Congenital Hypothyroidism

CONGENITAL
HYPOTHYROIDISM
• Dr C Naveen Kumar,
• PG in Pediatrics
Dr Naveen Kumar Cheri
S.V. Medical College, Tirupati

Contents
 Brief review of Thyroid physiology
 Etiology of Congenital hypothyroidism
 Clinical features
 Post-natal changes in thyroid hormone levels
 Screening Approaches for Congenital Hypothyroidism
 Approach to a newborn with positive screening test
 Antenatal Diagnosis
 Treatment and monitoring of Congenital hypothyroidism
 Prognosis

Thyroid Physiology

Introduction
The gland has two primary functions.
 The first is to secrete the thyroid hormones, which maintain the
level of metabolism in the tissues that is optimal for their normal
function.
 Second function of the thyroid gland is to secrete calcitonin, a
hormone that regulates circulating levels of calcium.

Iodide transport across the thyrocyte
 Iodine is an essential raw material for thyroid hormone
synthesis.
 Dietary iodide is absorbed by the intestine and enters the
circulation.
 The basolateral membrane of thyrocytes facing the capillaries
contain Na+ / I– symporter (NIS) that transports two Na + ions
and one I– ion into the cell with each cycle, against the
electrochemical gradient for I –.
 The process involved is secondary active transport, with the
energy provided by Na+ K+ ATPase.
 Cl – / I – exchanger known as Pendrin is present on the apical
membrane of thyrocytes.
 It mediates transport of iodide out of thyrocyte into the lumen,
where colloid (Thyroglobulin - TG) is located.

Iodide transport across the thyrocyte
Na+ / I– Symporter
Na+ K+ ATPase
Pendrin
Thyroglobulin

Synthesis & secretion of thyroid hormone
 As soon as iodide reaches apical membrane of thyrocyte, it
undergoes a two step process called organification.
 First, it is oxidized to iodine.
 Next step is incorporation of iodine into tyrosine residues of
thyroglobulin.
 DUOX2 (Dual Oxidase-2) located in the apical membrane
generates H2O2, which utilized by thyroid peroxidase (TPO) for
oxidation of iodide into iodine.
 Thyroid peroxidase (TPO) also catalyzes incorporation of iodine
into tyrosine residues of thyroglobulin.
 The thyroid hormones so produced remain part of the
thyroglobulin molecule (colloid) until needed.
 Colloid represents a reservoir of thyroid hormones, which can
serve body requirements up to 2 months. Dr Naveen Kumar Cheri

Na+ / I– Symporter
Na+ K+ ATPase
Pendrin
Thyroglobulin
Dual oxidase - 2
Thyroid Peroxidase

Synthesis & secretion of thyroid hormones
• During incorporation of iodine into Tyrosine residues of
Thyroglobulin, following molecules are formed:
o 3-iodo tyrosine – Monoiodotyrosine (MIT)
o 3,5-di-iodo tyrosine – Diiodotyrosine (DIT)
o Condensation of two DITs - 3,5,3',5'-Tetraiodothyronine (T4)
o Condensation of MIT with DIT - 3,5,3'-Triodothyronine (T3)
o Condensation of DIT with MIT - 3, 3',5'-Triodothyronine (RT3)
 Whenever is a need for thyroid hormone secretion, colloid is
internalized by endocytosis.
 Lysosomal degradation of thyroglobulin occurs. T4 (80 μg/day),
T3 (4 μg/day) & RT3 (2 μg/day) are secreted into circulation.
 MIT and DIT are not secreted, they are deiodinated by a
microsomal iodotyrosine deiodinase and are reutilized.

Transport & metabolism of thyroid hormones
 T4 and T3 are relatively lipophilic, their free forms in plasma are
in equilibrium with a much larger pool of protein-bound thyroid
hormones in plasma.
 Protein binding:
 Maintains large pool of hormone that can readily be mobilized
as needed.
 Prevents excess uptake by the first cells encountered and
promotes uniform tissue distribution
 The plasma proteins that bind thyroid hormones are Albumin,
Transthyretin (Thyroxine-binding Prealbumin) and Thyroxine-
Binding Globulin (TBG).

