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pediatric endocrinology Board Review Manual
Statement of
Editorial Purpose
The Hospital Physician Pediatric Endocrinology
Board Review Manual is a study guide for fel­
lows and practicing physicians preparing for
board examinations in pediatric endocrinology.
Each manual reviews a topic essential to the
current practice of pediatric endocrinology.
PUBLISHING STAFF
PRESIDENT, Group PUBLISHER
Bruce M. White
editorial director
Debra Dreger
Associate EDITOR
Tricia Faggioli
EDITORial assistant
Congenital and
Acquired Hypothyroidism
Editor:
Jill D. Jacobson, MD
Professor of Pediatrics, Section of Endocrinology and Diabetes,
Children’s Mercy Hospital and Clinics, University of Missouri–Kansas
City School of Medicine, Kansas City, MO
Contributor:
John S. Fuqua, MD
Associate Professor of Clinical Pediatrics, Section of Pediatric
Endocrinology and Diabetology, Indiana University School of
Medicine, Indianapolis, IN
Farrawh Charles
executive vice president
Barbara T. White
executive director
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PRODUCTION Director
Suzanne S. Banish
PRODUCTION associate
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Table of Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Thyroid Development and Physiology. . . . . . . . . . . . . 2
NOTE FROM THE PUBLISHER:
This publication has been developed with­
out involvement of or review by the Amer­
ican Board of Pediatrics.
Endorsed by the
Association for Hospital
Medical Education
Congenital Hypothyroidism. . . . . . . . . . . . . . . . . . . . . 3
Acquired Hypothyroidism. . . . . . . . . . . . . . . . . . . . . . . 8
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Cover Illustration by May S. Cheney
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Pediatric Endocrinology Volume 1, Part 2 Pediatric Endocrinology Board Review Manual
Congenital and Acquired Hypothyroidism
John S. Fuqua, MD
INTRODUCTION
Hypothyroidism refers to a state of decreased production and release of thyroid hormone from the thyroid
gland. It is one of the most common endocrine abnormalities seen by primary care physicians and pediatric endocrinologists alike. Hypothyroidism in childhood may
be congenital (present at birth) or acquired. Both forms
of hypothyroidism can be further categorized as primary
or central. This manual reviews clinical knowledge that
is essential when caring for patients who present with
laboratory or clinical evidence of hypothyroidism. The
manual begins with an overview of thyroid development
and physiology and then follows a case-based approach to
review the causes, approach to evaluation, and treatment
of congenital and acquired hypothyroidism.
THYROID DEVELOPMENT AND PHYSIOLOGY
EMBRYOLOGY AND FETAL THYROID FUNCTION
Thyroid gland organogenesis begins at 26 days gestation, with the evagination of the medial thyroid bud
from the floor of the developing pharynx. By 7 weeks,
the developing gland lies in the thyroid bed. Function
of the gland is first detected at 10 weeks, when the thyroid becomes able to trap iodide and synthesize thyroid
hormone precursors. Thyrotropin-releasing hormone
(TRH) and thyroid-stimulating hormone (TSH) are secreted between 15 and 18 weeks, and by 18 to 20 weeks,
the thyroid gland is able to release thyroid hormone in
significant amounts in response to stimulation.1,2
The fetus has relatively low circulating levels of triiodothyronine (T3) and high levels of reverse T3 (rT3).
Although maternal thyroxine (T4) and T3 can cross the
placenta, only a small amount enters the fetal circulation, because the placental type 3 deiodinase (D3) avidly converts maternal T4 and T3 to inactive metabolites,
limiting passage to the fetus. During the first half of
gestation, the fetus relies on maternal thyroid hormone
to support normal development of the central nervous
system (CNS). In the hypothyroid fetus, the fetal brain
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is partially protected against low circulating levels of
thyroid hormone by upregulation of type 2 deiodinase
(D2) activity, which serves to increase the levels of T3 in
the CNS.3 Nevertheless, otherwise healthy infants born
to mothers with inadequately treated hypothyroidism
have lower developmental scores, underscoring the
importance of early fetal euthyroidism.4,5
After 30 weeks gestation, the level of fetal T3 gradually increases, the level of rT3 decreases, and fetal
pro­duction of T4 and TSH increases. Most circulating
thyroid hormones at this point are derived from the
fetal thyroid. The ratio of TSH to T4 decreases, indicating the development and maturation of the fetal
hypothalamic-pituitary-thyroid axis.2,3 Hence, in mid­
gestation, levels of both T4 and T3 are low compared
to a term infant, and TSH secretion is relatively high
as a result of the immaturity of the negative feedback
system.
NEONATAL THYROID FUNCTION
At delivery, exposure to the cold extrauterine environment causes a surge in TSH secretion, with the concentration peaking at 70 mIU/mL by 30 minutes after
birth. This TSH surge stimulates T4 secretion. The T3
level also increases, partly as a result of direct secretion
from the thyroid gland and partly as a result of increases
in tissue type 1 deiodinase (D1) and the absence of
the deactivating placental D3. TSH gradually declines
over the first 3 to 5 days of life to levels at or below
10 mIU/mL, while the increased T4 and T3 levels persist
for weeks to months.
THYROID HORMONE PHYSIOLOGY
Synthesis of Thyroid Hormones
Dietary iodide is actively taken up by the sodiumiodide symporter located on the basement membrane
of the thyrocyte (Figure 1). The iodide is oxidized
to iodine by thyroid peroxidase (TPO) and is incorporated into tyrosine residues on the thyroglobulin
molecule. This process is termed organification. During
organification, the iodinated tyrosine residues are also
cross-linked to form the precursors of T3 and T4. The
iodinated thyroglobulin is then stored in the colloid
of the thyroid follicles. During secretion of thyroid
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Pediatric Endocrinology Volume
1, Part 3 Congenital and Acquired Hypothyroidism
hormone, thyroglobulin is taken up from the colloid
by endocytosis, and T3 and T4 are hydrolyzed from the
thyroglobulin protein.
