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Chapter 565 Hypothyroidism 2665

Chapter 565
Hypothyroidism
Stephen H. LaFranchi and
Stephen A. Huang

Hypothyroidism results from deficient production of thyroid hormone,


either from a defect in the gland itself (primary hypothyroidism) or a
result of reduced thyroid-stimulating hormone (TSH) stimulation
(central or hypopituitary hypothyroidism; Table 565-1). The disorder
may be manifested from birth (congenital) or acquired. When symp-
toms appear after a period of apparently normal thyroid function, the
disorder may be truly acquired or might only appear so as a result of
one of a variety of congenital defects in which the manifestation of the
deficiency is delayed.

CONGENITAL HYPOTHYROIDISM
Most cases of congenital hypothyroidism are not hereditary and result
from thyroid dysgenesis. Some cases are familial; these are usually
caused by one of the inborn errors of thyroid hormone synthesis (dys-
hormonogenesis) and may be associated with a goiter. Most infants
with congenital hypothyroidism are detected by newborn screening
programs in the 1st few wk after birth, before obvious clinical symp-
toms and signs develop. In infants born in areas with no screening
program, severe cases manifest features in the 1st few wk of life, but in
cases of milder deficiency, manifestations may be delayed for months.

Epidemiology
The prevalence of congenital hypothyroidism based on nationwide
programs for neonatal screening was initially reported at 1 in 4,000
infants worldwide. Over the last 2 decades, the prevalence has dropped
to 1 in 2,000, likely the result of detection of milder cases of hypothy-
roidism. Studies from the United States report that the prevalence is
lower in black Americans and higher in Asian-Americans and Pacific
Islanders, Hispanics, and Native Americans as compared to white
babies.

Etiology
See Table 565-1.

Primary Hypothyroidism
Thyroid Dysgenesis. Some form of thyroid dysgenesis
(aplasia, hypoplasia, or an ectopic gland) is the most common cause
of permanent congenital hypothyroidism, accounting for 80-85% of
cases. In approximately 33% of cases of dysgenesis, even sensitive
radionuclide scans can find no remnants of thyroid tissue (aplasia). In
the other 66% of infants, rudiments of thyroid tissue are found in an
ectopic location, anywhere from the base of the tongue (lingual
thyroid) to the normal position in the neck (hypoplasia). Thyroid dys-
genesis has a 2:1 female:male ratio.
The cause of thyroid dysgenesis is unknown in most cases. Thyroid
dysgenesis occurs sporadically, but familial cases occasionally have
been reported. The finding that thyroid developmental anomalies, such
as thyroglossal duct cysts and hemiagenesis, are present in 8-10% of
1st-degree relatives of infants with thyroid dysgenesis supports an
underlying genetic component.
Mutations in several transcription factors important for thyroid
morphogenesis and differentiation (including TTF-1/NKX2.1, TTF-2
[also termed FOXE1], and PAX8) are monogenic causes of approxi-
mately 2% of the cases of thyroid dysgenesis. In addition, genetic
2666 Part XXVI The Endocrine System

some motherinfant pairs, there is little evidence of their pathogenic-


Table 565-1 Etiologic Classification of Congenital ity. The demonstration of thyroid growth-blocking and cytotoxic anti-
Hypothyroidism bodies in some infants with thyroid dysgenesis, as well as in their
PRIMARY HYPOTHYROIDISM mothers, suggests a more likely pathogenetic mechanism.
Defect of fetal thyroid development (dysgenesis) Defective Synthesis of Thyroxine (Dyshormonogen-
Aplasia esis). A variety of defects in the biosynthesis of thyroid hormone can
Hypoplasia result in congenital hypothyroidism; these account for 15% of cases
Ectopia detected by neonatal screening programs (1 in 30,000-50,000 live births).
Defect in thyroid hormone synthesis (dyshormonogenesis) These defects are transmitted in an autosomal recessive manner. A goiter
Iodide transport defect from blood into follicular cell: mutation in is almost always present. When the defect is incomplete, compensation
sodiumiodide symporter gene occurs, and onset of hypothyroidism may be delayed for years.
Defective iodide transport from follicular cell into colloid:
mutation in Pendrin transport protein
Defect of Iodide Transport. Defect of iodide transport is
Thyroid organification, or coupling defect: mutation in thyroid rare and involves mutations in the sodiumiodide symporter. Among
peroxidase gene the several cases now reported, it has been found in 9 related infants of
Defects in H2O2 generation: mutations in DUOXA2 maturation the Hutterite sect, and approximately 50% of the cases are from Japan.
factor or DUOX2 gene Consanguinity is a factor in approximately 30% of the families.
Thyroglobulin synthesis defect: mutation in thyroglobulin gene In the past, clinical hypothyroidism, with or without a goiter, often
Deiodination defect: mutation in DEHAL1 gene developed in the 1st few months of life; the condition has been detected
TSH unresponsiveness in neonatal screening programs. In Japan, however, untreated patients
Mutation in TSH receptor acquire goiter and hypothyroidism after 10yr of age, perhaps because
Defective TSH signaling: Gs mutation (e.g., type IA
of the very high iodine content (often 19mg/24hr) of the Japanese diet.
pseudohypoparathyroidism)
Defect in thyroid hormone transport: mutation in monocarboxylate The energy-dependent mechanisms for concentrating iodide are
transporter 8 (MCT8) gene defective in the thyroid and salivary glands. In contrast to other defects
Resistance to thyroid hormone of thyroid hormone synthesis, uptake of radioiodine and pertechnetate
Maternal antibodies: thyrotropin receptorblocking antibody is low; a reduced saliva:serum ratio of 123I will support the diagnosis,
(TRBAb, measured as thyrotropin-binding inhibitor confirmed by finding a mutation in the sodiumiodide symporter
immunoglobulin) gene. This condition responds to treatment with large doses of potas-
Iodine deficiency (endemic goiter) sium iodide, but treatment with l-thyroxine is preferable.
Maternal medications Thyroid Peroxidase Defects of Organification and
Iodides, amiodarone
Propylthiouracil, methimazole
Coupling. Thyroid peroxidase defects of organification and cou-
Radioiodine pling are the most common of the thyroxine (T4) synthetic defects.
After iodide is trapped by the thyroid, it is rapidly oxidized to
CENTRAL (HYPOPITUITARY) HYPOTHYROIDISM reactive iodine, which is then incorporated into tyrosine units on
Isolated TSH deficiency: mutation in TSH -subunit gene thyroglobulin. This process requires generation of H2O2, thyroid per-
(depending on mutation, TSH may be undetectable, measurable oxidase, and hematin (an enzyme cofactor); defects can involve each
[normal], or elevated)
Isolated TRH deficiency: mutation in TRH gene
of these components, and there is considerable clinical and biochemi-
TRH unresponsiveness: mutation in TRH receptor gene cal heterogeneity. In the Dutch neonatal screening program, 23 infants
Multiple congenital pituitary hormone deficiencies (e.g., septooptic were found with a complete organification defect (1 in 60,000 live
dysplasia) births), but its prevalence in other areas is unknown. A characteristic
PIT-1 mutations finding in all patients with this defect is a marked discharge of thyroid
Deficiency of TSH radioactivity when perchlorate or thiocyanate is administered 2hr
Deficiency of growth hormone after administration of a test dose of radioiodine. In these patients,
Deficiency of prolactin perchlorate discharges 40-90% of radioiodine compared with <10% in
PROP-1 mutations normal persons. Several mutations in the thyroid peroxidase gene have
Deficiency of TSH
Deficiency of growth hormone
been reported in children with congenital hypothyroidism.
Deficiency of prolactin Dual oxidase maturation factor 2 (DUOXA2) is required to express
Deficiency of LH DUOX2 enzymatic activity, which is required for H2O2 generation, a
Deficiency of FSH crucial step in iodide oxidation. Biallelic DUOXA2 mutations produce
Deficiency of ACTH permanent congenital hypothyroidism, whereas monoallelic muta-
tions are associated with transient hypothyroidism. DUOX2 mutations
ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; LH,
luteinizing hormone; TRH, thyroid-releasing hormone; TSH, thyroid-stimulating can also cause permanent or transient congenital hypothyroidism.
hormone. DUOX2 mutations are relatively common, present in 30% of cases of
apparent dyshormonogenesis, whereas DUOXA2 mutations are rela-
tively rare, present in 2% of such cases.
defects leading to absent or ineffective thyrotropin (TSH) receptor Pendred syndrome is an autosomal recessive disorder caused by a
binding or signaling have been described. mutation in the chlorideiodide transport protein common to the
The transcription factor TTF-1/NKX2.1 is expressed in the thyroid, thyroid gland and the cochlea. Pendred syndrome is comprised of
lung, and central nervous system. Mutations in TTF-1/NKX2.1 are sensorineural deafness and goiter; it is the most common cause of
reported to result in congenital hypothyroidism, respiratory distress, syndromic deafness. Pendrin allows transport of iodide from the fol-
and persistent neurologic problems, including chorea and ataxia, licular cell into the colloid where it undergoes organification to iodine
despite early thyroid hormone treatment. NKX2.5 is expressed in the and incorporation into the tyrosine residues on thyroglobulin. Patients
thyroid and heart. Mutations in NKX2.5 are associated with congenital with a mutation in the pendrin gene have impaired iodide organifica-
hypothyroidism and cardiac malformations. PAX-8 is expressed in the tion and a positive perchlorate discharge.
thyroid and kidney. Mutations in PAX-8 are associated with congenital Defects of Thyroglobulin Synthesis. Defects of thyro-
hypothyroidism and kidney and ureteral malformations. globulin synthesis are a heterogeneous group of disorders character-
The common finding of thyroid dysgenesis confined to only 1 of a ized by goiter, elevated serum TSH, low T4 levels, and absent or low
pair of monozygotic twins suggests the operation of a deleterious factor levels of thyroglobulin. It has been reported in approximately 100
during intrauterine life. Maternal antithyroid antibodies might be that patients. Molecular defects, primarily point mutations, have been
factor. Although thyroid peroxidase antibodies have been detected in described in several patients.
Chapter 565 Hypothyroidism 2667