Transport & metabolism of thyroid hormones
 T3 is 3-5 times more potent than T4.
 Deiodination of T4 occurs at tissue level by Selenocysteine
containing enzyme Deiodinase (D1, D2 & D3 isoforms) to produce
T3 .
Deiodinase activity varies among different tissues & at different
periods.
 Cerebral cortex and pitutary gland have maximal Deiodinase
activity resulting in maximum T3/T4 ratio in them.
 Thyroid hormones enter cells and act by binding to nuclear
receptors. T3 is 3-5 times more potent than T4. RT3 is inert.
Hormone Total plasma level Free hormone level
T4 8 μg/dL 2 ng/dL (0.02%)
T3 0.15 μg/dL 0.3 ng/dL (0.2%)

Effects of thyroid hormones

Congenital
hypothyroidism

Introduction
 Congenital hypothyroidism (CH) is defined as thyroid hormone
deficiency present at birth.
 Most common preventable cause of mental retardation.
 Prevalence 1:3000-4000 Worldwide, 1:2500-2800 in India.
 Twice common in girls compared to boys.
 Till 18-20 weeks, the fetus is dependent on trans-placental passage of
maternal hormones.
 3-4 weeks of gestation
Thyroid gland develops as an endodermal
proliferation.
 12 weeks of gestation T3 & T4 synthesis and secretion begins.
 End of 1st trimester TRH, TSH are detectable.
 Till 18-20 weeks
Hypothyroid Pituitary Thyroid axis activity is
low.

Congenital Hypothyroidism - Terminology
 Primary hypothyroidism: Deficient production of thyroid
hormones, either due to structural (dysgenesis) or functional
(dyshormonogenesis) causes.
 Secondary or central hypothyroidism: Deficiency of thyroid
stimulating hormone (TSH)
 Peripheral hypothyroidism: Results from defects of thyroid
hormone transport, metabolism, or action at the target site.
 Permanent congenital hypothyroidism: Refers to a
persistentdeficiency of thyroid hormone that requires life-long
treatment.
 Transient congenital hypothyroidism: Refers to a temporary
deficiency of thyroid hormone, discovered at birth, but then
recovering to normal thyroid hormone production.
 Syndromic hypothyroidism: Some forms of CH are associated
with defects in other organ systems.

Etiology - Primary Hypothyroidism

Etiology - Secondary Hypothyroidism

Etiology

Thyroid dysgenesis
 It is the cause of > 85% cases of permanent hypothyroidism.
 Includes aplasia, hypoplasia and dysplasia.
 Dysplasia includes failure to descend - Ectopy
 Always sporadic, no increased risk in subsequent siblings.
 2:1 female to male preponderance.
 Rarely associated with abnormality in transcription factors
PAX8, TTF-2, NKX 2.1 etc.
 No goiter, low total and free T4 levels, elevated TSH, and normal
TBG.
 Thyroglobulin (TG) is low in aplasia and hypoplasia. It reflects
the amount of thyroid tissue present.
 Diagnosis: is by Ultrasound and/or thyroid scintiscanning (
Radioactive iodine (RAI) or Pertechnetate - 99mT c)

Thyroid dyshormonogenesis
 Responsible for 10-15 % cases of permanent hypothyroidism.
 Synthetic defects in thyroid hormone production.
 Abnormal thyroid peroxidase activity is the commonest one,
leading to impaired oxidation and organification of iodine.
 Autosomal Recessive inheritance, 25% increased risk in
subsequent siblings.
 Goiter may be present, low total and free T4 levels, elevated
TSH, and normal TBG.
 Thyroglobulin (TG) is low in TG synthetic defects and is high in
other thyroid hormone synthetic defects.
 Imaging: Normally placed thyroid gland, which may be of
normal size or enlarged.
 In cases with partial deficiency, onset of signs and symptoms is
delayed. Dr Naveen Kumar Cheri

