+++
Newborn Screening
for Congenital Hypothyroidism
++
Newborn screening is routine in most industrialized areas of
the world.19 Screening is conducted either with
combined T4 and thyroid-stimulating hormone (TSH) testing
or with TSH testing alone. Screening and follow-up evaluation are
usually accomplished within 2 weeks. Ten percent to 15% of
infants with congenital hypothyroidism have T4 values in the normal
range (7–10 μg/dL, or 90–127
nmol/L). Some infants may have an elevated TSH, but clinicians
need to remember that 3% to 5% of infants with
congenital hypothyroidism escape detection in newborn screening
programs and that the diagnosis in these cases must be made on clinical
grounds.
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Evaluation of
Infants with Presumptive Positive Screening Results
++
A positive screening report for congenital hypothyroidism in
a newborn demands prompt evaluation of the infant, including a history,
physical examination, and laboratory testing.6,7 A
history of autoimmune thyroid disease in the family suggests the
possibility of transient congenital hypothyroidism, either drug
or maternal thyroid-stimulating hormone (TSH) receptor autoantibody
induced. Recurrent congenital hypothyroidism in the same sibship
may also suggest maternal autoantibody-mediated disease. A history
of familial congenital thyroid disease suggests thyroid dyshormonogenesis, which
is usually transmitted as an autosomal-recessive trait.
+++
Clinical Features
of Congenital Hypothyroidism in the Infant
++
Physical examination may reveal one of several early and subtle
manifestations of hypothyroidism, including a large posterior fontanelle
(> 1 cm diameter), prolonged jaundice (hyperbilirubinemia > 7 days),
macroglossia, hoarse cry, distended abdomen, umbilical hernia, hypotonia,
or goiter. Less than 5% of infants are diagnosed on clinical
grounds before the screening report, but 15% to 20% of
infants with congenital hypothyroidism have suggestive signs when
carefully examined.
++
The diagnosis is confirmed by serum measurements of T4 and/or
free T4 (FT4) and thyroid-stimulating hormone
(TSH) concentrations (Fig. 527-1). In the
neonatal period (2–6 weeks), serum T4, FT4,
and TSH levels below 84 nmol/L (6.5 μg/dL),
10 pmol/L (0.8 ng/dL), and above 10 mU/L
(10 uIu/mL), respectively, suggest congenital hypothyroidism. In infants with proven disease,
90% have TSH levels above 50 mU/L, and 75% have
T4 and FT4 concentrations below 84 nmol/L
(6.5 μg/dL) and 10 pmol/L (0.8
ng/dL), respectively. Perhaps 20% of affected
infants have T4 and FT4 levels in the 84 to 165
nmol/L (6.5–13 μg/dL)
range and 10 to 25 pmol/L (0.8–1.9 ng/dL),
respectively, usually with clearly elevated TSH concentrations (>
30 mU/L). A few infants will manifest only modest TSH elevations
(7–30 mU/L). Such infants may require repeat examinations
in order to establish a diagnosis of congenital hypothyroidism.
Serum T3 or rT3 concentrations have limited practical
value in the diagnosis.
++
++
Hypothalamic-pituitary hypothyroidism is more difficult to diagnose.10,11Many
such infants are missed in screening programs unless repeat testing
at 5 to 6 weeks of age or a T4/TBG ratio measurement
is included as a FT4 surrogate in the testing. The disorder
is characterized by a low serum T4 concentration and low
T4/thyroid-binding globulin (TBG) ratio with a
normal or low-normal range TSH value. Measurements of serum FT4 concentrations
will distinguish these possibilities. An infant or child with a
low FT4 concentration and low TSH level should be carefully
examined for evidence of hypothyroidism, and other tests of pituitary
function should be conducted. A subnormal TSH response to thyrotropin-releasing hormone
(TRH) confirms a diagnosis of pituitary TSH deficiency. If the peak
level of TSH is normal and/or prolonged, and there is a
good 4-hour T4 (thyroid) response to TSH, hypothalamic
TRH deficiency is more likely. The TSH deficiency may be isolated
or associated with other pituitary hormone deficiencies.
++
All infants with proven congenital hypothyroidism should undergo
radionuclide scanning if possible, using either technetium or radioiodine.
Radioiodine123 is preferred, provides greater isotope concentration,
and allows later scanning (2–24 hours). The confirmation
of an ectopic thyroid gland provides a definitive diagnosis of thyroid
dysgenesis. The absence of uptake of radioisotope suggests thyroid
gland agenesis, but some infants may have low radioisotope uptake
and a nondetectable gland by scan due to a TSH receptor-blocking
antibody (TBA). These infants or the mother should have blood drawn
for measurement of TSH receptor-binding immunoglobulin (TBII) if there
is a history of maternal autoimmune thyroid disease. Thyroid ultrasound,
if available, will usually confirm thyroid gland dysgenesis.
