which catalyzes deiodination of T4 to reverse
triiodothyronine (rT3) and triiodothyronine (T3) to diiodothyronine (T2),
resulting in low serum T4 and T3 concentrations. Thyroid secretion is increased,
but not sufficiently to compensate for the large increase in T4 and T3
degradation.
Thyroid hormone resistance Children with generalized thyroid hormone
resistance may have some tissue-specific clinical manifestations of
hypothyroidism if they cannot sufficiently increase their serum thyroid hormone

concentrations to overcome the nuclear receptor defect in those tissues. (See


"Resistance to thyrotropin and thyrotropin-releasing hormone".)
Central hypothyroidism Any hypothalamic or pituitary disease can cause
central hypothyroidism. In children, it is most likely to be late-onset of a
congenital defect, such as septo-optic dysplasia, or to be caused by pituitary
tumors, the most common of which is craniopharyngioma. The effect of
pituitary tumors may either be direct or as a result of therapy. Other causes
include histiocytosis X and other infiltrative disorders, other brain tumors,
trauma, and radiotherapy (see 'Craniospinal irradiation' above). Isolated TSH
deficiency is less common and likely the result of a TSH subunit gene
mutation. (See "Central hypothyroidism".)
DIAGNOSIS Children suspected to have hypothyroidism should have
measurements of serum TSH and free T4 (or serum total T4 with some
assessment of serum binding proteins). The normal range for serum total T4
concentrations (and serum free T4 values) is slightly higher in children than in
adults (table 2) [48-50].
Children with primary hypothyroidism have high serum TSH concentrations and
low serum free T4 values. Questions exist regarding the upper limit of normal
for serum TSH concentration. TSH levels have diurnal variation, and one series
suggests that TSH values measured at 8 AM are more sensitive for the
diagnosis of mild primary hypothyroidism as compared with measurements at 4
PM [51]. However, normal ranges that are specific for time of day have not
been established. (See "Laboratory assessment of thyroid function".)
In children with mild elevations of serum TSH (5 to 10 mU/L), the test should be
repeated before making treatment decisions. This is because TSH levels are
normal in up to 70 percent of such patients when the test is repeated [52].
Moreover, mild elevations of TSH in obese children are common and are a
consequence of the obesity itself, and do not warrant treatment with thyroid
hormone. (See 'Disorders with associated autoimmune thyroid disease' above.)
Children with "subclinical hypothyroidism" have an elevated TSH and a normal
free T4 level. There is some controversy about whether or not to treat children
with subclinical hypothyroidism. In one study non-autoimmune subclinical
hypothyroidism was due to mutations in the TSH receptor gene in 29 percent of
patients [53].
Most children with central hypothyroidism have normal or low serum TSH
concentrations and low serum free T4 values. However, a few have slightly
high serum TSH concentrations because they secrete immunoreactive but
biologically inactive TSH [54]. The study noted above [51] suggests that central
hypothyroidism in children is characterized by a low ratio of the TSH values
taken at 8 AM and 4 PM (8AM:4PM ratio <1.3 in central hypothyroidism; normal

