A Introduction Thyroid Development and Function as Related to Etiopathogenesis of

© SUPPLEMENT TO JAPI • JANUARY 2011 • VOL. 59 35
Thyroid Function in Children
Meena P Desai
A
Introduction
mong endocrine disorders most commonly encountered in
the pediatric age group, disorders of the thyroid gland are
most frequent with hypothyroidism being the commonest. Goiter
(thyromegaly) with or without alterations in thyroid function is
not uncommon but hyperthyroidism is less frequent. The most
pronounced effect of thyroid dysfunction in this age group
is on growth and development but it also leads to metabolic
abnormalities similar to those in adults. Thyroid hormones
increase oxygen consumption, stimulate protein synthesis, affect
carbohydrate, lipid and vitamin metabolism, and influence
activity of other enzyme systems and growth factors. In the
brain they promote cell growth, cell differentiation and induce
neurotransmitter function. Their deficiency in fetal life and early
infancy can lead to irreversible impairment of neurocognitive
function emphasizing the crucial role of thyroid hormones on
developing brain. As thyroid hormone-dependent effects on
tissue maturation are age related and organ or tissue specific,
the clinical consequences of thyroid dysfunction relate to age
of the infant or child. Hypothyroidism after the age of three
years, when most of the thyroid hormone-dependent brain
development is complete, results in slow growth and delayed
skeletal maturation.1 However, permanent effect on cognition
and neurological development is not commonly reported. If
hypothyroidism remains unrecognized during early childhood,
physical growth potential can also be affected. Hyperthyroidism
can induce rapid linear and skeletal growth and maturation; it
can lead to craniosynostosis in infancy and other systemic effects
which are related to increased metabolic activity due to excess
of thyroid hormones. Approximately 100mg of thyroxine (T4)
is secreted by the thyroid gland daily and about 90mg of iodide
(15mg/kg) is the recommended daily intake during infancy and
childhood with higher requirements in preterms.
Prevelance of Thyroid Disorders in
Childhood in India
Siblings of index cases in India were found to have high
prevalence of goiter in cases of lymphocytic thyroiditis (74%)
and also in those with colloid goiter (71%). This is significantly
higher than earlier reported goiter prevalence of 23% in
14,762 schoolchildren in a comparable age group. The high
prevalence of goiter could be explained on the basis of common
environmental exposure to goitrogens and/or genetic factors.
Among the 71 index cases, overt hypothyroidism was seen in
17% and subclinical hypothyroidism in 32%. Group 1 siblings
had a 23% incidence of subclinical hypothyroidism and no overt
cases were reported. 2
Hon. Consultant & Head, Dept. of Pediatrics, Sir Hurkisondas
Nurrotumdas Hospital & Research Centre; Hon.Director, Sir H.N.
Medical Research Society; Raja Rammohan Roy Road, Mumbai;
Visiting Consultant, Endocrinology Division, Bai Jerbai Wadia
Hospital for Children & Institute of Child Health & Research Centre,
Parel, Mumbai.
Thyroid Development and Function
as Related to Etiopathogenesis of
Thyroid Function
Advances in several aspects of thyroid gland development
and function in past few decades have contributed to greater
understanding of etiopathogenesis of thyroid disease in infancy
and childhood. The human thyroid originates embryologically
from an evagination of the pharyngeal epithelium with cellular
contributions from the lateral pharyngeal pouches, followed
by a process of descent to the neck with occasional persistence
of the remnants along the tract as ‘lingual thyroid’, ectopic
thyroid, thyroglossal cyst or nodules. Occasionally, lingual
thyroid may be the sole functioning thyroid tissue which may
not maintain optimal euthyroid status. Three transcription
factors, TTF-1, TTF-2 and PAX8, are important for thyroid gland
morphogenesis and differentiation. Other genes (HOX genes)
regulate the expression of PAX-8 and TTF-1. Embryogenesis and
biochemical maturation of the thyroid gland and the pituitary
is largely complete by 10-12 weeks and thyroglobulin can be
detected in follicular cells with evidence of iodine uptake and
organification. T4 and T3 are detectable in fetal serum by 10-12
weeks with progressive increase in their levels. A transcription
factor, Pit-1 is important for growth and differentiation of
pituitary thyrotrophs which play an important role in regulating
thyroid gland development and function. This abnormality
causes central (pituitary / hypothalamic) hypothyroidism.
Faulty embryogenesis can lead to thyroid dysgenesis (aplasia,
hypoplasia, ectopia) which is the major underlying cause of
hypothyroidism in infancy and early childhood and involves
nearly 75% of newborns and infants with congenital primary
hypothyroidism (CH). It is usually non-genetic but the underlying
cause remains enigmatic. The thyroid gland concentrates iodide
from blood and synthesizes and secretes thyroxine (T4) along
with smaller amount of 3,3’5-tri-iodothyronine (T3). Deficiency
of iodine in various regions of endemic iodine deficiency is an
important cause of endemic cretinism and subnormal mental
development. It is considered one of the most economical
and easily preventable nutritional disorders. The synthesis
and secretion of thyroid hormones occurs through a series of
enzyme dependant steps. The thyroglobin so formed is stored
in colloid, functioning as a thyroid hormone precursor releasing
thyroid hormones in circulation as required and also permitting
storage of iodine. Inherited inborn errors of metabolism with
autosomal recessive transmission, lead to biosynthetic defects
of thyroid hormone production (dyshormonogenesis) usually
leading to familial goitrous hypothyroidism involving other
siblings. T4 and T3 circulate bound to transport proteins – the
thyroxine binding globulin (TBG), albumin and transthyretin.