++
A normal radioisotope scan and/or a palpable or ultrasound-positive
thyroid gland in the presence of hypothyroidism indicates impaired
thyroid hormone synthesis. Infants with mild to moderate TBA-mediated transient
congenital hypothyroidism may have normal thyroid scan results (Fig. 527-1). The maternal and family histories
should be carefully reviewed in such cases. A serum thyroglobulin
measurement may be helpful in infants with absent uptake or normal
scans. A very low or absent serum thyroglobulin level indicates
thyroid agenesis in an infant with absent radioisotope uptake and
suggests a defect in thyroglobulin synthesis in infants with a normal
imaging study.
++
Infants with thyroid dysgenesis have elevated serum thyroglobulin
levels that relate to the mass of residual thyroid tissue and degree
of stimulation. However, levels usually do not exceed 1000 pmol/L
(660 ng/mL). Very high thyroglobulin levels (> 1000 pmol/L)
may be observed in infants with congenital hypothyroidism due to
defective thyroxine synthesis not involving the capacity for thyroglobulin
production. Serum calcitonin levels are also low in congenital hypothyroidism
(CH) infants with thyroid agenesis but offer no advantage over the
thyroglobulin measurement in diagnosis. A bone age study is useful
in assessing the extent of fetal hypothyroidism.
+++
Management of Congenital Hypothyroidism
++
Initial evaluation, should be accomplished promptly and should
require no more than 5 to 7 days. Treatment should be instituted
with early, adequate thyroid hormone replacement therapy. Most of
the requisite brain cell T3 is derived from local T4 to
T3 conversion. Thus, the preferred thyroid hormone preparation
for treatment of infants with congenital hypothyroidism is thyroxine.3,21The
dosage of T4 should normalize the serum T4 level
as quickly as possible. To guarantee adequate hormone to all infants,
it is desirable to maintain the serum T4 and/or
free T4 in the upper half of the normal range during therapy.
The initial target range for the total T4 concentration
is 130 to 210 nmol/L (10–16.3 μg/dL).
This assumes a normal serum T4-binding globulin (TBG) concentration.
This can be confirmed by measuring a normal range T3 resin
uptake, free thyroxine, or TBG level at the time of the first posttreatment
T4 measurement. The initial direct free T4 target
concentration should also be in the upper half of the normal infant
range. To rapidly normalize the serum T4 concentration
in the congenital hypothyroid infant, an initial dose of Na-L-T4 of
10 to 15 μg/kg/d is recommended.
For the average term infant of 3 to 4.5 kg, an initial dose of 50 μg
(0.050 mg) daily is appropriate (Table 527-3).
++
++
Serum thyroid-stimulating hormone (TSH) concentrations in some
treated infants with congenital hypothyroidism may remain relatively
elevated despite adequate replacement T4 and normalized
levels of T4 or free T4.21,22The relative
elevation of serum TSH is more marked during the early months of
therapy but can persist to some degree in about 10% of
patients through the second decade of life. The elevated serum TSH concentration
relative to T4 concentration in congenital hypothyroidism
infants is presumably due to a resetting of the feedback threshold
for T4 suppression of TSH release in these infants. This
resetting occurs in utero.23Nonetheless, after the first
few weeks of treatment serum, TSH is the most important marker for
therapy management.
++
Physical growth and development of infants with congenital hypothyroidism
are usually normalized by early adequate therapy.24,25IQ
values and mental and motor development are also normalized in most
infants with congenital hypothyroidism. However, low normal or occasionally
low IQ values and motor or functional impairments have been reported
in treated children with severe congenital hypothyroidism (very
low serum T4 and delayed bone maturation at birth).26,27 This
is more likely if treatment is delayed. The IQ deficit, although
variable, amounts to several IQ points for every week of delayed
early treatment. Overtreatment resulting in tachycardia, excessive
nervousness, or disturbed sleep patterns may occur
but can be eliminated by frequent dosage adjustment and carries
little or no risk if transient.
++
Infants with presumed transient hypothyroidism caused by maternal
goitrogenic drugs or maternal TSH receptor antibody do not need
to be treated unless the low serum T4 and elevated TSH
levels persist beyond the second week. The half-life of the maternal
autoantibody approximates 2 weeks and, depending on the initial
level, may require several months for degradation. In high titer
cases, treatment is usually required for 2 to 5 months.
++
Infants with thyroid resistance are very difficult to manage,
and treatment must be individualized. It is important to detect
infants with generalized resistance to thyroid hormone (GRTH) as
early as possible. Some patients will be adequately compensated
by the TSH-mediated thyroid hyperplasia and hyperthyroxinemia. Other
patients will be poorly compensated, and compensation will vary
among tissues. The serum TSH level in GRTH patients may be elevated
or within the normal range (albeit high in the face of the hyperthyroxinemia).
An elevated TSH level in the absence of clinical evidence for thyrotoxicosis
is an indication for treatment. Failure to thrive, delayed developmental milestones,
or delayed bone maturation are other indications for treatment.
The levothyroxine treatment dose must be based on the clinical and
laboratory features of the individual patient and may be three to
six times the usual replacement dose.