Defects in Deiodination. Monoiodotyrosine and diiodoty- Two infants of consanguineous matings are known to have an auto-
rosine released from thyroglobulin are normally deiodinated within somal recessive form of thyroid resistance. These infants had manifes-
the thyroid or in peripheral tissues by a deiodinase. The liberated tations of hypothyroidism early in life, and genetic studies revealed a
iodine is recycled in the synthesis of thyroid hormones. The DEHAL1 major deletion of the -thyroid receptor in 1 of them. The resistance
gene encodes iodotyrosine deiodinase in the thyroid. DEHAL1 muta- appears to be more severe in this form of the entity.
tions are relatively rare; patients with deiodinase deficiency experience Some patients have greater resistance to thyroid hormone in the
severe iodine loss from the constant urinary excretion of nondeiodin- pituitary gland as compared to peripheral tissues. Because the periph-
ated tyrosines, leading to hormonal deficiency and goiter. The deiodin- eral tissues are not resistant to thyroid hormones, the patient has a
ation defect may be limited to thyroid tissue only or to peripheral tissue goiter and manifestations of hyperthyroidism. The laboratory findings
only, or it may be universal. are the same as those seen with generalized thyroid hormone resistance.
Thyrotropin Hormone Unresponsiveness. A mutation This condition must be differentiated from a pituitary TSH-secreting
in the TSH receptor gene is a relatively uncommon autosomal recessive tumor. Different treatments, including d-thyroxine, triiodothyroacetic
cause of congenital hypothyroidism. Both homozygous and compound acid, and tetraiodothyroacetic acid, have been successful in some
heterozygous mutations in the TSH receptor gene have been reported. patients. Bromocriptine administration, which interferes with TSH
Infants with a severe defect have elevated TSH levels and will be secretion, was reported to be successful in another patient. Whether
detected by newborn screening, whereas other patients with a mild isolated pituitary resistance to thyroid hormone exists as a distinct
defect remain euthyroid without treatment. A study of infants with entity is controversial; it may be a variant of generalized resistance to
congenital hypothyroidism detected by newborn screening from Tokyo thyroid hormone with varying tissue responsiveness.
reported TSH receptor mutations in 4.3% of patients (1 in 118,000 live Although the majority of patients with resistance have mutations in
births), with a founder mutation (p.R450H) accounting for 70% of gene the thyroid hormone receptor gene, a child with a mutation in the
defects. thyroid hormone receptor gene has been reported. This patient pre-
Mild congenital hypothyroidism has been detected in newborn sented at age 6yr with growth retardation, delayed development, and
infants who subsequently proved to have type Ia pseudohypoparathy- constipation. Genetic analysis showed a heterozygous nonsense muta-
roidism. The molecular cause of resistance to TSH in these patients is tion in the thyroid hormone receptor gene that, like gene muta-
the generalized impairment of cyclic adenosine monophosphate acti- tions, inhibited wild-type receptor action in a dominant negative
vation caused by genetic defect of the subunit of the guanine nucleo- manner.
tide regulatory protein Gs (see Chapter 572). Thyrotropin Receptor-Blocking Antibody. Maternal
Defects in Thyroid Hormone Transport. Passage of TSH receptor-blocking antibody (TRBAb) is an unusual cause of tran-
thyroid hormone into the cell is facilitated by plasma membrane trans- sitory congenital hypothyroidism. Transplacental passage of maternal
porters. A mutation in one such transporter gene, monocarboxylate TRBAb inhibits binding of TSH to its receptor in the neonate. Maternal
transporter 8 (MCT8), located on the X chromosome (Allan-Herndon- TRBAb accounts for 2% of cases detected by neonatal screening pro-
Dudley syndrome), has now been reported in multiple patients. The grams (1 in 50,000-100,000 infants). It should be suspected whenever
defective transporter impairs passage of T4 and triiodothyronine (T3) there is a history of maternal autoimmune thyroid disease, including
into cells; this syndrome is characterized by elevated serum T3 levels, Hashimoto thyroiditis or Graves disease, maternal hypothyroidism on
low T4 levels, and normal or mildly elevated TSH levels. Neurologic replacement therapy, or recurrent congenital hypothyroidism of a tran-
manifestations include severe developmental delay, reduced muscle sient nature in previous siblings. In these situations, maternal levels of
mass, initial hypotonia that evolves into spastic paraplegia, dysarthria, TRBAb (measured as thyrotropin-binding inhibitor immunoglobulin)
and athetoid movements. should be determined during pregnancy. Affected infants and their
mothers also can have thyrotropin receptorstimulating antibodies
Resistance to Thyroid Hormone and thyroid peroxidase antibodies. Technetium pertechnetate and 123I
This autosomal dominant disorder is caused by mutations in the scans might fail to detect any thyroid tissue, mimicking thyroid agen-
thyroid hormone receptor. Most patients have a goiter, and levels of T4, esis, but ultrasonography will show a thyroid gland. After the condition
T3, free T4, and free T3 are elevated. These findings often have led to remits, a normal thyroid gland is demonstrable by scanning following
the erroneous diagnosis of Graves disease, although most affected discontinuation of replacement therapy. The half-life of the antibody
patients are clinically euthyroid. The unresponsiveness can vary among is 21 days, and remission of the hypothyroidism occurs in approxi-
tissues. There may be subtle clinical features of hypothyroidism, mately 3-6mo. Correct diagnosis of this cause of congenital hypothy-
including developmental delay, growth retardation, and delayed skel- roidism prevents unnecessary protracted treatment, alerts the clinician
etal maturation. On the other hand, there may be clinical features to possible recurrences in future pregnancies, and allows a favorable
compatible with hyperthyroidism, such as tachycardia and hyperre- prognosis.
flexia. It is presumed that these patients have varying tissue resistance Radioiodine Administration. Hypothyroidism can occur as
to thyroid hormone. One neurologic manifestation is an increased a result of inadvertent administration of radioiodine during pregnancy
association of attention-deficit/hyperactivity disorder; the converse is for treatment of Graves disease or cancer of the thyroid. The fetal
not true because patients with attention-deficit/hyperactivity disorder thyroid is capable of trapping iodide by 70-75 days of gestation. When-
do not have an increased risk of thyroid hormone resistance. ever radioiodine is administered to a woman of childbearing age, a
TSH levels are diagnostic in that they are not suppressed as in Graves pregnancy test must be performed before a therapeutic dose of 131I is
disease but instead are moderately elevated or normal but inappropri- given, regardless of the menstrual history or putative history of con-
ate for the levels of T4 and T3. The failure of TSH suppression indicates traception. Administration of radioactive iodine to lactating women
that the resistance is generalized and affects the pituitary gland as well also is contraindicated because it is readily excreted in milk.
as peripheral tissues. More than 40 distinct point mutations in the Iodine Exposure. Congenital hypothyroidism can result from
hormone-binding domain of the -thyroid receptor are identified. Dif- fetal exposure to excessive iodides. Perinatal exposure can occur with
ferent phenotypes do not correlate with genotypes. The same mutation the use of iodine antiseptic to prepare the skin for caesarian section or
has been observed in patients with generalized or isolated pituitary painting of the cervix before delivery. It has also been reported in
resistance, even in different members of the same family. A child infants born to mothers who consumed large amounts of iodine daily
homozygous for the receptor mutation showed unusually severe resis- (up to 12mg) in the form of nutritional supplements and in mothers
tance. These cases support the dominant negative effect of mutant in Japan who consumed large quantities of iodine-rich seaweed. These
receptors, in which the mutant receptor protein inhibits normal recep- conditions are transitory and must not be mistaken for the other forms
tor action in heterozygotes. Elevated levels of T4 on neonatal thyroid of hypothyroidism. In the neonate, topical iodine-containing antisep-
screening should suggest the possibility of this diagnosis. No treatment tics used in nurseries and by surgeons can also cause transient con-
is usually required unless growth and skeletal retardation are present. genital hypothyroidism, especially in low-birthweight infants, and can
2668 Part XXVI The Endocrine System