Primary hypothyroidism - etiology
Defects of organification and coupling: These are the most
common of the T4 synthetic defects.
 After iodide is trapped by the thyroid, it is rapidly oxidized to
reactive iodine, which is then incorporated into tyrosine units
on thyroglobulin.
 This process requires generation of H2O2, thyroid peroxidase,
DUOX2 Dual Oxidase 2 and hematin (an enzyme cofactor).
 Defects can involve each of these components.
 DUOX2 defects are transmitted in autosomal dominant manner.
 Normal or increased uptake of radioiodine is seen.
 Increased discharge in perchlorate discharge test.

Perchlorate Discharge Test
 Perchlorate discharge test: A test dose of radioiodine
administered first, and then 2 hrs later Potassium perchlorate or
thiocyanate is administered.
• Perchlorate or thiocyanate is a competitive inhibitor of iodine
transport into thyrocyte.
• In normal individuals in whom the organification and coupling
remain intact only <10% of radioiodine is discharged (leaked),
when iodine transport is inhibited.
• In individuals with defective organification and coupling, 40-90%
of radioiodine is discharged (leaked), when iodine transport is
inhibited.

Primary hypothyroidism - etiology
Pendred syndrome:
Autosomal recessive, mutations in PDS gene 7q31 (which encodes
Pendrin - Chloride Iodine exchanger). Bilateral sensorineuronal
hearing loss and congenital hypothyroidism with goiter.
Defect of Iodide Trasport :
 Mutations in the sodium-iodide symporter.
 The energy-dependent mechanisms for concentrating iodide are
defective in the thyroid and salivary glands.
 Uptake of radioiodine and pertechnetate is low.
 Eutopic and normal or enlarged gland on sonography.
Defects of Thyroglobulin (TG) synthesis:
 Characterized by goiter, elevated TSH, low T4 levels, and absent
or low levels of thyroglobulin (TG). Dr Naveen Kumar Cheri

Secondary hypothyroidism - etiology
Thyrotropin and Thyrotropin Releasing Hormone deficiency :
 They can occur in any of the conditions associated with
developmental defects of the pituitary or hypothalamus.
 Usually present with multiple pituitary enzyme deficiencies.
 Features: Hypoglycemia (Growth hormone and ACTH
deficiency), micropenis (gonadotropin deficiency) in association
with septo-optic dysplasia (de Morsier syndrome - optic nerve
hypoplasia, agenesis of septum pellucidum and
hypopituitarism), midline cleft lip.
 PIT-1 & PROP-1 mutations – multiple hormone deficiencies

Peripheral hypothyroidism - etiology
Includes
 Defects in deiodination :
DEHAL1 gene (encodes Iodotyrosine deiodinase) mutations.
 Defects in transport :
Monocarboxylase Trasporter 8 is required to transport T3 into
neurons.
MCT8 mutations lead X Linked hypothyroidism Allan-Herndon-
Dudley syndrome.
It is characterized by mental retardation, quadriplegia, elevated
serum T3 levels, low T4 and normal TSH.

Peripheral hypothyroidism - etiology
 Thyroid hormone unresponsiveness :
Autosomal dominant disorder.
Mutations in the thyroid hormone receptor.
Most patients have a goiter.
Levels of T4, T3, free T4, and free T3 are elevated.
TSH levels are also elevated.

Transient congenital hypothyroidism
 Transfer of maternal blocking antibodies - Maternal
antithyroid antibodies can cross the placenta and block the
TSH receptor in the neonatal thyroid. This effect can last up to
3 to 6 months after birth as maternal antibody levels fall.
 Fetal exposure to antithyroid drugs – They can decrease
neonatal thyroid hormone synthesis which lasts for a few days
to two weeks after birth.
 Maternal iodine exposure - Maternally administered
Amiodarone may cause transient hypothyroidism in infants.
This seems to resolve at around 4-5 months of age. Iodinated
contrast material and iodinated antiseptics administered to
mother can also cause transient hypothyroidism in the infant,
depending on dose and severity of exposure.