8AM:4PM ratio >1.5), when serum free T4 is in the lower third of the normal
range. (See "Laboratory assessment of thyroid function" and "Central
hypothyroidism".)
Chronic autoimmune thyroiditis can be confirmed as the cause of
hypothyroidism by measuring antithyroid antibodies, best done by measuring
TPO Ab. Approximately 85 to 90 percent of children with chronic autoimmune
thyroiditis have high serum TPO Ab concentrations, while 30 to 50 percent have
positive Tg Ab levels [55]. In one study, 8 of 83 children (9.2 percent) with
autoimmune thyroiditis had positive TSH receptor blocking antibodies; all had
associated overt hypothyroidism [56].
Pendrin, an apical protein on thyroid follicular cells, is another antigen in
autoimmune thyroid disease. Pendrin antibodies were found in 81 percent of
patients with autoimmune thyroid disease compared with 9 percent of controls
[57]. Measurement of pendrin antibodies is not yet commercially available.
Other studies, such as thyroid ultrasonography or radionuclide scanning, are
rarely indicated in children with primary hypothyroidism. In a study of 105
children with antibody positive Hashimoto's thyroiditis, only one-third showed
typical ultrasound changes (scattered hypo- and hyperechogenicity) at
diagnosis [58]. During 7 to 14 month follow-ups, more than half of the
remaining children developed typical ultrasound changes. Children with central
hypothyroidism should undergo cranial imaging with contrast, preferably
magnetic resonance imaging, and tests for other pituitary hormone
deficiencies. If the patient has a markedly asymmetric goiter or a prominent
nodule, or a smaller nodule that enlarges during follow-up, fine-needle
aspiration biopsy is indicated. (See "Diagnosis of hypopituitarism" and "Thyroid
nodules and cancer in children".)
The diagnostic studies that should be performed in children suspected of
having a late-onset form of congenital hypothyroidism are reviewed elsewhere.
(See "Clinical features and detection of congenital hypothyroidism".)
Skeletal maturation is delayed, and therefore bone age, like height age, is less
than chronologic age [59]. Indeed, because bone age increases so little after
the onset of hypothyroidism, it may indicate the age of onset.
TREATMENT AND PROGNOSIS Levothyroxine (T4) is the treatment of choice
in children with hypothyroidism. The goals of treatment are to restore normal
growth and development, including pubertal development. There is some
controversy about the need to treat children with mild subclinical
hypothyroidism, characterized by TSH elevations between 6 and 10 mU/L.
There is general agreement to treat children with subclinical hypothyroidism
and TSH levels >10 mU/L, to prevent any subtle effects on growth and
development. (See 'Diagnosis' above.)

T4 dose Children clear T4 more rapidly than adults; as a result, the daily
replacement dose on a weight basis is higher:
Age 1 to 3 years 4 to 6 mcg/kg body weight
Age 3 to 10 years 3 to 5 mcg/kg
Age 10 to 16 years 2 to 4 mcg/kg
Alternatively, the replacement dose can be calculated as a function of body
surface area, in which case the dose at any age is approximately 100
mcg/m2/day. Body surface area can be determined from height and weight
using a calculator (calculator 1).
In children with primary hypothyroidism, the recommended target range for
TSH is in the lower half of the reference range (optimally 0.5 to 2.0 mU/L) and
for T4 or free T4 is in the upper half of the reference range [60]. The optimal T4
range is between 9 and 13 ug/dL (116 to 167 nmol/L). Because the normal free
T4 reference range varies according to the assay method, clinicians need to
determine the range for their specific laboratory. As an example, if the normal
free T4 reference range is 0.6 to 1.8 ng/dL (8 to 23 pmol/L), the corresponding
optimal free T4 range would be between 1.2 and 1.8 ng/dL (15 to 23 pmol/L).
In children with central hypothyroidism, only measurement of serum free T4 or
T4 is useful for dosage monitoring. The target serum free T4 or T4 in these
children should be the same as in children with primary hypothyroidism.
Adult height may be diminished among children treated just before or during
puberty as compared with children treated earlier [61]. Although
hypothyroidism may cause weight gain, this is typically attributable to fluid
retention rather than adiposity. Treatment does not lead to substantial changes
in weight or body mass index for most children [62].
For most children, therapy should be initiated with a T4 dose in the middle of
the appropriate range for age. Severe long-standing hypothyroidism is
associated with a significant height deficit after treatment, ranging from 8 to 14
cm in one study, and use of a lower initial dose of T4 has been suggested as a
strategy to avoid overly rapid acceleration of skeletal maturation, which could
lead to loss of adult height [59]. However, the efficacy of this strategy is
challenged by a study that reported no correlation between slow or rapid
correction of hypothyroidism and skeletal maturation [63]. In the same study,
use of other growth-promoting therapies such as gonadotropin-releasing
hormone agonists and growth hormone also failed to improve adult height
outcome. Children with more chronic (or severe) hypothyroidism also are at
higher risk of poorer school achievement and hyperactivity during treatment
[64].