lead to abnormal results on neonatal screening tests. In older children, often normal. Preterm babies also have a higher incidence of delayed
the usual sources of iodides are proprietary preparations used to treat TSH elevation and apparent transient primary hypothyroidism. Pre-
asthma. In a few instances, the cause of hypothyroidism was amioda- mature infants of <28wk of gestation might have problems resulting
rone, an antiarrhythmic drug with high iodine content. In most of from a combination of immaturity of the hypothalamic-pituitary-
these instances, goiter is present (see Chapter 567). thyroid axis and loss of the maternal contribution of thyroid hormone
Iodine-Deficiency Endemic Goiter. See Chapter 567.3. and so may be candidates for temporary thyroid hormone replace-
Iodine deficiency or endemic goiter is the most common cause of ment; further studies are needed.
congenital hypothyroidism worldwide. The recommended intake of
iodine in adults is 150g daily, increasing to 250g daily during Clinical Manifestations
pregnancy to allow for fetal iodine requirements. Despite efforts at Most infants with congenital hypothyroidism are asymptomatic at
universal iodization of salt in many countries, economic, political, and birth, even if there is complete agenesis of the thyroid gland. This situ-
practical obstacles make achieving this objective difficult. While the ation is attributed to partial transplacental passage of maternal T4,
U.S. population is iodine-sufficient as a whole, approximately 15% of which provides fetal levels that are approximately 33% of normal at
women of reproductive age fall into the iodine-deficient category. Bor- birth. Despite this maternal contribution of T4, hypothyroid infants
derline iodine deficiency is more likely to cause problems in preterm still have a low serum T4 and elevated TSH level and so will be identi-
infants who depend on a maternal source of iodine for normal thyroid fied by newborn screening programs.
hormone production. The clinician depends on neonatal screening tests for the diagnosis of
congenital hypothyroidism. Some babies escape newborn screening,
Central (Hypopituitary) Hypothyroidism and laboratory errors occur, so awareness of early symptoms and signs
Thyrotropin and Thyrotropin-Releasing Hormone must be maintained. Congenital hypothyroidism caused by thyroid
Deficiency. Deficiency of TSH and central hypothyroidism can dysgenesis, the most common etiology, is twice as common in girls as
occur in any of the conditions associated with developmental defects in boys. Before neonatal screening programs, congenital hypothyroid-
of the pituitary or hypothalamus (see Chapter 557). More often in these ism was rarely recognized in the newborn because the signs and symp-
conditions, the deficiency of TSH is secondary to a deficiency of toms are usually not sufficiently developed. It can be suspected and the
thyrotropin-releasing hormone (TRH). TSH-deficient hypothyroidism diagnosis established during the early weeks of life if the initial, but
is found in 1 in 30,000-50,000 infants; most screening programs are less characteristic, manifestations are recognized. Birthweight and
designed to detect primary hypothyroidism, so most of these cases are length are normal, but head size may be slightly increased because of
not detected by neonatal thyroid screening. The majority of affected myxedema of the brain. The anterior and posterior fontanels are open
infants have multiple pituitary deficiencies and present with hypogly- widely; observation of this sign at birth can serve as an initial clue to
cemia, persistent jaundice, and micropenis in association with sep- the early recognition of congenital hypothyroidism. Only 3% of normal
tooptic dysplasia, midline cleft lip, midface hypoplasia, and other newborn infants have a posterior fontanel larger than 0.5cm. Prolon
midline facial anomalies. gation of physiologic jaundice, caused by delayed maturation of
Mutations in genes coding for transcription factors essential to glucuronide conjugation, may be the earliest sign. Feeding difficulties,
pituitary development, cell type differentiation, and hormone synthe- especially sluggishness, lack of interest, somnolence, and choking
sis are associated with congenital TSH deficiency. PIT-1 mutations spells during nursing, are often present during the 1st mo of life. Respi-
include TSH deficiency associated with growth hormone and prolac- ratory difficulties, partly caused by the large tongue, include apneic
tin deficiency. Patients with PROP-1 mutations (prophet of pit-1) episodes, noisy respirations, and nasal obstruction. Some infants may
have not only TSH, growth hormone, and prolactin deficiency but develop respiratory distress syndrome. Affected infants cry little, sleep
also luteinizing hormone and follicle-stimulating hormone defi- much, have poor appetites, and are generally sluggish. There may be
ciency and variable adrenocorticotropic hormone deficiency. HESX1 constipation that does not usually respond to treatment. The abdomen
mutations are associated with TSH, growth hormone, prolactin, and is large, and an umbilical hernia is usually present. The temperature is
adrenocorticotropic hormone deficiencies and are found in some subnormal, often <35C (95F), and the skin, particularly that of the
patients with optic nerve hypoplasia (septooptic dysplasia syndrome; extremities, may be cold and mottled. Edema of the genitals and
see Chapter 591). extremities may be present. The pulse is slow, and heart murmurs,
Isolated deficiency of TSH is a rare autosomal recessive disorder that cardiomegaly, and asymptomatic pericardial effusion are common.
has been reported in several sibships. DNA studies in affected family Macrocytic anemia is often present and is refractory to treatment with
members reveal defects in the TSH -subunit gene, including point hematinics. Because symptoms appear gradually, the clinical diagnosis
mutations, frame shifts causing a stop codon, and splice-site mutations. is often delayed.
Depending on the specific mutation, serum TSH levels may be unde- Approximately 10% of infants with congenital hypothyroidism have
tectable, measureable, or elevated. The diagnosis is usually delayed associated congenital anomalies. Cardiac anomalies are most common,
because the serum TSH level is not elevated in most cases, and so such but anomalies of the nervous system and eye have also been reported.
patients are not detected by newborn screening programs. Infants with congenital hypothyroidism may have associated hearing
Thyrotropin-Releasing Hormone Receptor Abnor- loss. As noted under Etiology above, specific mutations in genes
mality. Mutations in the TRH receptor gene, a rare cause of con- involved in thyroid gland development result in syndromic congeni-
genital central hypothyroidism, have now been reported in a few tal hypothyroidism. Mutations in NKX2.1 (TTF-1), present in the
families. This condition, which results in isolated TSH deficiency and thyroid gland, lungs, and brain, are characterized by congenital hypo-
hypothyroidism, was suspected because of failure of both TSH and thyroidism, respiratory distress syndrome, and ataxia, or even choreo-
prolactin to respond to TRH stimulation. athetosis. Mutations in NKX2.5 result in congenital hypothyroidism
and associated congenital heart defects. Mutations in TTF-2, present
Thyroid Function in Preterm Babies in the thyroid gland, palate, and hair, include congenital hypothyroid-
Postnatal thyroid function in preterm babies is qualitatively similar but ism, cleft palate, and spiky hair. Mutations in PAX-8, present in the
quantitatively reduced compared with that of term infants. The cord thyroid gland and kidneys, present with congenital hypothyroidism
serum T4 is decreased in proportion to gestational age and birthweight. and genitourinary anomalies, including renal agenesis.
The postnatal TSH surge is reduced, and the more premature, very- If congenital hypothyroidism goes undetected and untreated, these
low-birthweight infants with complications of prematurity, such as manifestations progress. Retardation of physical and mental develop-
respiratory distress syndrome, actually experience a decrease in serum ment becomes greater during the following months, and by 3-6mo of
T4 in the 1st wk of life. As these complications resolve, the serum T4 age the clinical picture is fully developed (Fig. 565-1). When there is
gradually increases so that generally by 6wk of life it enters the T4 only partial deficiency of thyroid hormone, the symptoms may be
range seen in term infants. Serum free T4 concentrations seem less milder, the syndrome incomplete, and the onset delayed. Although
affected, and when measured by equilibrium dialysis, these levels are breast milk contains significant amounts of thyroid hormones,
Chapter 565 Hypothyroidism 2669

