Approach to Management of Congenital Hypothyroidism-Juniper Publishers
Juniper Publishers-Journal of Pediatrics
Abstract
Congenital hypothyroidism (CH) is the commonest cause
of preventable developmental delay with an incidence of 1/3500-4500
newborns. The incidence of symptomatic cases has decreased dramatically
in the developed countries with the advent of newborn screening.
However, much work still needs to be done in the developing world in
improving awareness and devising newborn screening strategies etc. In
this article, we discuss the diagnosis and management of congenital
hypothyroidism.
Keywords: Red blood cell transfusion; Malondialdehyde; Ferritin; PretermAbbreviations: CH: Congenital Hypothyroidism; DHG: Dyshormonogenesis; TSH: Thyroid Stimulating Hormone; T4: Thyroxine; TBG: Thyroid Binding Globulin; TS: Thyroid Scintigraphy; TRB-Ab: Thyroid Receptor Blocking Antibody;
Introduction
Congenital hypothyroidism (CH) is the commonest cause
of preventable developmental delay with an incidence of 1/3500-4500
newborns. Thyroxine is essential for normal brain development, and its
deficiency in early infancy leads to irreversible developmental delay in
addition to other features of hypothyroidism, referred to as cretinism.
However, with the advent of newborn screening, it is rare to see
established congenital hypothyroidism in the developed countries. It is
mainly sporadic with some familial cases (2-5%). Majority are permanent,
though some cases are transient. Primary hypo-thyroidism is the main
category, with dysgenesis in 85% and dyshormonogenesis (DHG) in 10-15%
[1]. Central hypothyroidism of pituitary origin is much rarer (1 in
30,000-50,000) [1]. In this article, we don’t intend to review
physiology of thyroid hormonogenesis, focusing mainly on diagnosis and
management of congenital hypothyroidism.
Diagnosis
With the worldwide implementation of newborn
screening (with the exception of some developing countries), majority of
cases of CH are diagnosed following abnormal newborn screening. Most
countries measure Thyroid stimulating hormone (TSH) as the primary test,
with the test being done beyond 48 hours after
birth to avoid false positives from the postnatal TSH surge. False
negative screening result may be seen in preterm babies, central
hypothyroidism and hypothyroxinaemia. It is unlikely that missing
central hypothyroidism by this method is a significant problem, as most
such babies are diagnosed early due to manifestations of other anterior
pituitary hormone deficiencies.
Some countries measure Thyroxine (T4) which is
advantageous in detecting primary hypothyroidism, thyroid binding
globulin (TBG) deficiency, central hypothyroidism and hypothyroxinaemia.
False negatives may be seen in patients with initial normal T4 and
delayed TSH increase [2]. Screening is done at 2-5 days of age in most
countries. The cutoff is variable in different centres [3], ranging
between 8-10 mu/L. TSH≥10 mU/L on second screening requires evaluation.
Ideally, evaluation after abnormal screening results and start of
treatment should happen by 10 days of age.
Confirmation of Diagnosis
Immediate endocrine evaluation is required on
obtaining an abnormal screening result. History of maternal drugs,
medications, maternal hypothyroidism and family history should be
elicited.
Tests include repeat TSH, free T4 (fT4) and T3. Combination of
low fT4, low normal T3 and elevated TSH confirm diagnosis of
primary CH [2]. Treatment should be initiated as soon as possible
and no later than 2 weeks of age, preferably immediately after
confirmatory venous TFT [4].
Investigations
Though clinical practice is variable in terms of which
investigations are carried out after diagnosis of CH, it is
recommended to carry out ultrasound and radio-isotope scanning
in all cases early. This will help in understanding the underlying
cause, reinforcing to the parents the potentially lifelong treatment
needed as well as removing the need for possible re-evaluation at
2-3 years in most cases.
Ultrasonography (US)
US can detect thyroid tissue not identified on thyroid
scintigraphy (TS) and also pick up morphological thyroid
abnormalities. Absent gland is seen in agenesis and small ectopic
nubbin in dysgenesis. In maternal thyroid receptor blocking
antibody (TRB-Ab) and DHG, the gland is normal and goitrous
respectively [5,6].
Thyroid Scintigraphy (TS)
TS is the gold standard in evaluating CH especially ectopia
and also helps diagnose agenesis. Iodine-123 or technetium
pertechnetate are used of which the former is preferred. As TSH
suppression decreases uptake, it should be carried out within
3-5 days of start of treatment (with TSH >5 mU/l) [5]. Absent
radioactive Iodine uptake (RAIU) indicates aplasia or hypoplasia
but if US is normal, may indicate TSH-receptor defect, iodinetransport
defect (N/I symporter (NIS)) and maternal antibody
TRB-Ab [2]. Uptake in a normal or goitrous gland is suggestive
of DHG. Scintingraphy may not be considered essential by some
as it may not change the treatment indication and the dose and
treatment should not be delayed to perform scintigraphy [5,6].