Patients with longstanding hypothyroidism are at risk for developing


pseudotumor cerebri shortly after initiation of levothyroxine treatment [65].
Children with persistent headaches or vision changes should contact their
physician.
Consequences of overtreatment Prolonged overtreatment with T4 should be
avoided. The potential consequences of overtreatment vary with age: infants
with open cranial sutures may develop craniosynostosis, and older children
may develop adverse behavior changes and lower school performance [64].
Both hypothyroidism and overtreatment can affect bone mineral density [66].
On the other hand, at least one study found no difference in bone density at
diagnosis or after long-term T4 therapy in adolescent girls with subclinical
hypothyroidism compared with normal girls [67].
Course Hypothyroidism caused by chronic autoimmune thyroiditis is not
invariably permanent; some children treated for several years have persistently
normal thyroid function after T4 treatment is discontinued [68,69]. One study,
for example, evaluated 18 children with subclinical hypothyroidism; after
approximately four years, 10 still had subclinical hypothyroidism, seven were
euthyroid, and one had overt hypothyroidism [69]. In another study from
Taiwan, 11 of 22 patients with Hashimoto's thyroiditis (goiter and positive
thyroid auto-antibodies) and who had signs of hypothyroidism and thyroid
dysfunction (subclinical or overt) became euthyroid after a mean follow-up
period of 6.4 3.9 years [70].
Once T4 therapy is started, it probably is best to continue treatment until
growth and pubertal development are complete. At that time, the question of
permanency of hypothyroidism can be addressed by discontinuing T4 and
measuring serum TSH one month later.
SUMMARY AND RECOMMENDATIONS
Acquired hypothyroidism is the most common abnormality of thyroid function in
children and is most often caused by chronic autoimmune thyroiditis. In the
United States, 6 percent of adolescents have positive antithyroid antibodies
and 2 percent have an elevated serum TSH. (See 'Chronic autoimmune
(Hashimotos) thyroiditis' above.)
Many children with acquired hypothyroidism, particularly those with subclinical
hypothyroidism, will be asymptomatic. In those with overt disease, clinical
features include declining growth velocity, short stature, and/or the presence of
a goiter. Adolescents may also have signs of pubertal delay. (See 'Clinical
manifestations' above.)

Patients with symptoms or findings on physical examination compatible with


hypothyroidism should be evaluated with measurements of serum free T4 and
TSH concentrations, and the results should be compared to age-specific normal
values (table 2). If another etiology is not obvious, testing for anti-thyroglobulin
antibodies (Tg Ab) and anti-thyroid peroxidase antibodies (TPO Ab) should be
performed. (See 'Diagnosis' above.)
In children with mild elevations of serum TSH (5 to 10 mU/L), the test should be
repeated before making treatment decisions. This is because TSH levels are
normal in up to 70 percent of such patients when the test is repeated.
Moreover, mild elevations of TSH in obese children are common and are a
consequence of the obesity itself, and do not warrant treatment with thyroid
hormone.
T4 is the treatment of choice in children with hypothyroidism. The goals of
treatment are to restore normal growth and development. If subclinical
hypothyroidism is detected and confirmed by repeat testing, we suggest T4
treatment (Grade 2C) to prevent any untoward effects on growth and
development. Once growth and pubertal development are complete, thyroid
hormone treatment can be discontinued and thyroid function re-evaluated.
(See 'Treatment and prognosis' above.)
Patients and families should be aware that treatment may sometimes cause
temporary behavior symptoms, poorer school achievement, and may not
restore full growth potential in children with long-standing hypothyroidism and
marked delay in skeletal maturation. (See 'Treatment and prognosis' above.)
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REFERENCES
Rallison ML, Dobyns BM, Keating FR, et al. Occurrence and natural history of
chronic lymphocytic thyroiditis in childhood. J Pediatr 1975; 86:675.
de Vries L, Bulvik S, Phillip M. Chronic autoimmune thyroiditis in children and
adolescents: at presentation and during long-term follow-up. Arch Dis Child
2009; 94:33.
Ozer G, Yksel B, Kozanolu M, et al. Growth and development of 280
hypothyroidic patients at diagnosis. Acta Paediatr Jpn 1995; 37:145.
Purandare A, Co Ng L, Godil M, et al. Effect of hypothyroidism and its treatment
on the IGF system in infants and children. J Pediatr Endocrinol Metab 2003;
16:35.
Atchison JA, Lee PA, Albright AL. Reversible suprasellar pituitary mass
secondary to hypothyroidism. JAMA 1989; 262:3175.