A B
Figure 565-1 Congenital hypothyroidism in an infant 6mo of age. The infant ate poorly in the neonatal period and was constipated. She had
a persistent nasal discharge and a large tongue; she was very lethargic and had no social smile and no head control. A, Notice the puffy face,
dull expression, and hirsute forehead. Tests revealed a negligible uptake of radioiodine. Osseous development was that of a newborn. B, Four
mo after treatment, note the decreased puffiness of the face, the decreased hirsutism of the forehead, and the alert appearance.

particularly T3, it is inadequate to protect the breastfed infant who has at the base of the tongue or in the midline of the neck, usually at the
congenital hypothyroidism, and it has no effect on neonatal thyroid level of the hyoid. Occasionally, ectopia is associated with thyroglossal
screening tests. duct cysts. It can occur in siblings. Surgical removal of ectopic thyroid
The childs growth will be stunted, the extremities are short, and the tissue from a euthyroid patient usually results in hypothyroidism,
head size is normal or even increased. The anterior fontanel is large because most such patients have no other thyroid tissue.
and the posterior fontanel may remain open. The eyes appear far apart,
and the bridge of the broad nose is depressed. The palpebral fissures Laboratory Findings
are narrow and the eyelids are swollen. The mouth is kept open, and In developed countries, infants with congenital hypothyroidism are
the thick, broad tongue protrudes. Dentition will be delayed. The neck identified by newborn screening programs. Blood obtained by heel-
is short and thick, and there may be deposits of fat above the clavicles prick between 2 and 5 days of life is placed on a filter paper card and
and between the neck and shoulders. The hands are broad and the sent to a central screening laboratory. The early approach to newborn
fingers are short. The skin is dry and scaly, and there is little perspira- screening in North America and Europe began with measure of levels
tion. Myxedema is manifested, particularly in the skin of the eyelids, of T4, followed by measurement of TSH when T4 is low. This approach
the back of the hands, and the external genitals. The skin shows general identifies infants with primary hypothyroidism, some with central or
pallor with a sallow complexion. Carotenemia can cause a yellow dis- hypopituitary hypothyroidism, and infants with a delayed elevation in
coloration of the skin, but the sclerae remain white. The scalp is thick- TSH levels. Over time, many neonatal screening programs in North
ened, and the hair is coarse, brittle, and scanty. The hairline reaches far America, Europe, and elsewhere in the world have switched to an
down on the forehead, which usually appears wrinkled, especially initial TSH measurement. This approach will detect infants with
when the infant cries. primary hypothyroidism and infants with milder, subclinical hypothy-
Development is usually delayed. Hypothyroid infants appear lethar- roidism (normal T4, elevated TSH), but it may not detect infants with
gic and are late in learning to sit and stand. The voice is hoarse, and delayed TSH elevation or with central or hypopituitary hypothyroid-
they do not learn to talk. The degree of physical and intellectual delay ism. With any of these tests, special care should be given to the normal
increases with age. Sexual maturation may also be delayed or might range of values for age of the patient, particularly in the 1st weeks of
not take place at all. life (Table 565-2). Regardless of the approach used for screening, some
The muscles are usually hypotonic, but in rare instances generalized infants escape detection because of technical or human errors; clini-
muscular pseudohypertrophy occurs (Kocher-Debr-Smlaigne cians must maintain their vigilance for clinical manifestations of
syndrome). Affected older children can have an athletic appearance hypothyroidism.
because of pseudohypertrophy, particularly in the calf muscles. Its Serum levels of T4 or free T4 are low; serum levels of T3 may be
pathogenesis is unknown; nonspecific histochemical and ultrastruc- normal and are not helpful in the diagnosis. If the defect is primarily
tural changes seen on muscle biopsy return to normal with treatment. in the thyroid, levels of TSH are elevated, often to >100mU/L. Serum
Boys are more prone to development of the syndrome, which has been levels of thyroglobulin are usually low in infants with thyroid agenesis
observed in siblings born from a consanguineous mating. Affected or defects of thyroglobulin synthesis or secretion, whereas they are
patients have hypothyroidism of longer duration and severity. elevated with ectopic glands and other inborn errors of T4 synthesis,
Some infants with mild congenital hypothyroidism have normal but there is a wide overlap of ranges.
thyroid function at birth and so are not identified by newborn screen- Special attention should be paid to identical twins; in several reported
ing programs. In particular, some children with ectopic thyroid tissue cases, neonatal screening failed to detect the affected twin with hypo-
(lingual, sublingual, subhyoid) produce adequate amounts of thyroid thyroidism, and the diagnosis was not made until the infants were
hormone for many years, or it eventually fails in early childhood. 4-5mo of age. In these cases, transfusion of euthyroid blood from the
Affected children come to clinical attention because of a growing mass unaffected twin normalized the serum levels of T4 and TSH in the
2670 Part XXVI The Endocrine System