Binding and Transport
Approximately 99% of circulating thyroid hormones
are bound to carrier proteins. Thyroxine-binding globulin (TBG) avidly binds both T4 and T3 and carries 70%
of thyroid hormones. Two other proteins, transthyretin
(formerly known as thyroxine-binding prealbumin) and
albumin, have lower affinity but carry 10% and 15% to
20% of circulating thyroid hormones, respectively. Protein binding influences laboratory measurements of T4
and T3. Assays of total T4 levels do not measure the more
physiologically relevant free fraction of T4. Direct (nonequilibrium dialysis) assays of free T4 are used frequently
and are less influenced by abnormalities of binding
proteins, such as TBG deficiency or excess. Equilibrium
dialysis assays are more accurate but are not as readily
available and are more time-consuming and expensive.
Metabolism
All circulating T4 is derived from the thyroid gland.
Only 20% of T3 is secreted from the thyroid; the remaining 80% is produced from peripheral metabolism
of T4. Both T4 and T3 are metabolized through the action of several deiodinases (Figure 2). D1, an activating
enzyme that converts T4 to T3, is present in a variety of
tissues and is responsible for the extrathyroidal production of T3. D1 is inhibited by propylthiouracil. D2 is
confined to the brain, pituitary, placenta, and brown
adipose tissue and is involved in the negative feedback
regulation of the thyroid. D3, an inactivating enzyme, is
located in the brain, placenta, and skin. Eighty percent
of T4 is metabolized by deiodinases, and the other 20%
is conjugated and excreted by the liver.
ROLE OF THYROID HORMONE
Thyroid hormones cross the plasma membrane
through both passive diffusion and active transport.
In the nucleus, T3 binds to thyroid hormone receptors. The hormone-receptor complex dimerizes and
causes the activation or repression of the expression of
numerous genes controlling many physiologic and developmental processes, including mitochondrial-based
cellular respiration, which regulates energy economy
and thermogenesis. Thyroid hormone also has important effects on lipid metabolism. In children, thyroid
hormone has important developmental effects in the
CNS, bone, heart, lung, skin, and gastrointestinal system. In the developing brain, thyroid hormone is critical for normal neuronal differentiation, myelinization,
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MIT
T4
Thyroglobulin
molecule
T3
Thyroid colloid
stores
Peroxidase
enzyme
complex
DIT
IThyroglobulin MIT
DIT
Sodiumiodide
symporter
I-
I-
RNA
DNA T T
4 3
TSH receptor
T4 T3
TSH
Blood vessel
Figure 1. Synthesis and processing of thyroid hormones. Under
thyroid-stimulating hormone (TSH) stimulation, iodide is actively
taken up by the sodium-iodide symporter and thyroglobulin is syn­
thesized. Iodide is incorporated into thyroglobulin by the thyroid
peroxidase complex. TSH also stimulates the uptake of iodinated
thyroglobulin by endocytosis. The iodothyronines are cleaved off,
and thyroxine (T4) and triiodothyronine (T3) are released, while
the iodine from monoiodotyrosine (MIT) and diiodotyrosine
(DIT) is recycled. (Adapted from Fisher DA. Thyroid disorders
in childhood and adolescence. In: Sperling, MA, editor. Pediatric
endocrinology. 2nd ed. Philadelphia: Saunders; 2002:190. Copyright
2002, with permission from Elsevier.)
dendritic arborization, and synapse formation. Its effect
on growth is well known and is mediated in part by its
influence on growth hormone (GH) secretion.
CONGENITAL HYPOTHYROIDISM
CASE 1 PRESENTATION
An 8-day-old female infant is referred to a pediatric
endocrinologist after laboratory tests conducted as
part of newborn screening revealed a TSH level of
374 mIU/mL and a total T4 level of 3.7 mg/dL. The
mother states that the baby is breast-feeding well and
has 6 to 8 wet diapers and 3 to 4 stools per day. She
sleeps for several hours at a time but wakes regularly
to nurse. On examination, the baby has regained her
birth weight (3.2 kg) and appears healthy.
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Congenital and Acquired Hypothyroidism
Thyroxine (T4)
I
H H
I
HO
O
I
Type 1 and type 2
deiodinases
I
Triiodothyronine (T3)
I
H H
HO
O
I
C
I
C
C
H NH2
Type 3
deiodinase
C
C
C
H NH2
O
OH
Type 3
deiodinase
Reverse triiodothyronine (rT3)
I
H H
O
HO
OH
O
I
I
H H
O
I
C
I
C
H NH2
C
H NH2
Type 1 and type 2
deiodinases
Diiodothyronine (T2)
HO
C
C
C
O
OH
Figure 2. Metabolism of the thyroid hor­
mones occurs via the action of 3 isoen­
zymes that catalyze deiodination. Type 1
deiodinase (D1) removes an iodine atom
from the outer ring of thyroxine (T4) to
form triiodothyronine (T3). Type 2 deio­
dinase (D2) also removes an iodine from
the outer ring, converting T4 to T3. Type 3
deiodinase (D3) removes an iodine from the
inner ring of T4 and T3, resulting in reverse
T3 (rT3) and diiodothyronine (T2), both of
which are physiologically inactive.
O
OH
• What are the signs and symptoms of congenital hypothyroidism?
the most common cause of congenital hypothyroidism
and preventable mental retardation worldwide.
CLINICAL FEATURES
Dysgenesis of the Thyroid Gland
Patients with thyroid dysgenesis most often have an
ectopically located gland as a result of partial failure of
both development and migration of the thyroid into
the inferior neck. There is no goiter, although a small
mass of thyroid tissue may rarely be seen on the posterior tongue near the foramen cecum, the embryonic
origin of the thyroid bud. Some patients may also have
residual thyroid tissue located in the superior neck in
the midline, along the path of the thyroglossal duct.