Rallison ML, Dobyns BM, Meikle AW, et al. Natural history of thyroid
abnormalities: prevalence, incidence, and regression of thyroid diseases in
adolescents and young adults. Am J Med 1991; 91:363.
Demirbilek H, Kandemir N, Gonc EN, et al. Hashimoto's thyroiditis in children
and adolescents: a retrospective study on clinical, epidemiological and
laboratory properties of the disease. J Pediatr Endocrinol Metab 2007; 20:1199.
Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid
antibodies in the United States population (1988 to 1994): National Health and
Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;
87:489.
Radetti G, Gottardi E, Bona G, et al. The natural history of euthyroid
Hashimoto's thyroiditis in children. J Pediatr 2006; 149:827.
Radetti G, Maselli M, Buzi F, et al. The natural history of the normal/mild
elevated TSH serum levels in children and adolescents with Hashimoto's
thyroiditis and isolated hyperthyrotropinaemia: a 3-year follow-up. Clin
Endocrinol (Oxf) 2012; 76:394.
Matsuura N, Konishi J, Yuri K, et al. Comparison of atrophic and goitrous autoimmune thyroiditis in children: clinical, laboratory and TSH-receptor antibody
studies. Eur J Pediatr 1990; 149:529.
Pueschel SM, Pezzullo JC. Thyroid dysfunction in Down syndrome. Am J Dis Child
1985; 139:636.
Grueiro de Papendieck L, Iorcansky S, Coco R, et al. High incidence of thyroid
disturbances in 49 children with Turner syndrome. J Pediatr 1987; 111:258.
Chiovato L, Larizza D, Bendinelli G, et al. Autoimmune hypothyroidism and
hyperthyroidism in patients with Turner's syndrome. Eur J Endocrinol 1996;
134:568.
Kondo T. Klinefelter syndrome associated with juvenile hypothyroidism due to
chronic thyroiditis. Eur J Pediatr 1993; 152:540.
Mazen I, El-Ruby M, El-Bassyouni HT. Variable associations of Klinefelter
syndrome in children. J Pediatr Endocrinol Metab 2010; 23:985.
Bjrn AM, Bojesen A, Gravholt CH, Laurberg P. Hypothyroidism secondary to
hypothalamic-pituitary dysfunction may be part of the phenotype in klinefelter
syndrome: a case-control study. J Clin Endocrinol Metab 2009; 94:2478.
Ivarsson SA, Ericsson UB, Gustafsson J, et al. The impact of thyroid
autoimmunity in children and adolescents with Down syndrome. Acta Paediatr
1997; 86:1065.

Karlsson B, Gustafsson J, Hedov G, et al. Thyroid dysfunction in Down's


syndrome: relation to age and thyroid autoimmunity. Arch Dis Child 1998;
79:242.
van Trotsenburg AS, Vulsma T, van Rozenburg-Marres SL, et al. The effect of
thyroxine treatment started in the neonatal period on development and growth
of two-year-old Down syndrome children: a randomized clinical trial. J Clin
Endocrinol Metab 2005; 90:3304.
El-Mansoury M, Bryman I, Berntorp K, et al. Hypothyroidism is common in
turner syndrome: results of a five-year follow-up. J Clin Endocrinol Metab 2005;
90:2131.
Elsheikh M, Wass JA, Conway GS. Autoimmune thyroid syndrome in women with
Turner's syndrome--the association with karyotype. Clin Endocrinol (Oxf) 2001;
55:223.
Riley WJ, Maclaren NK, Lezotte DC, et al. Thyroid autoimmunity in insulindependent diabetes mellitus: the case for routine screening. J Pediatr 1981;
99:350.
Cassio A, Ricci G, Baronio F, et al. Long-term clinical significance of thyroid
autoimmunity in children with celiac disease. J Pediatr 2010; 156:292.
Sattar N, Lazare F, Kacer M, et al. Celiac disease in children, adolescents, and
young adults with autoimmune thyroid disease. J Pediatr 2011; 158:272.
DeBoer MD, LaFranchi S. Differential presentation for children with autoimmune
thyroiditis discovered because of symptom development or screening. J Pediatr
Endocrinol Metab 2008; 21:753.
Neufeld M, Maclaren N, Blizzard R. Autoimmune polyglandular syndromes.
Pediatr Ann 1980; 9:154.
Segni M, Borrelli O, Pucarelli I, et al. Early manifestations of gastric
autoimmunity in patients with juvenile autoimmune thyroid diseases. J Clin
Endocrinol Metab 2004; 89:4944.
Reinehr T. Thyroid function in the nutritionally obese child and adolescent. Curr
Opin Pediatr 2011; 23:415.
Longhi S, Radetti G. Thyroid function and obesity. J Clin Res Pediatr Endocrinol
2013; 5 Suppl 1:40.
Martinez-Soto T, Deal C, Stephure D, et al. Pericardial effusion in severe
hypothyroidism in children. J Pediatr Endocrinol Metab 2010; 23:1165.