Table 565-2 Thyroid Function Tests


AGE U.S. REFERENCE VALUE CONVERSION FACTOR SI REFERENCE VALUE
THYROID THYROGLOBULIN, SERUM
Cord blood 14.7-101.1ng/mL 1 14.7-101.1g/L
Birth to 35mo 10.6-92.0ng/mL 1 10.6-92.0g/L
3-11yr 5.6-41.9ng/mL 1 5.6-41.9g/L
12-17yr 2.7-21.9ng/mL 1 2.7-21.9g/L
THYROID-STIMULATING HORMONE, SERUM
Premature Infants (28-36wk)
1st wk of life 0.7-27.0mIU/L 1 0.7-27.0mIU/L
Term Infants
Birth to 4 days 1.0-17.6mIU/L 1 1.0-17.6mIU/L
2-20wk 0.6-5.6mIU/L 1 0.6-5.6mIU/L
5mo-20yr 0.5-5.5mIU/L 1 0.5-5.5mIU/L
THYROXINE-BINDING GLOBULIN, SERUM
Cord blood 1.4-9.4mg/dL 10 14-94mg/L
1-4wk 1.0-9.0mg/dL 10 10-90mg/L
1-12mo 2.0-7.6mg/dL 10 20-76mg/L
1-5yr 2.9-5.4mg/dL 10 29-54mg/L
5-10yr 2.5-5.0mg/dL 10 25-50mg/L
10-15yr 2.1-4.6mg/dL 10 21-46mg/L
Adult 1.5-3.4mg/dL 10 15-34mg/L
THYROXINE, TOTAL, SERUM
Full-Term Infants
1-3 days 8.2-19.9g/dL 12.9 106-256nmol/L
1wk 6.0-15.9g/dL 12.9 77-205nmol/L
1-12mo 6.1-14.9g/dL 12.9 79-192nmol/L
Prepubertal Children
1-3yr 6.8-13.5g/dL 12.9 88-174nmol/L
3-10yr 5.5-12.8g/dL 12.9 71-165nmol/L
Pubertal Children and Adults
>10yr 4.2-13.0g/dL 12.9 54-167nmol/L
THYROXINE, FREE, SERUM
Full-term (3 days) 2.0-4.9ng/dL 12.9 26-63.1pmol/L
Infants 0.9-2.6ng/dL 12.9 12-33pmol/L
Prepubertal children 0.8-2.2ng/dL 12.9 10-28pmol/L
Pubertal children and adults 0.8-2.3ng/dL 12.9 10-30pmol/L
THYROXINE, TOTAL, WHOLE BLOOD
Newborn screen (filter paper) 6.2-22g/dL 12.9 80-283nmol/L
TRIIODOTHYRONINE, FREE, SERUM
Cord blood 20-240pg/dL 0.01536 0.3-0.7pmol/L
1-3 days 180-760pg/dL 0.01536 2.8-11.7pmol/L
1-5yr 185-770pg/dL 0.01536 2.8-11.8pmol/L
5-10yr 215-700pg/dL 0.01536 3.3-10.7pmol/L
10-15yr 230-650pg/dL 0.01536 3.5-10.0pmol/L
>15yr 210-440pg/dL 0.01536 3.2-6.8pmol/L
TRIIODOTHYRONINE RESIN UPTAKE TEST (RT3U), SERUM
Newborn 26-36% 0.01 0.26-0.36 fractional uptake
Thereafter 26-35% 0.01 0.26-0.35 fractional uptake
TRIIODOTHYRONINE, TOTAL, SERUM
Cord blood 30-70ng/dL 0.0154 0.46-1.08nmol/L
1-3 days 75-260ng/dL 0.0154 1.16-4.00nmol/L
1-5yr 100-260ng/dL 0.0154 1.54-4.00nmol/L
5-10yr 90-240ng/dL 0.0154 1.39-3.70nmol/L
10-15yr 80-210ng/dL 0.0154 1.23-3.23nmol/L
>15yr 115-190ng/dL 0.0154 1.77-2.93nmol/L
Adapted from Nicholson JF, Pesce MA: Reference ranges for laboratory tests and procedures. In Behrman RE, Kliegman RM, Jenson HB, editors: Nelson textbook of
pediatrics, ed 17, Philadelphia, 2004, WB Saunders, pp. 24122413; TSH from Lem AJ, de Rijke YB, van toor H, etal: Serum thyroid hormone levels in healthy children
from birth to adulthood and in short children born small for gestational age. J Clin Endocrinol Metab 97:31703178, 2012; free T3 from Elmlinger MW, Kuhnel W,
Lambrecht H-G, 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 39:973979, 2001.

affected twin at the initial screening. Many newborn screening pro- ine life. The distal femoral and proximal tibial epiphyses, normally
grams perform a routine second test in same-sex twins. present at birth, are often absent (Fig. 565-2A). In undetected and
Retardation of osseous development can be shown radiographi- untreated patients, the discrepancy between chronologic age and
cally at birth in approximately 60% of congenitally hypothyroid infants osseous development increases. The epiphyses often have multiple
and indicates some deprivation of thyroid hormone during intrauter- foci of ossification (epiphyseal dysgenesis; Fig. 565-2B); deformity
Chapter 565 Hypothyroidism 2671

A B
Figure 565-2 Congenital hypothyroidism. A, Absence of distal femoral epiphysis in a 3mo old infant who was born at term. This is evidence
for the onset of the hypothyroid state during fetal life. B, Epiphyseal dysgenesis in the head of the humerus in a 9yr old girl who had been inad-
equately treated with thyroid hormone.