Thyroid gland ectopy must be distinguished from
agenesis of the thyroid gland, or athyreosis. Athyreosis
accounts for approximately 20% to 30% of cases of thyroid dysgenesis.7 Typically, athyreotic patients exhibit
very high TSH and low T4 levels. Finally, some dysgenetic thyroid glands may be normally placed in the thyroid
bed but are hypoplastic, with decreased function.
Most infants presenting for evaluation of an abnormal
newborn screening result will appear healthy and have
few or no specific signs or symptoms that lead the physician to suspect a thyroid disorder. However, a thorough
history and physical examination should be performed
to identify factors that may affect the patient’s treatment
or outcome. A careful family history might reveal affected
relatives. A baby with severe congenital hypothyroidism
lasting more than 4 to 6 weeks may present with poor
feeding, constipation, lethargy or excessive sleeping, and
hoarse cry. The physical examination may reveal failure
to thrive, large anterior and posterior fontanelles, dry
skin, jaundice, mottling, abdominal protuberance, an
umbilical hernia, or coarsening of the facies. A goiter
may be present.
• What are potential causes of hypothyroidism?
ETIOLOGIES
The causes of congenital hypothyroidism can be
roughly categorized into 4 groups: (1) dysgenesis of
the thyroid gland, accounting for approximately 80%
of cases; (2) inborn errors of thyroid hormone biosynthesis (collectively termed dyshormonogenesis), which
cause approximately 10% to 15% of cases; (3) central
hypothyroidism, accounting for less than 5% of cases;
and (4) transient hypothyroidism, which occurs in approximately 5% of patients (Table 1).6 Although it is
uncommon in the United States, iodine deficiency is
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Dyshormonogenesis
Dyshormonogenesis refers to a group of genetic defects that may affect any step in the biosynthetic process;
the most common defect is TPO deficiency. Most dyshormonogenesis defects are inherited in an autosomal recessive fashion, although TSH receptor (TSHR) defects
may be autosomal dominant.8 Hence, most causes of
dyshormonogenesis have a recurrence risk in subsequent
pregnancies of 25%. Thyroid abnormalities are variable.
Typically, the hypothyroidism is milder than that in patients with athyreosis.
TPO deficiency. TPO oxidizes intracellular iodide,
Pediatric Endocrinology Volume 1, Part 2 Congenital and Acquired Hypothyroidism
Table 1. Etiologies of Congenital Hypothyroidism
Etiology
TSH
T4
Goiter
Scan Results
Ultrasound Results
Athyreosis
Increased
Decreased
No
No uptake
No gland
Ectopic thyroid
Increased
Decreased
No
Positive uptake at
base of tongue
No gland
Eutopic thyroid
Increased
Decreased
No
Positive uptake
Small gland
TSH receptor defect
Increased
Decreased
No
No uptake
Normal to small gland
Na-I symporter defect
Increased
Decreased
Yes
No uptake
Enlarged gland
Organification defect
Increased
Decreased
Yes
Positive uptake
Enlarged gland
Thyroglobulin synthesis defect
Increased
Decreased
Yes
Positive uptake
Enlarged gland
Deiodination defect
Increased
Decreased
Yes
Positive uptake
Enlarged gland
Central hypo­thyroidism
Low to normal Decreased
No
Positive uptake
Normal to small gland
Transient hypo­thyroidism
Increased
Thyroid dysgenesis
Dyshormonogenesis
Decreased If iodine-deficient or
Positive uptake
or normal
exposed to goitrogen
Normal gland
Na-I symporter = sodium-iodide symporter.; T4 = thyroxine; TSH = thyroid-stimulating hormone. (Adapted from Fuqua J. Genetics, clinical manage­
ment and natural history of congenital hypothyroidism. Expert Rev Endocrinol Metab 2006;1:270, with permission of Future Drugs Ltd.)
covalently binds the resulting intermediate to tyrosine
residues on the thyroglobulin backbone, and couples
monoiodotyrosines and diiodotyrosines to form the
precursors of T3 and T4. In a recent study, mutations
of the TPO gene were found in 24% of patients with
congenital hypothyroidism and eutopic glands.9
TSHR defects. The TSHR is a 7 transmembrane
domain, G protein–coupled receptor. Mutations of the
TSHR gene are thought to be a rare cause of congenital hypothyroidism. Similar biochemical findings may
be seen in patients with pseudohypoparathyroidism
with the Albright’s hereditary osteodystrophy phenotype, which results from mutations in the GNAS gene.2
Pendred's syndrome. This uncommon cause of congenital hypothyroidism is the result of mutations in the
gene coding for pendrin, a chloride-iodide transporter
located at the apical membrane of the thyrocyte. Pendrin is involved in the presentation of iodide to TPO
for organification. Affected patients present with an
associated sensorineural hearing loss. Although thyroid
function often is normal, some patients may present
with elevated TSH and low T4. Goiter is a common feature but usually is not noted until childhood.
Central Congenital Hypothyroidism
Deficiencies of TRH or TSH are uncommon causes
of congenital hypothyroidism. Patients present with either low or inappropriately normal or near-normal TSH
and low T4. There is no goiter. Abnormalities of other
hypothalamic-pituitary hormone systems are common.
Midline CNS defects are often present. Some affected
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individuals with combined deficiencies of TSH, GH, and
prolactin have defects in one of the pituitary transcription
factors, such as PROP1 or PIT1.