Alink J, de Vries TW. Unexplained seizures, confusion or hallucinations: think


Hashimoto encephalopathy. Acta Paediatr 2008; 97:451.
Caldwell KL, Pan Y, Mortensen ME, et al. Iodine status in pregnant women in the
National Children's Study and in U.S. women (15-44 years), National Health and
Nutrition Examination Survey 2005-2010. Thyroid 2013; 23:927.
Samaan NA, Schultz PN, Yang KP, et al. Endocrine complications after
radiotherapy for tumors of the head and neck. J Lab Clin Med 1987; 109:364.
Ogilvy-Stuart AL, Shalet SM, Gattamaneni HR. Thyroid function after treatment
of brain tumors in children. J Pediatr 1991; 119:733.
Rose SR, Lustig RH, Pitukcheewanont P, et al. Diagnosis of hidden central
hypothyroidism in survivors of childhood cancer. J Clin Endocrinol Metab 1999;
84:4472.
Bonato C, Severino RF, Elnecave RH. Reduced thyroid volume and
hypothyroidism in survivors of childhood cancer treated with radiotherapy. J
Pediatr Endocrinol Metab 2008; 21:943.
Agate L, Mariotti S, Elisei R, et al. Thyroid autoantibodies and thyroid function
in subjects exposed to Chernobyl fallout during childhood: evidence for a
transient radiation-induced elevation of serum thyroid antibodies without an
increase in thyroid autoimmune disease. J Clin Endocrinol Metab 2008;
93:2729.
Massimino M, Gandola L, Collini P, et al. Thyroid-stimulating hormone
suppression for protection against hypothyroidism due to craniospinal
irradiation for childhood medulloblastoma/primitive neuroectodermal tumor. Int
J Radiat Oncol Biol Phys 2007; 69:404.
Safa AM, Schumacher OP, Rodriguez-Antunez A. Long-term follow-up results in
children and adolescents treated with radioactive iodine (131I) for
hyperthyroidism. N Engl J Med 1975; 292:167.
Nebesio TD, Siddiqui AR, Pescovitz OH, Eugster EA. Time course to
hypothyroidism after fixed-dose radioablation therapy of Graves' disease in
children. J Pediatr 2002; 141:99.
Nabhan ZM, Kreher NC, Eugster EA. Hashitoxicosis in children: clinical features
and natural history. J Pediatr 2005; 146:533.
Tamai H, Kasagi K, Takaichi Y, et al. Development of spontaneous
hypothyroidism in patients with Graves' disease treated with antithyroidal
drugs: clinical, immunological, and histological findings in 26 patients. J Clin
Endocrinol Metab 1989; 69:49.