The transport carrier proteins though nonessential for normal
thyroid function, serve as extrathyroidal storage pool of thyroid
hormone, releasing the free hormone on demand and protecting
tissues from ill effects of elevated levels. TBG deficiency
(incidence 1:5 to 8000), because of low circulating total T4 levels
can lead to a mistaken diagnosis of hypothyroidism in newborns
screened for CH; normal thyroid stimulating hormone (TSH) and
36
free T4 values exclude this possibility. Seventy-five percent of
circulating T3 in blood is derived by monodeiodination of T4 in
liver, kidney and other peripheral tissues with the simultaneous
formation of reverse T3 (rT3), which is metabolically inactive.
There is a certain amount of tissue autonomy in the production
of T3 from T4. This constitutes an important homeostatic
mechanism which can protect the fetus and a hypothyroid
patient against untoward effects of excess doses of levothyroxine.
The concentrations of free T4 and free T3, active at the cellular
level approximates 0.03 and 0.30 percent of total circulating
hormones respectively (of the total hormone concentration). T3
is almost four times more potent than T4 and 85 percent of the
bioactivity of T4 is attributed to T3. The thyroid gland is under
the regulatory control of the pituitary thyrotropin or TSH which
in turn is regulated by the hypothalamic thyrotropin-releasing
hormone (TRH). According to Fisher, maturation of the H-P-T
axis occurs through three stages, the first stage coinciding with
embryogenesis, hypothalamic maturation occurring during
second stage and feedback control during the third stage by third
trimester probably continuing in the first four weeks post natally.
This may occasionally lead to difficulties in interpretation of
neonatal screening results in preterm and distressed newborns.
TSH is detectable in fetal serum by mid-gestation reaching a
level of 10mU/ml at term. Delay in the development of feed
back control may lead to a mistaken diagnosis of CH in some
newborns. Inherited or acquired deficiency of TSH and TRH lead
to secondary and tertiary forms of hypothyroidism which may
be due to a developmental CNS abnormality or genetic mutation
(e.g. Pit-1). On neonatal screening central hypothyroidism may be
detected with a frequency of 1 in 60,000 newborns. The acquired
form is often related to intracranial trauma, infection, neoplasia
or radiation. The fetal thyroid gland and the hypothalamicpituitary-thyroid axis function largely independently of that of
the mother. Maternal TRH can cross the placenta but not TSH,
and placenta is also believed to permit limited transfer of T4
throughout gestation. Transplacental transfer of maternal T4
constitutes nearly 20 to 50% of neonatal T4, probably explaining
the lack of symptoms in newborns with CH. However, during
first half of pregnancy, maternal euthyroid status and optimal
levels of maternal thyroid hormones seem to be neuroprotective
for the fetus. Presence of maternal hypothyroidism is detrimental
to the fetus for future neuro-intellectual outcome. In the
newborn, thyroid function is influenced by the neonate’s own
thyroid gland but also by transplacental passage of maternal
factors that affect fetal thyroid gland. Placental permeability
also extends to the anti-thyroid drugs and Iodine which gain
easy access to the fetus causing fetal and neonatal goiters or
a state of transient hypothyroidism requiring treatment. In
women with past or present history of thyrotoxicosis maternal
TSH receptor stimulating or blocking antibodies can also
traverse across the placenta and can cause transient fetal and
neonatal hyperthyroidism or hypothyroidism. Of infants born
to mothers having Grave’s disease, 2 to 3% may have transient
neonatal hyperthyroidism requiring treatment, which can last
for a period of 6 weeks to 3-4 months. Measurement of maternal
TSH receptor antibody during 15th to 30th week of pregnancy can
be used to identify newborns at risk. Marked fetal tachycardia
may be an indication of fetal hyperthyroidism which can be
treated by administering anti-thyroid drugs to the pregnant
mother. During antenatal period monitoring mothers known
to have past or present history of thyroid disease (hypo or
hyperthyroidism) and maintenance of euthyroid status is of
extreme importance to ensure optimal outcome of pregnancy
as well as prevention of thyroid dysfunction in neonatal period
© SUPPLEMENT TO JAPI • JANUARY 2011 • VOL. 59
and future neurocognitive problems in childhood and later. 3,4
Physiologic Changes in Thyroid
Hormone in the Neonate
During fetal life there is a progressive increase in circulating
T4 and rT3 but T3 tends to be low (fetal protective measure)
and may be in hypothyroid range at birth. It is important to be
aware of the physiological variations in the levels of TSH and
circulating thyroid hormones which occur soon after birth. There
is an acute surge in the TSH level within 30 minutes of birth
which is followed by rise in serum T3 and T4 levels by 24 hours,
with a gradual decline in their levels as well as that of TSH and
rT3 by end of first week. TSH surge in the premature infant is of
a lesser magnitude with a greater decline in T4 concentration in
the following 2 weeks. These physiologic changes have helped
determine the timing (at birth from cord blood, or heel prick 2-5
days) and the source of blood collection (chord blood or heel
prick) in neonatal screening programmes for CH. Most screening
protocols use filter paper TSH or T4, or less commonly both TSH
as well as T4. Appropriate interpretation of TSH, T3, T4 values
is extremely important in arriving at the correct diagnosis when
newborns are screened for congenital hypothyroidism, with due
attention to gestational age, fetal and maternal health status
and medications. Neonatal screening for CH which is the most
cost effective of all neonatal screening programmes is usually
performed within 3 to 5 days of birth by heel prick, when TSH
and T4 levels are expected to normalize or from cord blood
(placental end of cord) as soon as baby is delivered. Based on
data compiled over the past 4 decades majority of newborns have
TSH values less than 20 mIU/ml or < 10 (with the newer assays)
while as 90% of them having CH have TSH > 50 mIU/ml, T4 levels
tend to be above 6 mg/dl in normal term newborn infants. Levels
of TSH more than 20 mIU/ml or T4 levels below 6 mg/dl in a full
term infant should arouse suspicion and need to be rechecked
within a week. If feasible thyroid USG (by an experienced
sonologist) or Tcm99 scan should be performed if the TSH
remains higher or T4 is low. Imaging studies even in a confirmed
case of CH are useful to determine the underlying cause of
CH, whether it is thyroid dysgenesis or dyshormonogenesis.