Transient congenital hypothyroidism
• Neonatal Iodine exposure - Exposure of newborns to high
amounts of iodine can cause hypothyroidism. (Wolff –
Chaikoff effect).
This can occur especially in preterm infants.
• Liver hemangiomas - Congenital liver hemangiomas produce
large amounts of the enzyme Type 3 iodothyronine
deiodinase. This produces a consumptive type of
hypothyroidism in which large doses of thyroxine are required
to maintain euthyroidism. Serum T4 levels are low, TSH is
elevated, and reverse T3 levels are also increased.

Bamforth - Lazarus Syndrome
 Autosomal Recessive inheritance.
 It is due to loss-of-function missense
mutations in the FOXE1 gene (9q22),
encoding Thyroid Transcription Factor 2
(TTF-2).
 Newborns present at birth with thyroid
dysgenesis (in most cases athyreosis)
leading to congenital hypothyroidism.
 All of them have cleft palate and spiky
hair.
 Some may also present with choanal
atresia and bifid epiglottis.

Congenital Hypothyroidism - Two scenarios
NORMOTHYROID MOTHER &
HYPOTHYROID FETUS
HYPOTHYROID MOTHER &
HYPOTHYROID FETUS
Ex: Thyroid dysgenesis Ex: Iodine deficiency
1. Transplacental passage of
hormones and
2. Increased Type-2 Deiodinase
activity in fetal brain
confer neuro protection.
These mechanisms are impaired.
Near normal cognitive outcome
is possible if post natal therapy
is initiated early.
Significant neuro-intellectual
impairment occurs.

Clinical features of Congenital Hypothyroidism
 Most infants with congenital hypothyroidism are asymptomatic at
birth to the trans-placental passage of maternal T4.
 Post maturity (In 20%, gestation extends beyond 42 weeks)
 Birth weight and length are normal.
 Head size may be slightly increased because of myxedema of the
brain.
 Wide posterior fontanelle
 Prolongation of physiologic jaundice. (Immaturity of hepatic
glucuronyl transferase).
 Sluggishness, cry little
 Poor appetite - feeding difficulties
 Lack of interest, Somnolence
 Protruberent abdomen, umbilical hernia
 Macroglossia
 Cold or mottled skin, hypotonia

 By 3-6 mo of age the clinical picture is fully developed, if
untreated.
 The child’s growth will be stunted, the extremities are short,
and the head size is normal or even increased.
 Coarse facial features: The eyes appear far apart, and the
bridge of the broad nose is depressed. The palpebral fissures
are narrow and the eyelids are swollen. The mouth is kept
open, and the thick, broad tongue protrudes.
 Dentition will be delayed.
 The neck is short and thick, and there may be deposits of fat
above the clavicles and between the neck and shoulders.
 The hands are broad and the fingers are short. The skin is dry
and scaly, and there is little perspiration.

 Myxedema is manifested, particularly in the skin of the
eyelids, the back of the hands, and the external genitals.
 Carotenemia can cause a yellow discoloration of the skin, but
the sclerae remain white.
 The scalp is thickened, and the hair is coarse, brittle, and
scanty. The hairline reaches far down on the forehead.
 Development is delayed.
 Voice is hoarse.
 Sexual maturation may be delayed.

Post natal changes in Thyroid hormones
 TSH
• Within 30-60 min after delivery, there is an early post natal surge
upto 60-80 mU/L in response to cold in utero environment.
• Rapid fall to 20 mU/L in 24 hours.
• Falls to 10 mU/L by one week.
 T4
• Peaks to 17 μg/dL at 24-36 hours.
• Gradual decline over 4-5 weeks.
 Pre-terms exhibit similar but blunted response.