Calaciura F, Motta RM, Miscio G, et al. Subclinical hypothyroidism in early


childhood: a frequent outcome of transient neonatal hyperthyrotropinemia. J
Clin Endocrinol Metab 2002; 87:3209.
Cambiaso P, Orazi C, Digilio MC, et al. Thyroid morphology and subclinical
hypothyroidism in children and adolescents with Williams syndrome. J Pediatr
2007; 150:62.
Indolfi G, Stagi S, Bartolini E, et al. Thyroid function and anti-thyroid
autoantibodies in untreated children with vertically acquired chronic hepatitis C
virus infection. Clin Endocrinol (Oxf) 2008; 68:117.
Huang SA, Tu HM, Harney JW, et al. Severe hypothyroidism caused by type 3
iodothyronine deiodinase in infantile hemangiomas. N Engl J Med 2000;
343:185.
Nelson JC, Clark SJ, Borut DL, et al. Age-related changes in serum free thyroxine
during childhood and adolescence. J Pediatr 1993; 123:899.
Elmlinger MW, Khnel W, Lambrecht HG, Ranke MB. Reference intervals from
birth to adulthood for serum thyroxine (T4), triiodothyronine (T3), free T3, free
T4, thyroxine binding globulin (TBG) and thyrotropin (TSH). Clin Chem Lab Med
2001; 39:973.
Strich D, Edri S, Gillis D. Current normal values for TSH and FT3 in children are
too low: evidence from over 11,000 samples. J Pediatr Endocrinol Metab 2012;
25:245.
Rose SR. Improved diagnosis of mild hypothyroidism using time-of-day normal
ranges for thyrotropin. J Pediatr 2010; 157:662.
Lazar L, Frumkin RB, Battat E, et al. Natural history of thyroid function tests
over 5 years in a large pediatric cohort. J Clin Endocrinol Metab 2009; 94:1678.
Nicoletti A, Bal M, De Marco G, et al. Thyrotropin-stimulating hormone receptor
gene analysis in pediatric patients with non-autoimmune subclinical
hypothyroidism. J Clin Endocrinol Metab 2009; 94:4187.
Persani L, Ferretti E, Borgato S, et al. Circulating thyrotropin bioactivity in
sporadic central hypothyroidism. J Clin Endocrinol Metab 2000; 85:3631.
Zois C, Stavrou I, Svarna E, et al. Natural course of autoimmune thyroiditis after
elimination of iodine deficiency in northwestern Greece. Thyroid 2006; 16:289.
Feingold SB, Smith J, Houtz J, et al. Prevalence and functional significance of
thyrotropin receptor blocking antibodies in children and adolescents with
chronic lymphocytic thyroiditis. J Clin Endocrinol Metab 2009; 94:4742.

Yoshida A, Hisatome I, Taniguchi S, et al. Pendrin is a novel autoantigen


recognized by patients with autoimmune thyroid diseases. J Clin Endocrinol
Metab 2009; 94:442.
Vlachopapadopoulou E, Thomas D, Karachaliou F, et al. Evolution of
sonographic appearance of the thyroid gland in children with Hashimoto's
thyroiditis. J Pediatr Endocrinol Metab 2009; 22:339.
Rivkees SA, Bode HH, Crawford JD. Long-term growth in juvenile acquired
hypothyroidism: the failure to achieve normal adult stature. N Engl J Med 1988;
318:599.
Baloch Z, Carayon P, Conte-Devolx B, et al. Laboratory medicine practice
guidelines. Laboratory support for the diagnosis and monitoring of thyroid
disease. Thyroid 2003; 13:3.
Chiesa A, Grueiro de Papendieck L, Keselman A, et al. Final height in long-term
primary hypothyroid children. J Pediatr Endocrinol Metab 1998; 11:51.
Lomenick JP, El-Sayyid M, Smith WJ. Effect of levo-thyroxine treatment on
weight and body mass index in children with acquired hypothyroidism. J Pediatr
2008; 152:96.
Nebesio TD, Wise MD, Perkins SM, Eugster EA. Does clinical management
impact height potential in children with severe acquired hypothyroidism? J
Pediatr Endocrinol Metab 2011; 24:893.
Rovet JF, Daneman D, Bailey JD. Psychologic and psychoeducational
consequences of thyroxine therapy for juvenile acquired hypothyroidism. J
Pediatr 1993; 122:543.
Van Dop C, Conte FA, Koch TK, et al. Pseudotumor cerebri associated with
initiation of levothyroxine therapy for juvenile hypothyroidism. N Engl J Med
1983; 308:1076.
Vestergaard P, Mosekilde L. Fractures in patients with hyperthyroidism and
hypothyroidism: a nationwide follow-up study in 16,249 patients. Thyroid 2002;
12:411.
Saggese G, Bertelloni S, Baroncelli GI, et al. Bone mineral density in adolescent
females treated with L-thyroxine: a longitudinal study. Eur J Pediatr 1996;
155:452.
Sklar CA, Qazi R, David R. Juvenile autoimmune thyroiditis. Hormonal status at
presentation and after long-term follow-up. Am J Dis Child 1986; 140:877.
Moore DC. Natural course of 'subclinical' hypothyroidism in childhood and
adolescence. Arch Pediatr Adolesc Med 1996; 150:293.