During infancy TSH levels upto 10mU/ml are considered normal
provided serum T4 levels are in normal range. Circulating levels
of T3 and T4 are maintained higher during infancy and early
childhood hence age appropriate standard charts should be
used for correct interpretation. The mean total T4 and T3 levels
+ 2 SD during infancy are 10.5µg/dl (7.5 to 15.5) and 1.68ng/
ml (1.13 to 2.4) respectively, between 1 to 5 years of age mean
levels are 10.5 µg/dl and 1.65ng/ml and between 5 to 10 years of
age 9.3 µg/dl and 1.50ng/ml respectively. TSH beyond infancy
is maintained in the usual 0.3 to 0.5 to 5µIU/ml. Thus, while
treating a hypothyroid child maintenance of serum T4 levels in
upper normal range is important with TSH in the normal range.
As stated earlier thyroid hormone actions also vary with age,
with maximal effects on somatic, skeletal growth and maturation,
brain growth and development in infancy and childhood. 5
Thyroid also influences the onset and progress of normal sexual
maturation, Puberty may be delayed or occasionally precocious
in children with hypothyroidism. Adequate understanding of
etiopathogenesis of thyroid disease is enhanced by appreciation
of the developmental biology of thyroid gland and H-P-T
axis. As hypothyroidism is the most frequent thyroid disease
encountered in pediatric age group with consequences which
can be life long, it is discussed in detail.
© SUPPLEMENT TO JAPI • JANUARY 2011 • VOL. 59 Transient Hypothroxinemia
It is seen to some extent in many preterm infants. Immaturity
of the hypothalamic-pituitary axis may be physiologically
normal for the infant’s gestational age. Preterm serum T4 and FT4
concentrations are lower than those of term infants, but the TSH
concentrations are comparable to term infants. In preterm infants,
serum TBG were found to be only marginally low and do not
correlate with the degree of hypothyroxinemia. As a result, the
FT4 is rarely as low as the total T4. Serum inhibitors of T4 binding,
present in many patients with non-thyroidal illness, may be an
additional contributor to the decreased T4 values. 6 The presence
of midline facial abnormalities, hypoglycaemia, microphallus, or
visual abnormalities should prompt one to exclude the possibility
of a hypothalamic-pituitary abnormality before considering
hypothyroxinemia. Septo-optic dysplasia, often associated
with pituitary hormone deficiencies, can manifest as central
hypothyroidism. Genetic mutation in HESX-1 has been described
in septo-optic dysplasia. Clinical symptoms of hypopituitarism,
such as neonatal hypoglycaemia (from growth hormone and
adrenocorticotropic hormone deficiencies), polyuria (from
antidiuretic hormone deficiency), or small phallus in boys
(from gonadotropin deficiencies), along with the presence of
blindness, congenital nystagmus, or midline defects of the brain,
should alert the physician to suspect the diagnosis of septo-optic
dysplasia. Alternatively, multiple pituitary hormone deficiencies
suggest a genetic defect in the cascade leading to fetal pituitary
formation, such as PROP1, LHX3, and POU1F1. DNA screening
for these molecular abnormalities could be beneficial in the future
for the rapid and accurate detection of these affected infants
during the first weeks of life, but is not yet available clinically.
Isolated TSH-releasing hormone (TRH) deficiency may cause
low-normal T4 and low or normal TSH concentrations. Secondary
(or central) hypothyroidism may be suspected in infants with low
T4 and FT4 and low TSH concentrations. Mutations have been
identified in the ß subunit of TSH, TRH gene, and TRH receptor
gene. Congenital TSH and growth hormone deficiencies may
occur in consequence to a difficult birth or anoxia. 2
Hypothyroidism in Infancy and
Childhood
Etiology
Primary hypothyroidism due to thyroid dysgenesis is
the most common thyroid dysfunction seen in childhood.
Autoimmune thyroid disease (chronic lymphocytic thyroiditis
– CLT) is the other important cause of hypothyroidism acquired
later in childhood. Pituitary or hypothalamic disease can
cause secondary or tertiary forms of hypothyroidism which
may be congenital or acquired following intracranial disease.