Age based reference values of thyroid hormones

Screening for Congenital Hypothyroidism
 Ideal is universal newborn screening at 3-4 days of age.
 Universal screening: Most cases are sporadic in Iodine sufficient
areas and intellectual impairment can be prevented if treatment
is initiated early.
 In the absence of universal screening, newborns with following
indications must be screened:
1. Having clinical features of congenital hypothyroidism or family
history.
2. History of thyroid disease or anti-thyroid medication intake in
mother.
3. Presence of other conditions like Down’s syndrome, trisomy 18,
neural tube defects, congenital heart disease, metabolic
disorders, familial autoimmune disorders and Pierre- Robin
syndrome which are associated with higher prevalence of
congenital hypothyroidism.

Quebec Clinical Scoring for Congenital Hypothyroidism
CLINICAL STIGMATA SCORING
1. Feeding Problems 1
2. Constipation 1
3. Lethargy 1
4. Hypotonia 1
5. Coarse Facies 3
6. Macroglossia 1
7. Open Posterior Fontanel 1.5
8. Dry Skin 1.5
9. Mottling Of Skin 1
10. Umbilical Hernia 1
Total 13
If the score is > 4 / 13, hypothyroidism is suspected and the child is investigated
accordingly.

Screening Approaches
 Newborn screening is done using cord blood or by heel prick
sample on dried blood spot filter paper at 3-4 days of life.
 Three approaches are being used for screening:
1. Primary TSH, back upT4
2. Primary T4, back up TSH
3. Concomitant T4 and TSH
1. Primary TSH, back upT4:
• TSH is measured first.
• T4 is measured only if TSH is > 20 mu/L.
• This approach is likely to miss central hypothyroidism, thyroid
binding globulin (TBG) deficiency and hypothyroxinema with
delayed elevation of TSH.

Screening Approaches
2. Primary T4, back up TSH:
• T4 is checked first
• If it is low (< 6.5 μg/dL), then TSH is also checked.
• This is likely to miss milder/ subclinical cases of CH in which T4 is
initially normal with elevated TSH.
3. Concomitant T4 and TSH:
• It is the most sensitive approach but incurs higher cost.
 Abnormal values on screening should always be confirmed by a
venous sample, using age appropriate cut-offs.

Significance of free T4 levels
 In most situations, total T4 is sufficient for diagnosis and
monitoring treatment.
 But Free T4 is a more robust marker, as represents the
bioavailable fraction of T4.
In following situations, it is preferable to use free T4:
 Premature or sick newborns: Immature liver function, under-
nutrition & proteinuria >>> Low levels of TBG (Thyroxine Binding
Globulin) or abnormal protein binding.
 Low total T4 and normal TSH:
a) If free T4 is normal >>> Congenital complete or partial TBG
deficiency.
b) If free T4 is low >>> Suspect central hypothyroidism.
 During post treatment monitoring:
First post treatment measurement should include free T4 or TBG.

Approach to a newborn with positive
screening test for Congenital Hypothyroidism
Positive screening test on filter paper sample
Serum T4 / Free T4, TSH
Normal Abnormal
Thyroid Scan
Normal EctopicAbsent Uptake
Ectopic Thyroid Gland
START
TREATMENT -
DON’T WAIT
FOR SCAN

Abnormal T4, TSH & Normal Thyroid Scan
Tg (Thyroglobulin) measurement
Normal Absent
Tg synthetic defect
Transient
congenital
hypothyroidism
Thyroid hormone
synthetic defect
or drug effect
TBII (Thyroid Binding Inhibitory
Immunoglobulin) measurement
Positive Negative

Abnormal T4, TSH & Absent uptake on Thyroid Scan
Ultrasound
Normal gland No thyroid tissue
Thyroid agenesis
TSH receptor or
Thyroid hormone
biosynthetic defect
Transient
congenital
hypothyroidism
TBII (Thyroid Binding Inhibitory
Immunoglobulin) measurement
Positive Negative

Role of investigations other than serum tests in CH
 Tests other than T4 & TSH are not needed to initiate treatment
in congenital hypothyroidism.
 They are required to confirm the etiological diagnosis.
 Useful to take treatment decision in cases with borderline test
results.
 Useful to separate transient & permanent cases.
 If a familial form is encountered, useful for genetic counseling.