(beaking) of the 12th thoracic or 1st or 2nd lumbar vertebra is confirming aplasia, should be started at the higher end of the dosage
common. X-rays of the skull show large fontanels and wide sutures; range.
intersutural (wormian) bones are common. The sella turcica is often l-T4 is available only in tablet form in the United States; there is an
enlarged and round; in rare instances, there may be erosion and thin- approved liquid l-T4 preparation in Europe. The daily tablets should
ning. Formation and eruption of teeth can be delayed. Cardiac enlarge- be crushed and mixed with a small volume of liquid. l-T4 tablets should
ment or pericardial effusion may be present. not be mixed with soy protein formulas, concentrated iron, or calcium,
Scintigraphy can help to pinpoint the underlying cause in infants because these can bind T4 and inhibit its absorption. Although it is
with congenital hypothyroidism, but treatment should not be unduly recommended to administer l-T4 on an empty stomach and avoid
delayed for this study. 123I-sodium iodide is superior to 99mTc-sodium food for 30-60min, this is not practical in an infant. As long as the
pertechnetate for this purpose. Ultrasonographic examination of the method of administration is consistent day to day, dosing can be
thyroid is helpful, but studies show it can miss some ectopic glands adjusted based on serum thyroid test results to achieve the desired
shown by scintigraphy. Demonstration of ectopic thyroid tissue is diag- treatment goals.
nostic of thyroid dysgenesis and establishes the need for lifelong treat- Levels of serum T4 or free T4 and TSH should be monitored at rec-
ment with T4. Failure to demonstrate any thyroid tissue suggests ommended intervals (every 1-2mo in the 1st 6mo of life, and then
thyroid aplasia, but this also occurs in neonates with hypothyroidism every 2-4mo between 6mo and 3yr of age). The goals of treatment
caused by maternal TRBAb and in infants with the iodide-trapping are to maintain the serum free T4 or total T4 in the upper half of the
defect. A normally situated thyroid gland with a normal or avid uptake reference range for age (see Table 565-2), with serum TSH in the refer-
of radionuclide indicates a defect in thyroid hormone biosynthesis. In ence range for age, optimally 0.5-2.0mU/L. The dose of l-T4 on a
the past, patients with goitrous hypothyroidism have required exten- weight basis gradually decreases with age.
sive evaluation, including radioiodine studies, perchlorate discharge Later, confirmation of the diagnosis may be necessary for some
tests, kinetic studies, chromatography, and studies of thyroid tissue, to infants to rule out the possibility of transient hypothyroidism. This is
determine the biochemical nature of the defect. Most can be evaluated unnecessary in infants with proven thyroid ectopia or in those who
by genetic studies looking for a suspected mutation in the steps along manifest elevated levels of TSH after 6-12mo of therapy because of
the T4 biosynthetic pathway. poor compliance or an inadequate dose of T4. Discontinuation of
The electrocardiogram may show low-voltage P and T waves with therapy at about 3yr of age for 3-4wk results in a marked increase in
diminished amplitude of QRS complexes and suggest poor left ven- TSH levels in children with permanent hypothyroidism.
tricular function and pericardial effusion. Echocardiography can Care should be taken to avoid prolonged undertreatment or over-
confirm a pericardial effusion. The electroencephalogram often shows treatment. The only untoward effects of l-T4 are related to its dosage.
low voltage. In children older than 2yr of age, the serum cholesterol Overtreatment can risk craniosynostosis and temperament problems.
level is usually elevated. Brain MRI before treatment is reportedly
normal, although proton magnetic resonance spectroscopy shows high Prognosis
levels of choline-containing compounds, which can reflect blocks in Thyroid hormone is critical for normal cerebral development in the
myelin maturation. early postnatal months; biochemical diagnosis must be made soon after
birth, and effective treatment must be initiated promptly to prevent
Treatment irreversible brain damage. With the advent of neonatal screening pro-
Levothyroxine (l-T4) given orally is the treatment of choice. Although grams for detection of congenital hypothyroidism, the prognosis for
T3 is the biologically active form of thyroid hormone, most of the T3 affected infants has improved dramatically. Early diagnosis and ade-
in the brain is formed from local deiodination of T4. Because 80% quate treatment from the 1st weeks of life result in normal linear growth
of circulating T3 is formed by monodeiodination of T4, serum levels and development. Most studies report that psychometric testing in
of T4 and T3 return to normal with l-T4 treatment alone. The recom- infants detected by newborn screening shows verbal, psychomotor, and
mended initial starting dose is 10-15g/kg/day (totaling 37.5-50.0g/ global IQ scores similar to those of unaffected siblings or classmate
day for most term infants). The starting dose can be tailored to the controls. Some screening programs report that the most severely
severity of hypothyroidism. Rapid normalization of thyroid func- affected infants, as judged by the lowest T4 levels and retarded skeletal
tion has been demonstrated to be important in achieving optimal maturation, have reduced IQs (by 5-20 points) and other neuropsycho-
neurodevelopmental outcome. Newborns with more severe hypothy- logic sequelae, such as incoordination, hypotonia or hypertonia, short
roidism, as judged by a serum T4 <5g/dL and/or imaging studies attention span, and speech problems, even with early diagnosis and
2672 Part XXVI The Endocrine System

adequate treatment. Psychometric testing can show problems with regulator) gene. Less-common features include thyroiditis (~10%), type
vocabulary and reading comprehension, arithmetic, and memory. 1 diabetes mellitus, primary hypogonadism, pernicious anemia, viti-
Approximately 20% of children have a neurosensory hearing deficit. ligo, alopecia, chronic active hepatitis, and malabsorption syndrome.
Outcome studies in adults, detected and treated as neonates, reveal APS-2 (Schmidt syndrome) most commonly consists of autoimmune
delayed social development, lower self-esteem, and a lower health- thyroiditis (~70%), Addison disease, and type 1 diabetes mellitus. Less-
related quality of life. The latter appears to be related to those individu- common features include primary hypogonadism, pernicious anemia,
als with lower neurocognitive outcome and associated congenital and vitiligo. APS-2 occurs more commonly than APS-1, generally pres-
malformations. ents in early adulthood, and has a female preponderance. The underly-
Delay in diagnosis, failure to correct initial hypothyroxinemia ing immunologic defect remains to be determined.
rapidly, inadequate treatment, and poor compliance in the 1st 2-3yr
of life result in variable degrees of brain damage. Without treatment,
affected infants are profoundly intellectually challenged and growth
retarded. When onset of hypothyroidism occurs after 2yr of age, the Table 565-4 Autoimmune Polyglandular Syndromes 1
outlook for normal development is much better even if diagnosis and and 2
treatment have been delayed, indicating how much more important APS-1 APS-2
thyroid hormone is to the rapidly growing brain of the infant.
Incidence <1 in 100,000 1-2 in 10,000
ACQUIRED HYPOTHYROIDISM population/yr population/yr
Onset Infancy/early Late childhood/
Epidemiology childhood adulthood
Studies of school-age children report that hypothyroidism occurs in Male:female ratio 3:4 1:3
approximately 0.3% (1 in 333). Subclinical hypothyroidism (TSH Inheritance Monogenic Polygenic
>4.5mU/L, normal T4 or free T4) is more common, occurring in (AIRE gene) (HLA-associated)
approximately 2% of adolescents. Acquired hypothyroidism is most Mucocutaneous 73-100% None
commonly a result of chronic lymphocytic thyroiditis; 6% of children candidiasis
age 12-19yr have evidence of autoimmune thyroid disease, which Hypoparathyroidism 77-89% None
occurs with a 2:1 female:male preponderance. Addison disease 60-86% 70-100%
Type 1 diabetes 4-18% 41-52%
Etiology Autoimmune thyroid 8-40% 70%
disease
The most common cause of acquired hypothyroidism (Table 565-3) is
chronic lymphocytic (Hashimoto) thyroiditis (see Chapter 566). Auto- GONADAL FAILURE
immune thyroid disease may be part of polyglandular syndromes; Male 7-17% 5%
children with Down and Turner syndrome, possibly Klinefelter syn- Female 30-60% 3.5-10%
drome, and celiac disease or diabetes are at higher risk for associated Ectodermal dysplasia 77% None
Vitiligo 4-13% 4-5%
autoimmune thyroid disease (see Chapter 566) as are those with auto-
Pernicious anemia 12-15% 2-25%
immune polyglandular syndromes (APSs) (Tables 565-4 and 565-5). Alopecia 27% 2%
APS has 4 types, but APS-1 and APS-2 are the most common. APS-1 Autoimmune hepatitis 10-15% Rare
includes 2 components of the triad of hypoparathyroidism, Addison Malabsorption 10-18% Rare
disease (adrenal insufficiency) and mucocutaneous candidiasis (HAM
syndrome). Commonly referred to by the acronym APECED (autoim- HLA, human leukocyte antigen.
From Nambam B, Winter WE, Schatz DA: IgG4 antibodies in autoimmune
mune polyendocrinopathy-candidiasis-ectodermal dysplasia), it is polyglandular disease and IgG4-related endocrinopathies: pathophysiology and
autosomal recessive, caused by a mutation in the AIRE (autoimmune clinical characteristics. Curr Opin Pediatr 26:493499, 2014, Table 1, p. 494.