Transient Congenital Hypothyroidism
The causes of transient congenital hypothyroidism
vary. Maternal factors include transplacental passage
of TSH-blocking antibodies, maternal iodine deficiency, or transplacental passage of medications taken
by mothers with Graves' disease (propylthiouracil,
meth­imazole).2 These medications may also be passed
through breast milk and lead to thyroid suppression in
neonates. Infant factors leading to transient hypothyroidism include neonatal exposure to iodine contained
in surgical scrubs and intravenous contrast agents.10
Infants with transient congenital hypothyroidism usually present with mildly elevated TSH, although some
patients with transient dysfunction may be more severely
affected. A goiter may be present in cases of iodine deficiency. It is often difficult to distinguish infants with transient congenital hypothyroidism from those with permanent congenital hypothyroidism and eutopic, normally
sized thyroid glands. Maternally derived TSH-blocking
antibodies may persist in the infant’s circulation for
several months before being cleared.
• What is the next step in evaluating this baby?
EVALUATION
All infants with abnormal newborn screens should
have venous blood samples measured for TSH and
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Congenital and Acquired Hypothyroidism
total or free T4 concentrations, and treatment with
l-thyroxine should be started. If the venous sample
confirms congenital hypothyroidism, treatment may
be continued; if the tests are normal, treatment may be
stopped and the infant monitored.
It is common to obtain imaging studies to identify
the cause of congenital hypothyroidism.2 Classically,
this has included technetium 99m (99mTc) scanning
to identify the location of any residual functioning
thyroid tissue. 99mTc scanning is cheaper, quicker, and
more readily available than iodine 123 (123I) scanning.
Many physicians have begun using ultrasonography
to separate infants with a eutopic thyroid gland from
those with thyroid ectopy and athyreosis. Patients with
transient congenital hypothyroidism usually have a
normal-appearing thyroid gland on ultrasonography
and 99mTc scanning, although in the presence of TSHblocking antibodies, decreased tracer uptake may be
noted. Patients with dyshormonogenesis or subtle
dysgenesis may have mild hyperthyrotropinemia and a
normal-appearing thyroid gland.
If an organification defect is suspected, a perchlorate
discharge test may aid in the diagnosis. Perchlorate will
displace iodide from the thyroid that is not yet bound
to thyroglobulin. In the presence of an organification
defect, an abnormally large percentage of administered
123
I will be displaced upon administration of perchlorate, typically more than 10%.11 The test may be done
at the time of diagnosis of congenital hypothyroidism
or may be deferred until later in childhood.
• How should this baby be treated?
TREATMENT
The goal of treatment is to establish normal thyroid
function as quickly as possible. Normal thyroid function
is indicated by a TSH in the normal range for age (ie,
usually < 10 mIU/mL after 2 weeks of age). The American
Academy of Pediatrics recommends a starting dose of lthyroxine of 10 to 15 mg/kg/day, with consideration of a
higher dose in infants who are more severely affected and
who have a T4 less than 5 mg/dL.12 l-Thyroxine should be
prescribed as tablets, which may be crushed and mixed
with a small amount of water. Premade solutions of lthyroxine should not be used because of the potential
loss of stability. The family should be advised that soybased infant formulas can affect l-thyroxine absorption
from the gut.13 Patients with central congenital hypothyroidism often require lower replacement doses of
thyroid hormone than those with primary congenital
hypo­thyroidism,14 and the TSH level often declines to
near zero after treatment has begun.15
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Patients should be closely monitored, with regular
assessment of thyroid function. The first assessment
should occur 2 weeks after initiation of therapy to
avoid oversuppression of TSH, particularly if a high
dose is used.16 Long-term oversuppression of TSH
may lead to craniosynostosis and advancement of the
bone age. TSH and T4 levels should be measured every
4 to 6 weeks during the first year and every 2 to 3 months
during the second and third years. After the third birthday, levels should be checked every 6 to 12 months. To
avoid the chance that the patient will outgrow his or
her dose, the TSH level should be maintained in the
mid to lower portion of the normal range and the T4
level kept in the upper half of the normal range. Following dose changes, the TSH and T4 levels should be
measured after 4 to 6 weeks to ensure that the new dose
is appropriate. As the child’s age advances, the dose of
l-thyroxine per kg of body weight gradually declines.
If diagnostic imaging showed a normally placed
gland or if no imaging studies were obtained, the possibility exists that the patient may have had transient congenital hypothyroidism. In this case, it is advisable to
temporarily stop l-thyroxine treatment after the child
is 3 years old to confirm persistent hypothyroidism.
One month later, if the TSH is elevated, treatment may
resume.12 If the TSH is normal, the patient should have
further observation off therapy and periodic monitoring of thyroid function.12
CASE 1 CONCLUSION
The baby is started on l-thyroxine at a dose of
50 mg/day (15.6 mg/kg/day). Repeat thyroid function
studies from a venous sample obtained prior to treat­
ment show that the baby’s TSH is 384 mIU/mL and free
T4 is 0.27 ng/dL. A 99mTc scan shows no tracer uptake,
consistent with athyreosis. Two weeks later, a repeat
TSH measurement is 7.7 mIU/mL. Thyroid function
studies are monitored every 4 to 6 weeks, during which
time the infant appears to grow and develop normally.
CASE 2 PRESENTATION
A 3-month-old male infant is urgently referred for
evaluation of abnormal thyroid function. The baby
was previously thought to be well until his 2-month
checkup, at which time his pediatrician noted poor
weight gain and poor linear growth, constipation, cool
dry skin, and a high-pitched cry. Thyroid function
studies showed a TSH of 89 mIU/mL and a total T4 of
3.6 mg/dL, prompting the referral.
• Why was this infant’s hypothyroidism missed on newborn screening?