It is usually associated with deficiency of other pituitary
hormones.8 Worldwide prevalence of congenital hypothyroidism
approximates 1:3500 to 4000 newborns as revealed by neonatal
screening programmes implemented in several parts of the world
with racial and ethnic differences in its incidence. It is twice as
common in females. Our earlier data on neonatal screening of
40,000 newborns indicated higher incidence of nearly 1:2,500
to 1:2,800, but it could be even higher. Most of the infants
detected on screening are asymptomatic in the first few weeks
of life, thus fulfilling one of the major objectives of screening
which is to detect asymptomatic infants and treat them very
early so as to prevent or minimize intellectual impairment and
neuropsychologic damage which can be irreversible when the
treatment is delayed beyond the first few weeks of life. Inherited
37
biosynthetic defects (dyshormonogenesis) with autosomal
recessive transmission leading to goitrous hypothyroidism
has a reported incidence of 10 to 15% of children with CH, but
nearly 19 to 20% in our experience10. Siblings are also affected
hence family study is important. Autoimmune thyroid disease
(CLT) causing hypothyroidism is common beyond midchildhood and in adolescents and discussed later. Endemic
iodine deficiency still remains an important cause of endemic
cretinism and hypothyroidism in some parts of the world and
in sub Himalayan regions of India. CLT which is the most
common cause of hypothyroidism in pediatric age group beyond
5 years of age deserves special mention. CLT, an auto-immune
disease is closely related to Graves’ disease. In both CLT and
Graves’ disease, an inherited predisposition to autoimmunity
and additional environmental and hormonal factors trigger and
modulate the disease process. In CLT, lymphocyte and cytokinemediated thyroid destruction predominates whereas, in Graves’
disease, antibody-mediated thyroid stimulation occurs but
overlap may occur in some patients. Both goitrous (Hashimoto’s
thyroiditis) and non-goitrous (primary myxedema) variants of
thyroiditis have been distinguished. The disease has a striking
predilection for females and a family history of autoimmune
thyroid disease (both CLT and Graves’ disease) is found in
upto 40% or more of patients. The common age at presentation
is beyond mid childhood and adolescence but the disease may
occur even in infancy. Patients with insulin-dependent diabetes
mellitus, 20% of whom have positive thyroid antibodies and 5%
have an elevated serum TSH level, have an increased prevalence
of CLT, which may also occur as part of an autoimmune polyglandular syndrome. 11 The incidence of CLT is increased in
patients with Turner, Down and Klinefelter syndromes. When
stimulatory TSH receptor antibodies are present, they may give
rise to a clinical picture of hyperthyroidism, the co-existence
of CLT and Graves’ disease being known as hashitoxicosis.
Blocking antibodies, on the other hand, have been postulated
to underlie both, hypothyroidism and the absence of goiter in
some patients with primary myxedema but are detectable in
only a minority of children. In rare instances, the disappearance
of blocking antibodies has been associated with normalization
of thyroid function in previously hypothyroid patients. Goiter,
which is present in approximately two-thirds of children with
CLT, results primarily from lymphocytic infiltration and, from
a compensatory increase in TSH. Children with CLT may be
euthyroid or may have compensated or overt hypothyroidism,
rarely an initial thyrotoxic phase is noted which occurs due
to the discharge of preformed T4 and T3 from the damaged
gland. Alternatively, thyrotoxicosis may be due to concomitant
thyroid stimulation by TSH receptor stimulatory antibodies
(hashitoxicosis). Children with thyroid hormone resistance
constitute a rare cause of hypothyroidism. There may be selective
pituitary resistance as distinct from generalized resistance to
thyroid hormone. They come to attention when thyroid function
tests are performed because of poor growth, hyperactivity, a
learning disability or other non-specific signs or symptoms
or a small goiter. The presentation is highly variable because
of genetic heterogeneity. Individuals may be asymptomatic,
or may have symptoms of thyroid hormone deficiency or
excess. Thyroid hormone resistance is almost always due to a
mutation in the TRb. There may be involvement of the thyroid
gland in generalized infiltrative (cystinosis), granulomatous
(histiocytosis X), mitochondrial disease or infectious disease
processes. Mantle irradiation of the neck for Hodgkin disease
or lymphoma or craniospinal irradiation can also result in
primary hypothyroidism. Family history of sibling affection can
38
often be elicited in presence of goitrous hypothyroidism due to
dyshormonogenesis. In children with autoimmune thyroiditis
elders often have thyroid disease both hypothyroidism and
thyrotoxicosis and familial or community prevalence may be
also be evident in endemic iodine deficiency. 12
Clinical manifestations
The symptoms and signs of congenital hypothyroidism
in the neonatal period are nonspecific and vague, leading
to difficulties in clinical diagnosis with less than 10% of
newborns detected on screening being recognized clinically.
Symptoms often predominate over signs. Growth retardation
so characteristic of this disorder in postnatal life is not seen
at birth. These infants may be large at birth and may be post
mature. Congenital hypothyroidism should be suspected when
4 or 5 early manifestations are present. These include prolonged
physiological jaundice, constipation, feeding difficulties,
inactivity, macroglossia, constipation, wide fontanelles,
mottling, hypothermia, and hoarse cry. Coarse hypothyroid
facies, puffiness of eyes, protruding tongue, pallor, lethargy,
altered skin and hair texture, hypotonia, distended abdomen
with umbilical hernia, low pitched irritable prolonged cry, all
these give a characteristic appearance to these infants4. Other
helpful signs are bradycardia, muffled heart sounds, delayed
relaxation while eliciting deep tendon reflexes. Failure to grow
and delayed milestones become increasingly obvious. Children
with dyshormonogenesis may present with goiter at birth or
during infancy. The incidence of other associated congenital
abnormalities with CH is around 8%. Hypothyroidism in
older children is usually caused by autoimmune thyroiditis
but occasionally children with thyroid dysgenesis having
hypoplastic or ectopic thyroid tissue or dyshormonogenesis may
present late. Subtle signs of hypothyroidism in older children
may be difficult to appreciate clinically but failure to grow
or short stature of insidious onset and lethargy should raise
suspicion. Presence of a small goiter which is firm in consistency
with a pebbly surface favours the possibility of thyroiditis
as opposed to dyshormonogenesis where the goiters may be
small or large but the consistency tends to be usually soft with
occasional presence of a bruit. Congenital hypothyroidism can
also present as obesity, goiters, scholastic problems, delayed
sexual maturation or uncommon sexual precocity or muscular
hypertrophy. 13
Diagnosis
•
The diagnosis of primary hypothyroidism is confirmed by
the presence of low serum T4 and T3 concentrations and
elevated serum TSH values. Estimation of free T4 and free
T3 is also available now.
•
TSH is an extremely sensitive index of primary
hypothyroidism.