Table 565-5 Organ-Specific Autoantigens in


Table 565-3 Etiologic Classification of Acquired
Autoimmune Polyglandular Syndromes
Hypothyroidism
DISEASE AUTOANTIGENS
Autoimmune
Hashimoto thyroiditis Addison disease P450c21, P450c17, P450scc
Autoimmune polyglandular syndromes types 1 and 2 (APS-1,
APS-2) Hashimoto thyroiditis Thyroid peroxidase, thyroglobulin
Drug-induced Graves disease TSH receptor
Excess iodide: amiodarone, nutritional supplements, expectorants
Anticonvulsants: phenytoin, phenobarbital, valproate Hypoparathyroidism Calcium-sensing receptor, NALP 5
Antithyroid drugs: methimazole, propylthiouracil (NACHT leucine-rich-repeat protein 5)
Miscellaneous: lithium, tyrosine kinase inhibitors, interferon alfa, Type 1 diabetes Insulin, glutamic acid decarboxylase-65,
stavudine, thalidomide, aminoglutethimide IA-2A, ZnT8
Postablative
Irradiation Hypogonadism P450c17, P450scc
Radioiodine Immune gastritis H+, K+-ATPase
Thyroidectomy
Systemic infiltrative disease Pernicious anemia Intrinsic factor
Cystinosis
Celiac disease Transglutaminase, gliadin
Langerhans cell histiocytosis
Hemangiomas (large) of the liver (type 3 iodothyronine deiodinase) Immune hepatitis P450D6, P4502C9, P4501A2
Hypothalamic-pituitary disease with multiple pituitary hormone
deficiencies Alopecia areata Tyrosine hydroxylase
Hypothalamic-pituitary tumors (e.g., craniopharyngioma) Vitiligo Tyrosinase
Meningoencephalitis
Cranial radiation ATPase, adenosine triphosphatase; TSH, thyroid-stimulating hormone.
Head trauma From Nambam B, Winter WE, Schatz DA: IgG4 antibodies in autoimmune
Langerhans cell histiocytosis polyglandular disease and IgG4-related endocrinopathies: pathophysiology and
clinical characteristics. Curr Opin Pediatr 26:493499, 2014, Table 2, p. 495.
Chapter 565 Hypothyroidism 2673