Pediatric Endocrinology Volume 1, Part 2 Congenital and Acquired Hypothyroidism
NEWBORN SCREENING FOR HYPOTHYROIDISM
Two major newborn screening strategies exist. The
goal of both is to identify infants with abnormal values
and to notify the appropriate physicians, ideally within
the first 7 to 10 days of life. The first strategy, employed
by most states in the United States, is primary measurement of T4. With this approach, all infants undergo
measurement of the T4 level in a filter paper blood spot
taken at approximately 48 hours of age, and those with
a T4 level below a preset limit undergo a TSH measurement performed on the same blood spot. Many states
also include a second round of newborn screening at 2
weeks of age. The second strategy, used in some states,
involves TSH measurements in all infants, with repeat
testing including T4 concentrations in those with TSH
levels above the preset cutoff.
Each screening strategy has its advantages. Primary
T4 measurement allows detection of central hypothyroidism, in which TSH is not typically elevated. This
strategy also allows detection of cases of congenital
hypothyroidism in which T4 is low and there is a delayed rise in TSH. It may also be a more reliable tool
for detecting neonatal hyperthyroidism.12 Primary TSH
measurement has the advantage of detecting “compensated hypothyroidism,” in which T4 is normal but TSH
is elevated. TSH-based screening also offers the advantage of nonisotopic assay techniques. Primary TSH
measurement does not detect cases of TBG deficiency,
a common nonpathologic cause of abnormal thyroid
function tests.
Unfortunately, screening programs do not detect every
infant with congenital hypothyroidism. The infant in this
case was screened in a primary T4 program. Although his
T4 was above the cutoff on initial screening, he clearly developed primary hypothyroidism by age 3 months. This
infant probably has a form of thyroid dysgenesis or dyshormonogenesis that was not severe enough at birth to
be detected. Primary care providers must maintain a high
index of suspicion for missed congenital hypothyroidism
and consider the diagnosis when signs and symptoms
consistent with congenital hypothyroidism are noted.
or near-normal with early initiation of treatment and
rapid normalization of the TSH level, studies consistently show that delays in initiating l-thyroxine replacement are associated with worse motor development
and IQ.18 There does not appear to be a safe minimum
age for initiation of treatment that guarantees a normal
developmental outcome. Developmental outcomes are
also related to the degree of severity of congenital
hypo­thyroidism. Children with athyreosis tend to have
lower scores on developmental testing than those with
mild dysgenesis or dyshormonogenesis, reflecting the
degree of in utero deprivation of thyroid hormone.19 If
there is simultaneous maternal and fetal hypothyroidism, the infant with congenital hypothyroidism is at
very high risk for a poor developmental outcome. The
osseous maturation of the skeleton is sometimes used
as a marker of severity. Infants with severe congenital
hypothyroidism do not have any ossification centers in
the knee, as opposed to normal neonates or those with
mild congenital hypothyroidism. Studies evaluating outcomes following different doses of l-thyroxine demonstrate the superiority of doses in the 10 to 15 mg/kg/day
range over lower doses.20 Infants with the most severe
degree of congenital hypothyroidism may benefit from
doses in the range of 12 to 17 mg/kg/day.21
Hence, the child in this case is at high risk for developmental problems. Treatment should be initiated immediately, and the child should be referred for developmental therapies and early intervention programs.
• What is this infant’s developmental prognosis?
CASE 3 PRESENTATION
A pediatric endocrinologist is called by the neonatal
intensive care unit (NICU) to see an 8-day-old female
infant who was born at 27 weeks gestation. She is intubated and conventionally ventilated and receiving trophic feedings via a nasogastric tube. She is completing
a course of antibiotics for suspected sepsis, although all
cultures thus far have been negative. Cardiac function
has been normal, and screening ultrasonography of the
head was normal. Newborn screening was remarkable
OUTCOME OF CONGENITAL HYPOTHYROIDISM
Long-term studies of growth and physical and mental development of children with congenital hypothyroidism have shown that, with proper treatment,
outcomes are good.17 Appropriately treated patients
experience normal pubertal development and achieve
normal adult height.
Although motor and cognitive outcomes are normal
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CASE 2 CONCLUSION
l-Thyroxine treatment is started at a dose of
50 mg/day. Follow-up thyroid function studies after
2 weeks show normalization of the TSH level. T4 and
TSH levels are measured monthly, and the patient is
enrolled in an early intervention program for infants
at risk for developmental delay. His thyroid function
remains normal, and at age 12 months, he is pulling
up to a stand but not cruising. He says “mama” and
“dada” nonspecifically, consistent with possible mild
developmental delay.
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Congenital and Acquired Hypothyroidism
for a low T4 of 6.2 mg/dL. The NICU staff obtained a
venous sample on day 6 of life, which showed a TSH of
6.4 mIU/mL, a total T4 of 5.9 mg/dL, and a free T4 of
0.81 ng/dL.
• Does this baby have congenital hypothyroidism?
THYROID FUNCTION IN THE PREMATURE INFANT
In preterm infants, particularly those less than
30 weeks gestation or with a birth weight less than 1500 g,
the normal surge in TSH following delivery is blunted,
and the increases in T4 and T3 are not as great as in
term infants. The lower T4 and T3 levels are thought
to be related to the immaturity of the hypothalamicpituitary-thyroid axis. In addition, very premature infants may exhibit a variety of illnesses, including pulmonary disease, intracranial hemorrhage, inadequate nutritional status, and hemodynamic instability requiring
dopamine infusion, all of which have been associated
with decreased thyroid hormones.22 Nevertheless, TSH
levels usually are in the normal range during this time,
and in the face of primary thyroid dysfunction, most
infants, even if pre­mature, are able to mount a TSH response, although the increase in TSH may be delayed.23,24
The low levels of T4 and T3 associated with normal TSH
levels is known as hypothyroxinemia of prematurity.
Decreased T4 levels have been associated with a
variety of adverse outcomes in premature infants,
including increased mortality, cerebral palsy, and low
scores on developmental testing.25 However, causality
has not been firmly established because of the association of increased severity of illness with low thyroid
hormone concentrations. Treatment of low T4 levels in
pre­mature infants remains controversial.