Low T4 and elevated TSH values
Any infant with a low T 4 concentration and TSH
concentration greater than 40mU/L* is considered to have
primary hypothyroidism. Such infants should be examined
immediately and have confirmatory serum testing performed to
verify the diagnosis. In infants with primary hypothyroidism,
replacement treatment with levothyroxine should be started
immediately following confirmatory tests even before the results
of these tests become available. In cases with a screening TSH
concentration only slightly elevated but lower than 40mU/L, a
second screening test should be performed using new fresh blood
sample obtained on a filter-paper. TSH values lie between 20
and 40 mU/L in nearly 10% of infants with confirmed CH. The
© SUPPLEMENT TO JAPI • JANUARY 2011 • VOL. 59
age appropriate normative values should be used as reference.
During the most common time of reevaluation (between 2 and
6 weeks of age), the reference range for TSH is 1.7 to 9.1mU/L.
Normal T4 and elevated TSH values
Hyperthyrotropinemia is characterized by elevated serum
TSH concentrations during the neonatal period despite normal
T4 and FT4 concentrations. Hyperthyrotropinemia can be a
permanent or transient thyroid abnormality or may involve
delayed maturation of the hypothalamic-pituitary axis. There
may be compensated, mild (subclinical) primary hypothyroidism
due to inactivation mutations of the TSH-R in the neonatal
period. Neonates with Down’s syndrome have a higher incidence
of both transient and persistent hyperthyrotropinemia and CH.
Transient neonatal hyperthyrotropinemia may persist till age 10
or later in some cases. 14
Low T4 and normal TSH values
Thyroid insufficiency is defined to occur when infants have
normal TSH but low T4 values (defined as 2 SDs below the
mean for the reference range for age, usually below 10µg/dL
in the newborn infant).The low T4 with normal TSH profile
is seen in 3% to 5% of neonates. This pattern may result from
hypothalamic immaturity (particularly in preterm infants, 12%
of all newborn infants). Low T4 but normal TSH results are also
observed during illness, with protein-binding disturbances
such as TBG deficiency (1 in 5000), in central hypothyroidism
(l in 25000 to l in 50000 newborn infants; see next 3 paragraphs),
or with primary hypothyroidism and delayed TSH elevation (l
in 100000 newborn infants). Newborn infants who are preterm
or ill are found with disproportionate frequency among those
with this set of laboratory values. In neonates/infants, inhibition
of TSH (causing low T4 concentrations) can result from constant
infusions of dopamine or high-dose glucocorticoids. Isolated
TSH-releasing hormone (TRH) deficiency may cause low-normal
T4 and low or normal TSH concentrations. Secondary (or central)
hypothyroidism may be suspected in infants with low T4 and FT4
and low TSH concentrations. Mutations have been identified in
the ß subunit of TSH, TRH gene, and TRH receptor gene. Finally,
congenital TSH and growth hormone deficiencies may occur as
a result of a difficult birth or anoxia.
Low T4 and delayed TSH increase
Many infants with low T4 concentrations and normal TSH
values on initial screening (l in 100000 newborn infants) who are
subsequently found to have an elevated TSH concentration are
LBW, VLBW, or critically ill preterm and term neonates. Serum
TSH values in these infants increase during the first few weeks of
life to concentrations characteristic of primary hypothyroidism.
It is unclear whether infants with this delayed TSH elevation
have an abnormality of pituitary-thyroid feedback regulation,
transient hypothyroidism (e.g. iodine induced), or a mild form
of permanent congenital hypothyroidism (CH). Long-term
follow-up of these infants has not been reported. It is important,
therefore, that serum FT4 and TSH be tested in infants with
overtly low T4 concentrations or in any infant with suggestive
signs of hypothyroidism. Infants with low T4 and a delay in
elevation of TSH values and those with normal T4 concentrations
and elevated TSH values might be missed on initial screening.
Neither a primary T4/backup TSH nor a primary TSH/backup
T4 screening strategy will detect the rare infant with a normal T4
at birth but delayed TSH increase. Five per cent to 10% of LBW
and VLBW infants with CH may have normal screening hormone
concentrations even in the absence of technical and human errors
and regardless of the approach used.13-15
© SUPPLEMENT TO JAPI • JANUARY 2011 • VOL. 59 Table 1 : The american academy of pediatrics guidelines
recommendations24
Initial workup
Detailed history and physical examination
Referral to pediatric endocrinologist
Recheck serum TSH and FT4
Thyroid ultrasonography and/or thyroid scan (see text for
recommendations)
Medications
L-T4: 10–15 µg/kg by mouth once daily
Monitoring
Recheck T4, TSH
2–4 wk after initial treatment is begun
Every 1–2 mo in the first 6 mo
Every 3–4 mo between 6 mo and 3 y of age
Every 6–12 mo from 3 y of age to end of growth
Goal of therapy
Normalize TSH and maintain T4 and FT4 in upper half of reference
range
Assess permanence of CH
If initial thyroid scan shows ectopic/absent gland, CH is permanent
If initial TSH is <50 mU/L and there is no increase in TSH after
newborn period, then trial off therapy at 3 y of age
If TSH increases off therapy, consider permanent CH
Radiographic studies
They demonstrate significant delay in skeletal maturation and
occasionally epiphyseal dysgenesis. The skeletal age may also
suggest the approximate age at which the disorder was initiated.
In long standing undiagnosed hypothyroidism more extensive
skeletal changes are observed which involve the thoracic cage
(bell shaped chest) and vertebrae which could be mistaken for
skeletal dysplasias. Marked enlargement of the sella turcica
due to pituitary thyrotrophic hyperplasia can be mistaken
for pituitary tumors. Imaging studies like ultrasonography
and radioisotope scans of thyroid gland, help in delineating
the anatomical and functional status of the gland but are not
mandatory.