Once the above two tests have been carried out, the diagnosis
can be narrowed down to dysgenesis (in which case no further
testing is needed) and DHG, in which case both genetic and enzyme
pathway based tests may be needed. Other tests in such cases
include Perchlorate discharge test (PDT), Thyroglobulin (Tg),
Serum TRB-Ab, genetic screening, urinary iodine and Thyrotrophin
releasing hormone (TRH) testing depending on history and
specific evaluation. Major congenital especially cardiovascular
anomalies are reported to occur in up to 10% of newborns with
CH [9]. All patients require hearing screen (hearing impairment
seen in 20%) and cardiac evaluation [7,8]. X-rays of the knee for
bone age to assess severity was previously done as it indicates
antenatal hypothyroidism. In central hypothyroidism, assessment
for other hormone deficiencies, MRI brain, and ophthalmology
evaluation are required. TSH beta mutation should be checked in
isolated TSH deficiency [9,10,11].
Management
Levothyroxine (L-T4)
After confirmation of diagnosis, immediate treatment with
L-T4 10-15 μg/kg normalizes T4 and TSH within 7-30 days [9].
Lower doses were found not to normalize TFT. Higher dosing (12-
17 μg/kg/d) normalizes fT4 in 3 days and the TSH in 2-4 weeks
with full scale IQ scores 11points higher than those started on
10-15 μg/kg/day but at risk of side effects [12,13]. Initial dose of
50 μg daily (14 μg/kg/day) is recommended for 5 to 7 days with
subsequent reduction to 37.5 μg (11 μg/kg/day) [9]. The tablet
should be crushed and suspended in a few ml of milk or water.
Concomitant intake of soya, iron, calcium, fiber should be avoided
[2]. Written information and education should be provided
focusing on etiology, need for early and regular treatment and
regular follow-ups. Pharmaceutically produced L-T4 liquid can
also be used [4]. The dose should be adjusted to ensure normal
growth and development aiming for low normal TSH (0.5-2.0
mU/L and fT4 in upper half of reference range in the first 3 years
of life [2,4]. The aim is to normalize T4 within 2 weeks and TSH
within 1 month [4,5].
Iodine
Iodide supplementation with/without thyroxine may be
useful in NIS defect and residual enzyme activity. Iodide intake is
beneficial in maintaining euthyroid status in Pendred syndrome
and in DUOX2 mutation. Lugol’s Iodine has been used as an
alternative to L-T4 treatment in dehalogenase deficiency [1,8].
Monitoring
Clinical review with growth, (weight, length and head
circumference) developmental and biochemical assessment is
required in the first 3 years of life. Thyroid function is rechecked
after 2-4 weeks, 1-2 monthly in the first 6 mo, 3-4 monthly between
6 months to 3 years of age and 6-12 monthly from 3 years of age till
completion of growth and more frequently if there are concerns
about compliance or with change in dose or source of medication.
TFT should be checked at least 4 hours after the last dose and dose
reduction should not be based on a single elevated fT4 levels. If
fT4 does not increase into the upper half of the reference range
by 2 weeks and/or TSH does not fall to <20 mU/L within 4 weeks,
compliance, dose and method of administration should be checked
[2]. Inadequate TSH suppression may be due to poor compliance,
malabsorption, or increased degradation (anticonvulsants,
large hemangiomas with high deiodinase activity). In persistent
TSH elevation due to resetting of feedback or relative pituitary
resistance, fT4 is used to titrate the dose. Overtreatment should
be avoided as prolonged hyperthyroidism has been associated
with craniosynostosis, poor concentration, behavioural problems,
acceleration of growth and skeletal maturation2.
Re-evaluation
Re-evaluation should be performed if initial diagnostic
assessment was not done or did not suggest permanent CH, initial TSH was <50 mU/L, especially in preterm/sick babies or
if no TSH increase was noted after the newborn period, normal/
slightly small gland was seen on USS with little or no uptake
on scintigraphy. It is not required if dual imaging at diagnosis
confirmed ectopy orathyreosis. L-T4 should be discontinued for
30 days after 3 years of age. After 30 days, if TSH is elevated to
10-20 mU/L and fT4 is low, the hypothyroidism is permanent
and treatment should be resumed. Alternatively, dose may be
reduced by 30-50% for 2-3 week. If the TSH is normal, the dose
can be reduced further or stopped, with retesting after another
2-3 weeks. TFT should be repeated if any symptoms arise, he/
she should not be lost to follow-up. If the results are inconclusive,
careful follow-up and subsequent testing will be necessary [4].
Outcome
After introduction of neonatal screening, the prevalence of
frank learning disability is minimal (1.4-4% attending special
schools) [5]. Median IQ is reported to be normal due transplacental
supply of maternal T4 and enhanced conversion to T3 offering
neuro protection, however, mean IQ difference of 8-10.3 has
been reported between patients and controls [5]. Problems with
aggression, attention, memory and concentration, anxiety and
less sociability have been reported. Some growth issues have
been described, but if treatment is started early, there is unlikely
to be any impact. Increased prevalence of hearing impairment
(HI) compared with controls (9.5% versus 2.5%) is reported, and
ongoing hearing monitoring is essential. Cardiovascular health
should be monitored as well. It is advisable to involve a pediatric
endocrinologist in the initial stage of the evaluation, after which the
pediatrician can follow up with support from the endocrinologist.
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