CASE 3 CONCLUSION
A second set of thyroid function studies is ordered.
At 12 days of age, the baby’s TSH is 5.15 mIU/mL and
free T4 is 0.95 ng/dL. These results are interpreted as
being normal for an ill premature infant. Prior to discharge 8 weeks later, the NICU obtains additional thyroid studies, and the child’s TSH is 2.05 mIU/mL and
free T4 is 1.49 ng/dL, clearly within normal limits.
However, since age 5, height velocity has dramatically
slowed. Recent measurements show that her height is
now 3 standard deviations below the mean. During this
same interval, she has continued to gain weight, and
her current weight is in the 10th percentile. The child
was recently seen by a new pediatrician, who obtained a
TSH level, which was greater than 500 mIU/mL.
• What are the signs and symptoms of acquired hypothyroidism?
CLINICAL FEATURES
Typical signs and symptoms of hypothyroidism are
listed in Table 2. Symptoms often develop gradually,
however, and the patient or parent may not be aware
that problems exist. In patients who abruptly discontinue thyroid hormone replacement, symptoms are
usually more apparent. Rarely, patients with primary
hypothyroidism may have evidence of precocious puberty, including breast development in girls and testicular enlargement in boys, usually without significant
pubic hair growth.26 The bone age in these children
is delayed. This phenomenon is sometimes called the
Van Wyk-Grumbach syndrome. The cause is unclear
but appears to involve stimulation of gonadotropin secretion or “cross talk” between gonadotropin-releasing
hormone and TRH.
CASE 4 CONTINUED
Upon further questioning, the parents think that the
child may have been less active than other children her
age. She has had occasional complaints of constipation
but has not required regular treatment for this problem.
She has never had any neck complaints. She has had no
skin rashes or complaints of bone pain. There is a family
history of hypothyroidism in a maternal aunt.
On physical examination, the patient is a small, slightly
chubby, quiet-appearing girl without much spontaneous
movement. Her dental development is delayed; she has
all of her primary dentition. She has no palpable goiter
and no neck tenderness. She is prepubertal. Her skin and
hair are somewhat dryer than average. Her reflexes are
1+, and there is a delay in their relaxation.
• What are the causes of acquired hypothyroidism?
ACQUIRED HYPOTHYROIDISM
CASE 4 PRESENTATION
An 8-year-old girl is referred for short stature. The
child’s growth records show that she had been growing
along the 25th percentile between ages 2 and 5 years.
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ETIOLOGIES
The causes of acquired hypothyroidism (Table 3)
may be divided into primary diseases of the thyroid
gland and central causes, including diseases of the
pituitary and hypothalamus. Autoimmune thyroid disease is by far the most common cause of acquired
Pediatric Endocrinology Volume 1, Part 2 Congenital and Acquired Hypothyroidism
Table 2. Symptoms and Signs of Hypothyroidism
Table 3. Etiologies of Acquired Hypothyroidism
Symptoms
Signs
Primary
Central
Fatigue
Poor growth
Mild obesity
Autoimmune thyroid disease (chronic
lymphocytic thyroiditis)
CNS tumor
Increased sleep
Dry skin
Mental slowness
Iodine deficiency
Chemotherapy
Hair loss
Dry skin
Medications
Head trauma
CNS irradiation
Constipation
Thin, coarse hair
Lithium
Cold intolerance
Cool skin
Amiodarone
Anorexia nervosa
Depression
Sallow complexion
Iodinated radiographic contrast
Meningitis
Menstrual disturbances
Nonpitting edema
Iodine-containing surgical scrubs
Congenial malformation
Neck enlargement/compression
Voice changes
Radioactive iodine
Dysphagia
Bradycardia
Propylthiouracil
Delayed puberty
Hyporeflexia
Methimazole
Galactorrhea
Delayed relaxation of deep
tendon reflexes
Subacute thyroiditis
Decreased pulse pressure
Histiocytosis
Goiter (depending on etiology)
Hemochromatosis
Delayed tooth eruption
Birth asphyxia
Septo-optic dysplasia
Other
Histiocytosis
Granulomatous diseases
External radiation
Cystinosis
hypothyroidism in the United States, although the
most common cause worldwide is iodine deficiency.
Hashimoto’s thyroiditis is the term used to describe
goitrous autoimmune thyroid disease, which is clinically
distinguished from atrophic autoimmune thyroid disease
by the presence or absence of a goiter. The prevalence of
thyroid autoimmunity is quite high, with positive antibodies found in as many as 18% of the general population.27
Autoimmune thyroiditis is more common in females
and can occur in young children, although it is rare in
infancy. In the pediatric population, there is a clear increase in frequency in peripubertal and pubertal girls. A
family history is often present. Physical examination often
reveals a goiter, which is typically described as exhibiting
a “pebbly” texture. In the atrophic form of autoimmune
thyroiditis, a goiter is not palpable. Histologic evaluation
of the thyroid tissue reveals a lymphocytic infiltrate, and
germinal centers are sometimes present. The majority of
individuals with autoimmune thyroiditis are biochemically euthyroid. Progression to hypothyroidism usually
occurs slowly, and many individuals remain euthyroid.28
Patients with iodine deficiency present with identical
clinical symptoms and signs, including the presence of a
goiter of varying size. Patients with central hypothyroidism may present with signs and symptoms that are identical to those of patients with primary hypothyroidism,
although a goiter is not present. In addition, there may
be evidence of other pituitary hormone deficiencies.
Patients with GH deficiency may occasionally develop
central hypothyroidism after institution of GH therapy,
possibly related to increases in somatostatin levels.29
10 Hospital Physician Board Review Manual
CNS = central nervous system.