Thyroid antibody studies
They are helpful in identifying autoimmune basis of the
disease, lymphocytic thyroiditis CLT or Hashimoto’s thyroiditis.
Thyroid antibodies specifically anti-microsomal (AMA) also
known as antiperoxidase antibodies (TPO) tend to be positive
in nearly 90% of those affected in the older age group.
Fine needle aspiration biopsy (FNAC)
It can confirm the diagnosis but is not mandatory in pediatric
age group. In secondary and tertiary forms of disease, the TSH
concentration may be low or undetectable with subnormal
levels of T3 and T4 as well as free T4 and T3. Usually associated
deficiency of other pituitary hormones is also present.
Treatment and monitoring
Once the diagnosis is established, the need for life long
therapy in congenital hypothyroidism should be adequately
stressed. In case the diagnosis is not beyond doubt therapy
can be continued for the initial 3 years when it can be omitted
for a period of about 6 to 8 weeks and restarted if needed after
complete evaluation.
The goal of therapy is to maintain the circulating serum T4
level in the upper normal range and normalize the elevated
TSH. The preferred preparation is sodium-levothyroxine
39
because of its uniform potency, reliable absorption and increased
bioavailability. Administration of L-T4 is the treatment of choice.
Although T3 is the more biologically active TH, most brain T3 is
derived from local monodeiodination of T4, so T3 should not be
used. The levothyroxine pill should be crushed and suspended
in small volume of formula milk, or breast milk, or water.
Soy, fiber, or iron should not be administered concomitantly.
Breastfeeding can continue. Only T4 tablets should be used. In
newborns detected on screening and in early infancy, 10 to 15mg/
kg has been recommended. Per kg dose often declines with age
upto 8 to 6mg/kg during late infancy and early childhood, 6 to
4mg/kg in later childhood and 4 to 2mg/kg in adolescents. The
daily requirement is about 100mg/m2 but therapy needs to be
individualized. In newborn period, full replacement therapy
can be initiated promptly. In longstanding thyroid deprivation
of whatever underlying cause, where the diagnosis is delayed
for months or occasionally for years, smaller doses upto quarter
of the daily dose can be administered initially and stepped up
gradually to full replacement dose, in 4 to 6 weeks. 16
The required dose is administered as one single dose,
preferably at a convenient fixed time during the day usually first
thing in the morning, on empty stomach to maximize absorption.
Regular therapy is extremely important.
Individualization of therapy by monitoring serum thyroid
levels and TSH is ideal and necessary. Therapeutic monitoring
is recommended with blood samples obtained at periodic
intervals for TSH and T4 estimations, more frequently in infancy,
initially after 4 weeks of initiating therapy and subsequently 2
monthly during infancy, about 3 monthly during first 3 years
of life and 4 to 6 monthly in older children and also within
6 to 8 weeks of any change in the dose. Clinical evaluation
and growth monitoring during therapy are important. While
most children with CLT who are hypothyroid initially remain
hypothyroid, spontaneous recovery may occur, particularly in
those with initially compensated hypothyroidism. On the other
hand, some initially euthyroid patients specifically those with
elevated thyroid antibodies (TPO) become hypothyroid later,
whether or no treatment is initiated. Clinical and laboratory
follow-up is advisable. 17
During therapy, the serum total T4 or FT4 should and might
be in the upper half of the reference range (target values depend
on the assay method used [T4: 10–16µg/dL (130–206nmol/L);
FT4: 1.4–2.3ng/dL (18–30pmol/L)]) during the first 3 years of
life with a low-normal serum TSH. The latter may sometimes
be delayed because of relative pituitary resistance. In such
cases, characterized by a normal or increased serum T4 and an
inappropriately high TSH concentration, the T4 value is used
to titrate the dose. The most frequent cause of persistent TSH
elevation is poor compliance and should be excluded first. Infants
with low serum T4 concentrations (below 10µg/dL [129nmol/L])
and a TSH concentration greater than 15mU/L during the first
year of life are at risk of having lower IQ values than patients
whose T4 concentrations are constantly controlled at higher
concentrations. Subsequently, thyroid function test values should
be kept at age-appropriate levels in children, which are different
from those for adults.. On TH-replacement therapy, TSH levels
should be maintained between 0.5 and 2.0mU/L during the
first 3 years of life.
During the first three years of age, the physician should
conduct clinical evaluation of the infant at frequent intervals.