In children with Down syndrome, antithyroid antibodies develop common in children) or a result of treatment for the tumor. Other
in approximately 30%, and subclinical or overt hypothyroidism occurs causes include cranial radiation, head trauma, or diseases infiltrating
in approximately 15-20%. In girls with Turner syndrome, antithyroid the pituitary gland, such as Langerhans cell histiocytosis.
antibodies develop in approximately 40%, and subclinical or overt
hypothyroidism occurs in approximately 15-30%, rising with increas- Clinical Manifestations
ing age. In children with type 1 diabetes mellitus, approximately 20% Deceleration of growth is usually the first clinical manifestation, but
develop antithyroid antibodies and 5% become hypothyroid. Addi- this sign often goes unrecognized (Figs. 565-3 and 565-4). Goiter asso-
tional autoimmune diseases with an increased risk of hypothyroidism ciated with Hashimoto thyroiditis, which may be a presenting feature,
include immune dysregulationpolyendocrinopathyenteropathyX- typically is nontender and firm, with a rubbery consistency and a
linked syndrome (IPEX) and IPEX-like disorders, immunoglobulin pebbly surface. Weight gain is mostly fluid retention (myxedema), not
G4related diseases, Sjgren syndrome, multiple sclerosis, pernicious true obesity. Myxedematous changes of the skin, constipation, cold
anemia, Addison disease, and ovarian failure. Although typically seen intolerance, decreased energy, and an increased need for sleep develop
in adolescence, it occurs as early as in the 1st yr of life. Williams syn- insidiously. Surprisingly, schoolwork and grades usually do not suffer,
drome is associated with subclinical hypothyroidism; this does not even in severely hypothyroid children. Additional features include bra-
appear to be autoimmune, as antithyroid antibodies are negative. dycardia, muscle weakness or cramps, nerve entrapment, and ataxia.
Protracted ingestion of medications containing iodidesfor Osseous maturation is delayed, often strikingly, which is an indication
example, expectorants or nutritional supplementscan cause hypo- of the duration of the hypothyroidism. Adolescents typically have
thyroidism, usually accompanied by goiter (see Chapter 567). Amioda- delayed puberty; older adolescent girls manifest menometrorrhagia.
rone, a drug used for cardiac arrhythmias and consisting of 37% iodine Younger children might present with galactorrhea or pseudoprecocious
by weight, causes hypothyroidism in approximately 20% of treated puberty. Galactorrhea is a result of increased TRH stimulating prolactin
children. It affects thyroid function directly by its high iodine content secretion. The precocious puberty, characterized by breast development
as well as by inhibition of 5-deiodinase, which converts T4 to T3. and vaginal bleeding in girls and macroorchidism in boys, is thought
Children treated with this drug should have serial measurements of T4, to be the result of abnormally high TSH concentrations binding to the
T3, and TSH. follicle-stimulating hormone receptor with subsequent stimulation.
Anticonvulsants, including phenytoin, phenobarbital, and valproate, Some children have headaches and vision problems; they usually have
may cause thyroid dysfunction, usually mild, subclinical hypothyroid- enlargement of the pituitary gland, sometimes with suprasellar exten-
ism. Certain anticonvulsants stimulate hepatic P450 metabolism and sion, after long-standing primary hypothyroidism. This condition,
excretion of T4. Children with Graves disease treated with antithyroid believed to be the result of thyrotroph hyperplasia, may be mistaken for
drugs (methimazole or propylthiouracil) can develop hypothyroidism. a pituitary tumor (see Chapter 557). Abnormal laboratory studies
Additional drugs that can produce hypothyroidism include lithium, include hyponatremia, macrocytic anemia, hypercholesterolemia, and
tyrosine kinase inhibitors, interferon-, stavudine, thalidomide, and elevated creatine phosphokinase. Table 565-6 lists the complications
aminoglutethimide. seen in severe hypothyroidism. All these changes return to normal with
Children who receive craniospinal irradiation, as with treatment adequate replacement of T4.
of Hodgkin disease or other head and neck malignancies or that is
administered before bone marrow transplantation, are at risk for Diagnostic Studies
thyroid damage. Approximately 30% of such children acquire elevated Children with suspected hypothyroidism should undergo measure-
TSH levels within a year after therapy, and another 15-20% progress ment of serum free T4 and TSH. Because the normal range for thyroid
to hypothyroidism within 5-7yr. Central (hypopituitary) hypothyroid- tests is slightly higher in children than adults, it is important to
ism may develop in approximately 10% of children receiving cranio- compare results to age-specific reference ranges. Measurement of anti-
spinal irradiation. thyroglobulin and antiperoxidase antibodies can pinpoint autoim-
Radioactive iodine ablative treatment or thyroidectomy for Graves mune thyroiditis as the cause. In cases with a goiter resulting from
disease or cancer results in hypothyroidism, as can removal of ectopic autoimmune thyroid disease, an ultrasound examination typically
thyroid tissue. Thyroid tissue in a thyroglossal duct cyst usually con- shows diffuse enlargement with scattered hypoechogenicity. However,
stitutes the only source of thyroid hormone, and excision results in generally, sonography is not indicated unless there is a suspicion of a
hypothyroidism. Ultrasonographic examination or a radionuclide scan thyroid nodule on neck palpation. In such cases, ultrasound examina-
before surgery is indicated in these patients. tion is the most accurate study to confirm the presence of a nodule
Children with nephropathic cystinosis, a disorder characterized by and determine if other, smaller nodules are present. In addition, an
intralysosomal storage of cystine in body tissues, acquire impaired ultrasound examination can determine the nodule dimensions, texture
thyroid function. Hypothyroidism may be overt, but subclinical forms (solid vs cystic nature), and presence or absence of other features that
are more common, and periodic assessment of TSH levels is indicated. might influence a decision to undertake fine-needle aspiration, such
By 13yr of age, two thirds of these patients require T4 replacement. as microcalcifications, blurred margins, taller-than-wide shape,
Histiocytic infiltration of the thyroid in children with Langerhans intranodular vascular flow, and pathologic-appearing adjacent lymph
cell histiocytosis (see Chapter 507) can result in hypothyroidism. nodes (see Chapter 569.1). In children with a nodule and suppressed
Children with chronic hepatitis C infection are at risk for subclini- TSH, a radioactive iodine uptake scan is indicated to determine if this
cal hypothyroidism; this does not appear to be autoimmune, because is a hot or hyperfunctioning nodule. A bone age x-ray at diagnosis
antithyroid antibodies are negative. is useful, in that the degree of delay approximates duration and sever-
Hypothyroidism can occur in children with large hemangiomas of ity of hypothyroidism.
the liver, because of increased type 3 deiodinase activity, which cata-
lyzes conversion of T4 to reverse T3 and T3 to diiodothyronine. Thyroid Treatment and Prognosis
secretion is increased, but it is not sufficient to compensate for the large l-T4 is the treatment of choice in children with hypothyroidism. The
increase in degradation of T4 to reverse T3. dose on a weight basis gradually decreases with age. For children age
Some patients with congenital thyroid dysgenesis and residual 1-3yr, the average l-T4 dosage is 4-6g/kg/day; for age 3-10yr,
thyroid function or with incomplete genetic defects in thyroid hormone 3-5g/kg/day; and for age 10-16yr, 2-4g/kg/day. Treatment should
synthesis do not display clinical manifestations until childhood and be monitored by measuring serum free T4 and TSH every 4-6mo as
appear to have acquired hypothyroidism. Although these conditions well as 6wk after any change in dosage. In children with central hypo-
are usually now detected by newborn screening programs, very mild thyroidism, where TSH levels are not helpful in monitoring treatment,
defects can escape detection. the goal should be to maintain serum free T4 in the upper half of the
Any hypothalamic or pituitary disease can cause acquired central normal reference range for age.
hypothyroidism (see Chapter 557). TSH deficiency may be the During the 1st yr of treatment, deterioration of schoolwork, poor
result of a hypothalamic-pituitary tumor (craniopharyngioma is most sleeping habits, restlessness, short attention span, and behavioral
2674 Part XXVI The Endocrine System

A B
Figure 565-3 A, Acquired hypothyroidism in a girl 6yr of age. She was treated with a wide variety of hematinics for refractory anemia for 3yr.
She had almost complete cessation of growth, constipation, and sluggishness for 3yr. The height age was 3yr; the bone age was 4yr. She had
a sallow complexion and immature facies with a poorly developed nasal bridge. Serum cholesterol, 501mg/dL; radioiodine uptake, 7% at 24hr;
protein-bound iodine (PBI), 2.8mg/dL. B, After therapy for 18mo, note the nasal development, increased luster and decreased pigmentation of
hair, and maturation of the face. The height age was 5.5yr; the bone age was 7yr. There was a decided improvement in her general condition.
Menarche occurred at 14yr. The ultimate height was 155cm (61in). She graduated from high school. The disorder was well controlled with
sodiumL-thyroxine daily.

Table 565-6 Pathogenesis of General Complications


in Management of Complicated
Hypothyroidism
COMPLICATION PATHOGENESIS
Heart failure Impaired ventricular systolic and diastolic
functions and increased peripheral
vascular resistance
Ventilatory failure Blunted hypercapnic and hypoxic
ventilatory drives
Hyponatremia Impaired renal free water excretion and
syndrome of inappropriate antidiuretic
hormone secretion
Ileus Bowel hypomotility
Medication sensitivity Reduced clearance rate and increased
sensitivity to sedative, analgesic, and
anesthetic agents
Hypothermia and lack Decreased calorigenesis
of febrile response to
sepsis
Delirium, dementia, Decreased central nervous system thyroid
seizure, stupor, and hormone actions, and encephalopathy
coma from hyponatremia and hypercapnia
Adrenal insufficiency Associated intrinsic adrenal or pituitary
disease, or reversible impairment of
A B hypothalamic-pituitary-adrenal stress
response
Figure 565-4 A, Short stature (108cm, <3rd percentile), generalized
myxedema, sleepy expression, protuberant abdomen, and coarse hair Coagulopathy Acquired von Willebrand syndrome (type
are signs of hypothyroidism in this 12yr old boy. Body proportions are 1) and decreased factors VIII, VII, V, IX,
immature for his age (1.25:1). B, Same boy 4mo after treatment. His and X
height increased by 4cm; note the marked change in body habitus
owing to loss of generalized myxedema, improved muscle tone, and From Roberts CG, Landenson PW: Hypothyroidism, Lancet 363:793803, 2004.
bright facial expression. (From LaFranchi SH: Hypothyroidism, Pediatr
Clin North Am 26:3351, 1979.)
problems might ensue, but these are transient; forewarning families
about these manifestations enhances appropriate management. These
may partially be ameliorated by starting at subreplacement T4 doses
and advancing slowly. The development of persistent headaches or
vision changes should prompt an evaluation for papilledema associated
with pseudotumor cerebri, a rare complication following initiation of
l-T4 treatment in older children (age 8-13yr).
In older children, after catch-up growth is complete, the growth rate
provides a good index of the adequacy of therapy. Periodic bone age
x-rays are useful to monitor treatment and future growth potential. In
children with long-standing hypothyroidism, catch-up growth may be
incomplete (see Fig. 565-4). During the 1st 18mo of treatment, skeletal
maturation often exceeds expected linear growth, resulting in a loss of
approximately 7cm of predicted adult height.

Bibliography is available at Expert Consult.

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