The case patient is known to have an abnormal
TSH. Hence, she clearly has primary hypothyroidism
but no goiter. She has no known history of exposure to
agents that cause hypothyroidism, and does not have
symptoms of other conditions that may cause primary
dysfunction of the thyroid, such as subacute thyroiditis
or histiocytosis. It is most likely that she has atrophic
autoimmune thyroiditis.
• What studies should be obtained in this case?
EVALUATION
Few laboratory studies are required for the typical
patient presenting with concerns about thyroid function. TSH measurement is needed, as is measurement
of the T4 level (free or total). Many clinicians prefer
to measure free T4, as this avoids errors related to
abnormalities of binding proteins. In this particular
patient, either test is adequate, as both are likely to be
low. For the patient who is not known to have a TSH
elevation, a free T4 level will help to avoid confusion
in cases of a protein-losing disease, genetic deficiency
of TBG, or TBG excess related to oral contraceptive
use. Measurement of T3 or free T3 is of little clinical use
in this setting. The autoimmune nature of the thyroid
disease can be assessed through the measurement of
anti­bodies to TPO and thyroglobulin antibodies.
Further diagnostic studies in a patient such as
this are probably not necessary. In patients with an
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Congenital and Acquired Hypothyroidism
asymmetrically enlarged gland or a palpable nodule,
imaging studies may prove useful. Ultrasonography in
patients with autoimmune thyroiditis shows a hetero­
geneous echogenicity, often with the presence of
num­erous small cysts or nodules; a dominant or large
nodule is not usually present.
Iodine deficiency is best assessed by measuring
urinary excretion of iodine. Central hypothyroidism
manifests as low levels of T4 without an appropriate
elevation in the TSH concentration. In patients with
central hypothyroidism resulting from hypothalamic
disease, the TSH may be slightly above the upper limit
of normal but is typically not as elevated as would be
expected in cases of primary hypothyroidism.
If a destructive lesion of the pituitary gland is present,
both T4 and TSH levels will be low. Other measures of
pituitary function may also be abnormal. Although it is
not currently available in the United States, TRH has
been used to assess for central hypothyroidism. Pituitary
disease is indicated by the absence of a response of TSH
to administration of TRH. Hypothalamic disease is indicated by a late and prolonged rise of TSH in response to
TRH. Primary hypothyroidism is indicated by an exaggerated TSH response to TRH.30
CASE 4 CONTINUED
Thyroid testing reveals the following: free T4,
0.4 ng/dL (normal, 0.8–2.1 ng/dL); TSH, 653 µIU/mL
(normal, 0.5–4.5 µIU/mL); TPO anti­bodies,
2599 IU/mL (normal, 0–20 IU/mL); and thyro­globulin
anti­bodies, 1953 IU/mL (normal, 0–100 IU/mL).
On the basis of the history, physical examination,
and laboratory studies, a diagnosis of atrophic auto­
immune thyroiditis is made.
• How should this patient be treated?
TREATMENT
Hypothyroidism is treated with thyroid replacement.
The l-thyroxine dose varies with age. The dose for an
individual patient is not entirely predictable based on
age and body weight alone, and monitoring of thyroid
function is essential. Treatment with other forms of
thyroid hormone, such as T3 or combined T4 and T3
therapy, is not recommended.
The goal of hormone replacement is to achieve a
TSH in the normal range. Thyroid function studies, typically including a TSH and either a total or free T4, are
obtained 4 to 6 weeks following initiation of treatment.
Because the half-life of l-thyroxine is approximately
1 week, measurement of levels before this length of
time does not allow for a steady-state l-thyroxine level
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to be reached and for the pituitary secretion of TSH to
stabilize. Following any dose change, repeat thyroid
studies should be obtained after a similar interval.
In patients with long-standing hypothyroxinemia, it
is often recommended to begin replacement therapy
with a low dose and then gradually advance to full replacement doses over a period of several months. This
is thought to minimize the risk of benign intracranial
hypertension (pseudotumor cerebri) and to delay the
rapid advancement in bone age that is usually seen in
treatment of severe, long-standing hypothyroidism.14
In cases of central hypothyroidism, TSH measurements are not helpful, and they often decline to near
zero with treatment. Measurement of total or free T4
is sufficient in such cases, and the goal should be to
obtain levels in the mid to upper range of normal for
age, without the induction of signs or symptoms of
hyperthyroidism. Patients with central hypothyroidism
often require doses that are lower than those used in
patients with primary hypothyroidism.15
A variety of medications may alter thyroid hormone
homeostasis (Table 4), and this may be reflected in
thyroid function tests. Exposure to iodine-containing
compounds may acutely decrease the iodination of
thyroid hormones and lower their serum levels, a phenomenon known as the Wolff-Chaikoff effect. This is
temporary and resolves over several days as the intrathyroidal concentration of iodide is down-regulated.
CASE 4 CONCLUSION
Treatment with l-thyroxine is initiated at a dose of
37.5 mg/day. Several weeks after beginning treatment,
the patient’s mother calls to report that her daughter
is sleeping less than before and seems much brighter.
Her energy level is clearly increased, but she seems very
“hyper” and is having behavior problems in school.
Thyroid function studies obtained 6 weeks after initiating l-thyroxine therapy show that the patient's TSH has
declined to 9.5 mIU/mL and free T4 is 1.4 ng/dL.
• What is this child’s prognosis?
LONG-TERM EFFECTS OF HYPOTHYROIDISM
Deterioration of school performance is a common
complaint in cases of newly treated long-standing hypothyroidism. It is helpful to inform families that this may
occur, so they can discuss this problem with teachers
and school administrators. Decreased school performance is usually temporary and typically resolves over
several months. Gradual escalation of l-thyroxine doses
may help reduce the severity.