Initial and ongoing counseling of parents is extremely significant
to emphasize the importance of major sequelae that may occur
40
© SUPPLEMENT TO JAPI • JANUARY 2011 • VOL. 59
WHEN TO SCREEN Normal hospital delivery at term - Filter paper collectiom ideally at 2-4 d of age or at time of discharge
NICU/preterm home birth - Within 7 d of birth
Maternal history of thyroid medication/family history of CH - Cord blood for screening
TTPE OF SCREENING
Primary TSH, Backup T4
Primary T4 Backup TSH
May miss - TBG deficiency
Will niss delayed TSH elevation with initial normal T 4
Hypothamic-pituitary hypothyroidism
Hypoyhyroxinemia with delayed TSH elevation
For better secsittivity - Use sensitive (20-25 mU/Lat 24 H of age )
Primary T4 and TSH
Ideal sereening approach
TLMELY FOLLOE -UP AND TRANSMISSION OF RESULTA (Refer to test)
INTERPETATION OF RESULTS
Low T4, TSH >4mU/L
Check serumT4, FT4,
and TSH as soon as
possible
Low T4, TSH slightly elevated
(<40mU/l)
Repeat neworn screen as soon as
possible ; check serum T4,FT4,
and TSH
Normal TSH at 2-12 wk is 9.1 m U/L
Normal T4,
Normal TSH
Low T4
Elevated TSH
Start treatment
TRANSIENT HYPOTHYROIDISM
Intrutrrine exposure to antithyroid meds,
Mateanal TRBAB
Heterozygous thyroid oxidase 2 deficiency
Maternal TSH -R
Endemic indide deficiency
Prenatal/ postnatal exposure to iodides
Low T4, Normal TSH
Normal T4, TSH
Recheck serumT4, FT4, and
TSh
Persistent
elevated TSH
(6-10mU/lat
1mo)
Transient/ permanent mild
CH Dleayed maturation of
hypothalami/pituitary axis
TH resistance
Down syndrome
Consider:
Transient hypothyroxinemia
Central hpyothroidism
TBG deficiency
(Refer to text)
Recheck TSH at 2-4 weeks
Low T4(<3µg/dl)
Delayed TSH
LBW, VLBW
Pretem
Sick term neworn
Recheck TSH T4,
and FT4 in 2 wk
Recheck serum T4,
FT4 TSH at 2 wk
Persistent T4,TSH
Clinically conistent
with central
hypothyroidism
Isolated low T4
(Monitor monthly)
Normal
TSH
Persistent TSH
(>10mU/L)
Start treatment
CH
a
No treatment
Start treatment
No treatment
CH Trial therapy at 3 y of age
Fig. 1 : Neonatal screening programme for CH
because of poor compliance and noncompliance. 18
Monitoring
Clinical examination, including assessment of growth and
development, should be performed every few months during
the first 3 years of life. Infants with CH appear to be at increased
risk of other congenital anomalies (approximately 10% of
infants with CH, compared with 3% in the general population).
Cardiovascular anomalies, including pulmonary stenosis, atrial
septal defect, and ventricular septal defect, are the most common.
Frequent laboratory and clinical evaluations of thyroid function,
growth, and development should be carried out in infants to
ensure optimal T4 dosage and adherence to therapy.
•
At 2 and 4 weeks after the initiation of L-T4 treatment
•
Every 1 to 2 months during the first 6 months of life
•
Every 3 to 4 months between 6 months and 3 years
•
Every 6 to 12 months until growth is completed; and
•
At more frequent intervals when compliance is questioned,
abnormal values are obtained, or dose or source of
medication has been changed; FT4 and TSH measurements
should be repeated 4 weeks after any change in L-T4 dosage.
The aim of therapy is to ensure normal growth and
development by maintaining the serum total T 4 or FT 4
concentration in the upper half of the reference range in the first
year of life, with a serum TSH in the reference range (optimally
0.5–2.0mU/L). Some infants will have serum TSH concentrations
in the range of 10 to 20mU/L despite T4 concentrations in the
upper half of the reference range. Elevated TSH relative to the FT4,
is hypothesized to occur as a result of in utero hypothyroidism
in rare cases. This produces a resetting of the pituitary-thyroid
feedback threshold. 19 A failure of the serum FT4 concentration
to increase into the upper half of the reference range by 2 weeks
and/or failure of the TSH concentration to decrease to less than
20mU/L within 4 weeks after initiation of L-T4 administration
should alert the physician that the child may not be receiving
adequate L-T 4 regularly. When therapy is not providing
presumed benefits, a careful inquiry regarding compliance, dose
of medication, and method of administration should be done.
While trying to achieve the optimal concentration of circulating
FT4, treating physicians should always keep the adverse effects of
excessive medication in mind and must be prepared to monitor
blood concentrations of FT4 closely. Prolonged hyperthyroidism
has been associated with premature craniosynostosis.
Prognosis and Outcome
The outcomes of patients with CH is closely dependent upon
the nature and severity of the underlying thyroid abnormality,
the age at diagnosis and onset of treatment, the adequacy and
regularity of therapy and compliance with the required degree
of clinical and laboratory follow-up. 20 Worldwide neonatal
screening programs for CH have had a significant impact on
reducing intellectual deficits in hypothyroid infants diagnosed
and treated early. Consequences of hypothyroidism acquired
beyond the age of 3 to 4 years differ from CH as stated earlier,
© SUPPLEMENT TO JAPI • JANUARY 2011 • VOL. 59 but are influenced by factors similar to that in CH. Mental
consequences are much less marked but behaviour alterations
are noted with institution of therapy.
Recommendation of the 2006
American Academy of Pediatric
Guidelines24 (Table 1)
•
Every newborn infant should be tested before discharge
from the nursery.
•
Due to the elevated levels of TSH shortly after birth, results
of screening of specimens taken within the first 24 to 48
hours of life occasionally are falsely positive for primary
hypothyroidism (using TSH as the primary screen).
•
It is better to screen before hospital discharge or before
transfusion than missing the diagnosis of hypothyroidism.
It should be kept in mind that screening very sick newborns
or after transfusion may give false negative results.
It is recommended to collect the blood when the infant is
between 2 and 4 days of age, but in certain situations, this is
virtually impossible. In infants discharged from the nursery
before 48 hours of age, blood should be obtained before
discharge. Blood should be obtained by 7 days of age in cases
such as home births or in the case of a critically ill or preterm
neonate. It should be recognized that samples obtained after
4 days of age are late for screening of congenital adrenal
hyperplasia or metabolic disease. Particular care must be
taken with infants in neonatal intensive care units (NICU.
In infants in the ICU, attention to urgent medical problems
may result in missed newborn screening. When an infant
is transferred to another hospital, the first hospital must
indicate whether the specimen has been collected. The
second hospital should obtain a specimen if there is no proof
that blood was collected before the transfer.
Early thyroid scanning of infants with suspected
hypothyroidism is controversial with regards to the riskbenefit ratio.