Wang SY, Tung YC, Tsai WY, et al. Long-term outcome of hormonal status in
Taiwanese children with Hashimoto's thyroiditis. Eur J Pediatr 2006; 165:481.
Topic 5838 Version 14.0
GRAPHICS
Causes of hypothyroidism in children and adolescents
Chronic autoimmune (Hashimoto's) thyroiditis
Iodine
Deficiency
Excess ingestion (eg, nutritional supplements, drugs [amiodarone,
expectorants])
Drugs
Antithyroid drugs (eg, methimazole, propylthiouracil)
Anticonvulsant drugs (eg, phenytoin, phenobarbital, valproate)
Tyrosine kinase inhibitors
Interferon alfa
Thyroid injury
External radiation therapy
Radioactive iodine treatment
Thyroidectomy
Infiltrative diseases
Langerhans cell histiocytosis
Cystinosis
Late-onset congenital hypothyroidism

Williams syndrome
Hemangiomas
Thyroid hormone resistance
Central hypothyroidism (hypothalamic-pituitary disease)
Graphic 55456 Version 9.0
Normal ranges for thyroid function tests in infants and children

Age

Free
T4*(ng/dL
)

T4(g/
dL)

Free
T3(pg/dL
)

T3(ng/
dL)

TSH(mU
/L)

TBG(mg/
dL)
1.4-9.4

Cord
blood

0.9-2.2

7.813.1

20-240

15-75

2.2-10.7

1 to 4
days

2.2-5.3

9.320.9

180-760

100740

2.7-26.5

4 to 30
days

0.9-3.4

8.021.8

293-508

105387

1.2-13.1

1.9-4.5

1 to 12
months

0.9-2.3

7.215.7

267-521

105245

0.6-7.3

1.9-4.4

1 to 5
years

0.8-1.8

6.413.5

273-495

105269

0.7-6.6

1.6-4.2

6 to 10
years

1.0-2.1

6.012.8

273-469

94-241

0.8-6.0

1.4-3.7

11 to 18
years

0.8-1.9

4.712.4

267-462

80-210

0.6-5.8

1.2-2.9

>18
years

0.9-2.5

5.310.5

210-440

70-204

0.4-4.2

1.5-3.4

* Because the normal free T4 reference range varies according to the assay
method, clinicians need to determine the range for their specific laboratory,
which may differ from the data presented in the table.
Data adapted from the following sources:

Nelson JC, Clark SJ, Bonut DL, et al. Age-related changes in serum free
thyroxine during childhood and adolescence. J Pediatr 1993; 123:899.
Elmlinger MW, Khnel W, Lambrecht HG, et al. Reference intervals from birth to
adulthood for serum thyroxine (T4), triiodothyronine (T3), free T3, free T4,
thyroxine binding globulin (TBG) and thyrotropin (TSH). Clin Chem Lab Med
2001; 39:973.
Mutlu M, Karagzel G, Alyaziciolu Y, et al. Reference intervals for thyrotropin
and thyroid hormones and ultrasonographic thyroid volume during the neonatal
period. J Matern Fetal Neonatal Med 2012; 25:120.
Strich D, Edri S, Gillis D. Current normal values for TSH and FT3 in children are
too low: evidence from over 11,000 samples. J Pediatr Endocrinol Metab 2012;
25:245.
Lem AJ, de Rijke YB, van Toor H, et al. Serum thyroid hormone levels in healthy
children from birth to adulthood and in short children born small for gestational
age. J Clin Endocrinol Metab 2012; 97:3170.
Esoterix (Endocrine Sciences).
Graphic 60095 Version 8.0
Disclosures
Disclosures:Stephen LaFranchi, MD Nothing to disclose. Douglas S Ross, MD
Grant/Research/Clinical Trial Support: Genzyme [thyroid cancer (rhTSH)].
Mitchell Geffner, MD Grant/Research/Clinical Trial Support: Genentech; Ipsen;
NovoNordisk; Pfizer; Versartis (for all-growth [somatropin]). Consultant/Advisory
Boards: Daiichi-Sankyo (T2DM [Colesevelam]); Endo (puberty [Histrelin
acetate]); Ipsen (growth [Mecasermin (IGF-I) Increlex]); Pfizer (growth
[Somatropin (GH) Genotropin]). Alison G Hoppin, MD Employee of UpToDate,
Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial
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