Linear growth is often impaired in children with
Pediatric Endocrinology Volume 1, Part 2 11
Congenital and Acquired Hypothyroidism
Table 4. Drugs That Alter Thyroid Hormone Concentrations
Mechanism
Dopamine
Reduce TSH secretion
Somatostatin analogs
Reduce TSH secretion
Glucocorticoids
Reduce TSH secretion
Reduce TRH secretion
Decrease T4 to T3 conversion
Decrease TBG concentration
Furosemide
Decrease T4 and T3 binding to TBG
Salicylates
Decrease T4 and T3 binding to TBG
Methimazole
Decrease thyroid hormone biosynthesis
Propylthiouracil
Decrease thyroid hormone biosynthesis
Decrease T4 to T3 conversion
Propranolol
Decrease T4 to T3 conversion
Iodine excess (including
iodinated patients)
Decrease thyroid hormone synthesis and
secretion (may cause thyrotoxicosis in
iodine-deficient contrast agents)
Lithium
Decrease thyroid hormone biosynthesis
Amiodarone
Decrease T4 to T3 conversion
Induction of thyroid autoimmunity
Interferon-α
Induction of thyroid autoimmunity
Phenytoin
Increase nondeiodinative metabolism of
T4 and T3 in liver
Carbamazepine
Increase nondeiodinative metabolism of
T4 and T3 in liver
Rifampin
Increase nondeiodinative metabolism of
T4 and T3 in liver
Phenobarbitol
Increase nondeiodinative metabolism of
T4 and T3 in liver
T3 = triiodothyronine; T4 = thyroxine; TBG = thyroxine-binding globu­
lin; TRH = thyrotropin-releasing hormone; TSH = thyroid-stimulating
hormone.
Serum hormone concentration
Medication
rT3
TSH
Normal
range
FT4
T4
T3
Mild
Moderate Severe
Recovery
Figure 3. Effect of critical illness on thyroid function. Levels of
triiodothyronine (T3) are typically low, while reverse T3 (rT3) levels
are elevated. Thyroxine (T4) may be suppressed, but free T4 (FT4)
levels are usually normal except in severely ill patients. Thyroidstimulating hormone (TSH) concentrations are usually normal,
although they may rise transiently during the recovery phase.
(Adapted with permission from Brent GA, Hershman JM. Effects
of nonthyroidal illness on thyroid function tests. In: Van Mid­
dlesworth L, editor. The thyroid gland: a practical clinical treatise.
Chicago: Year Book Medical Publishers; 1986:83–110.)
it is important to obtain a baseline bone age around
the time of the initial diagnosis. It is also important to
monitor closely for the possibilities of GH deficiency,
precocious puberty, rapid progression of puberty, and
other endocrine problems that may further compromise adult height.
CASE 5 PRESENTATION
A pediatric endocrinologist is asked to see an
11-year-old boy who has been in the pediatric intensive
care unit (PICU) with meningococcal septic shock
without meningitis for 1 week. The patient is intubated
and mechanically ventilated for acute respiratory distress syndrome. He is receiving dopamine for blood
pressure support. Thyroid function studies ordered by
the PICU staff revealed a low total T4 of 4.1 mg/dL and
a TSH of 0.95 mIU/mL.
long-standing hypothyroidism, as in this case patient.
The short stature is usually associated with a major delay
in bone age, initially suggesting that the child’s future
growth potential is good.31 Typically, a very rapid catchup growth is seen following institution of l-thyroxine
treatment. However, the rate of skeletal maturation is
often excessive, and long-term height gain may be limited. Although it is thought that gradual institution of
treatment may slow the bone age advancement, there is
little evidence to support this. Ultimately, early diagnosis
is the best way to ensure that adult height will not be
impaired.
Excessively high doses of thyroid hormone can
also cause rapid advancement in skeletal maturation.
Although height velocity may also be increased, the
unduly rapid bone age advancement may limit final
adult height. Because of the potential for compromised
adult height in patients with acquired hypothyroidism,
NONTHYROIDAL ILLNESS SYNDROME
Nonthyroidal illness syndrome, also known as sick euthyroid syndrome, is a poorly understood response to severe
illness. It is manifested biochemically by a suppression of
total and free T4 and total T3 levels without an increase in
TSH levels (Figure 3). The pathogenesis of sick euthroid
syndrome is marked by an alteration of the activity of D1,
leading to lower rates of synthesis of T3 and decreases in
12 Hospital Physician Board Review Manual
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• Does this boy have central hypothyroidism?
Congenital and Acquired Hypothyroidism
degradation of rT3, leading to elevated concentrations
of rT3. In severely ill individuals, the changes may occur
within a day. With recovery, there may be a transient increase in the TSH until the T4 and T3 levels return to normal. In critically ill patients, the use of dopamine or high
doses of glucocorticoids often causes suppression of TSH
levels that may lead to further reductions in T4 and T3.
Although there is a clear relationship between the severity of sick euthyroid syndrome and outcome measures
such as mortality, a causal link between the two has not
been established. The question of whether sick euthyroid
syndrome is an adaptive response or one that is at least
partly maladaptive remains unanswered. Treatment with
thyroid hormone has not proved beneficial in studies of
critically ill adults and is not recommended.
CASE 5 CONCLUSION
The specialist informs the PICU team that the patient
probably has sick euthyroid syndrome. The physician
requests a total T3 and rT3 and recommends that the
clinical team monitor the boy’s thyroid function tests. His
total T3 is 85 ng/dL (normal, 119–218 ng/dL), and his
rT3 is 262 ng/dL (normal, 10–50 ng/dL). He begins to
make a gradual recovery and is successfully weaned off
pressors and the ventilator. Ten days after the initial consult, the patient’s TSH is slightly elevated at 8.2 mIU/mL,
and his total T4 is up to 7.8 mg/dL. His free T4 is normal at
0.9 ng/dL, and his total T3 is 140 ng/dL. One week later,
his TSH, total T4, and free T4 are all normal.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
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Pediatric Endocrinology Volume 1, Part 2 13