For physicians who opt for imaging, the benefits can be
summarized as follows:
•
If an ectopic gland is demonstrated, a permanent form of
thyroid disease and CH has been established.
•
The absence of thyroid gland uptake is most often associated
with thyroid aplasia or hypoplasia. In the setting of an absent
radioiodine uptake but normal gland on ultrasonographic
examination, a TSH-R defect, iodine-transport defect, or
maternal transfer of TRBAbs should be considered.
•
Normal scan findings (or a goiter) indicate a functioning
thyroid gland with regard to iodine uptake and alert the
physician to a probable hereditary defect in T4 synthesis.
Measurement of serum thyroglobulin will help to separate
thyroglobulin synthetic defects from other causes of
hypothyroidism.. Exposure to goitrogens other than iodine,
such as anti-thyroid drugs produces a similar picture
Finally, some infants exposed to maternal TRBAbs may
have a normal scan if their hypothyroidism is partially
compensated. Genetically mediated thyroid synthetic
enzyme defects can be passed on to future generations
and their identification is especially important for families
planning on having additional children. In such cases, the
physician can arrange for genetic counseling after scans are
available.
41
•
Some infants having a transient form of hypothyroidism
may have normal scan findings at birth and do not fall
into one of the above categories. Such infants should be
carefully evaluated after 3 years of age, when discontinuing
treatment temporarily is relatively safe as described
under the conditions in “Assessment of Permanence of
Hypothyroidism.”
Treatment need not be delayed to perform the scan. Elevated
TSH found in patients with permanent CH rarely normalizes
within the first few days of treatment, allowing a thyroid scan to
be performed during this time. Serum TSH should be assessed
at the time of the scan. If due to levothyroxine therapy, the TSH
concentration becomes <30mU/L, ultrasonography can still
be performed. A scan can be performed after the child reaches
3 years of age; at this time TH treatment can be interrupted
without danger to the developing central nervous system. The
usual dose of 123I, the preferred isotope, is 0.925MBq (25µCi). This
represents a small amount of radiation exposure, equivalent to
the amount of exposure with 2 to 3 chest radiographs. However,
while performing the scan, the radiation dose and type should be
taken into account. When large doses of isotope are administered
or if 131I is used, the radiation exposure is potentially 100
times. Therefore, the procedure should be performed by wellexperienced personnel using optimal equipment and using the
minimally recommended tracer dose. 21
Assessment of permanent hypothyroidism as per the
American Academy of Pediatrics 2006 recommendations:
•
If the thyroid scan reveals an ectopic gland, or absent thyroid
tissue (that is confirmed by ultrasonographic examination),
or if the serum TSH rises above 10mU/L after the first year
of life presumably because of insufficient T4 replacement,
CH is considered permanent.
•
If the scan does not reveal any permanent cause of CH
or there’s no TSH increase after the newborn period,
levothyroxine administration should be discontinued for
30 days at some point after the child is 3 years of age.. After
30 days, serum should be obtained for measurement of FT4
and TSH values. It is critical that this follow-up laboratory
assessment be obtained in a timely manner and that there
be no loss of follow-up. However, if TSH is elevated with
low FT4 levels, permanent hypothyroidism is confirmed and
TH therapy should be reinstituted.
•
If the FT4 and TSH concentrations remain in the reference
range, euthyroidism is assumed and a diagnosis of transient
hypothyroidism recorded. It is important that the child not
be lost to follow-up. The physician should monitor the child
carefully and repeat the thyroid function tests at the slightest
suspicion of recurrence of hypothyroid symptoms. If the
results are inconclusive, careful follow-up and subsequent
testing will be necessary.
•
More severely affected children may become clinically
hypothyroid when treatment is discontinued for 30 days. An
alternative option is to reduce the TH-replacement dosage
by half. If after 30 days the TSH is elevated above 20mU/L,
the permanence of hypothyroidism is confirmed and full
replacement therapy should be resumed. If the serum
TSH value has not increased, then TH treatment should be
discontinued for another 30 days with repeated serum FT4
and TSH determination as described above.22
Conclusion
There is a high risk of development of autoimmune thyroiditis
42
in family members of children with lymphocytic thyroiditis in
India. If only one modality (i.e., thyroid antibody assessment or
FNAC) is used to diagnose autoimmune thyroiditis in children,
between 22%-33% of subjects are likely to be missed. There is a
high prevalence of thyroid dysfunction among parents (fathers,
22%; mothers, 42%) and siblings. It is advisable for first-degree
relatives of subjects with juvenile autoimmune thyroiditis, to
undergo screening using serum TSH level estimation. Screening
programs (in which specimens have been obtained at 4 to 6
weeks) have indicated that 10% of hypothyroid infants with T4
values in the normal range and elevated TSH values or with
initially low TSH values were missed during initial screening.
It is therefore, established that infantile hypothyroidism can
still develop even when the screening T4 value is reported to be
normal. Repeat testing should be done on serum during infancy
whenever there is a clinical suspicion of hypothyroidism or
when there is a family history of thyroid disease in pregnancy or
familial thyroid dyshormonogenesis. A high index of suspicion,
early diagnosis, timely intervention with adequate treatment,
periodic therapeutic monitoring and counseling may help
mitigate adverse effects and ensure optimal outcome. Screening
for CH is the most cost effective screening procedure available
till date. Adequate appreciation of the importance of thyroid
function during these formative years of life provides greater
insight and understanding of thyroid diseases in this age group.
In infants and children thyroid diseases have far reaching effects
on growth, development, maturation as well as cognitive skills
and intellect. Efforts are ongoing to establish the optimal therapy
that provides maximum potential for normal development for
infants with congenital hypothyroidism. Recent Indian data
has provided reference ranges for thyroid hormones in healthy
school aged children. 23,24
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