Antenatal Diagnosis
 Majority of cases of congenital hypothyroidism are sporadic, not
heritable.
 Women who are at high risk for fetal hypothyroidism are:
 Previous infant with congenital hypothyroidism (resulting from
dyshormonogenesis or maternal TRB-Ab)
 Pregnant woman with Graves’ disease and treated with anti-
thyroid drugs
 Iodide exposure during pregnancy, inadvertent treatment with
radioactive iodine (RAI) after 8-10 weeks gestation.

Antenatal Diagnosis
 Hypothyroidism is suspected if there is fetal goiter, increased
amniotic fluid and fetal bradycardia.
 Measurement of amniotic fluid TSH or thyroid hormone levels
are not reliable, and fetal umbilical cord blood levels are
necessary to diagnose fetal hypothyroidism.
 Genetic testing on fetal cells obtained by amniocentesis
confirms the diagnosis.

Congenital Goiter
 Most cases are sporadic. Dyshormonogenesis, maternal
antithyroid drugs and Iodide usage, endemic Iodine deficiency and
neonatal Graves’ disease are other important causes of congenital
goiter.

Treatment of fetal hypothyroidism
 Significant enlargement of the thyroid at birth may lead to
respiratory distress and can even cause death. Partial
thyroidectomy may be needed in such cases.
 Hypothyroidism diagnosed antenatally is treated with weekly
intra-amniotic injections of L-thyroxine. Initial dose is 250 mcg
of L-thyroxine per week (range 250 to 600 mcg).
 Subsequent dosing was based on the treatment effect in
reducing the size of the fetal and on repeat fetal cord blood
thyroid tests.
 Main aim of antenatal therapy is to shrink the goiter. Role in
long term neuro cognitive outcome is questionable.

Treatment of congenital hypothyroidism
 Infants with low T4 and elevated TSH should be started on L-
Thyroxine as soon as the diagnosis is made.
 Initial dose of L-Thyroxine is 10-15 μg/Kg/day.
 Infants with severe hypothyroidism (very low T4, very high TSH
and absence of distal femoral and proximal tibial epiphyses on
radiograph of knee) should be started with the highest dose of
15μg/Kg/day.
 Preferred preparation is Sodium Levothyroxine. It has uniform
potency, reliable absorption and good bioavailability.
 Daily dose should be crushed and placed directly on the tongue
in the morning.
 Iron and Calcium preparations interfere with its absorption.
 If a dose is missed, then double dose should be given on the
next day. Dr Naveen Kumar Cheri

 Goal of therapy: T4 should be kept in the upper half of normal range
(10-16 μg/dL) or free T4 in the 1.4-2.3 ng/dl range with the TSH
suppressed in the normal range.
 It takes less than a week for T4 to raise and 4-5 weeks for TSH to
normalize.
 Monitoring: T4 and TSH should be monitored according to following
schedule.
 Growth and development of infant should be monitored.
 Overtreatment: Premature fusion of cranial sutures, acceleration of
skeletal maturation, problems with temperament and behavior.
0 to 6 months Every 6 weeks
6 months to 3 years Every 3 months
Beyond 3 years Every 6 months
6 to 8 weeks after any dose change.

 In case of permanent hypothyroidism, the care givers should be
counselled regarding the nature of the condition, need for life
long therapy, compliance and therapeutic monitoring.
 Transient hypothyroidism presumed to be due to maternal
goitrogenic drugs: It needs to be treated, if low T4 and high.
Therapy can be discontinued after 8-12 weeks, if values return
to normal.
 Intake of anti-thyroid drugs can be continued by the
hyperthyroid mothers during breast feeding because
concentration of these drugs is very low in breast milk.

 Transient hypothyroidism presumed to be due to maternal
autoimmune thyroiditis:
 If TBII (Thyroxine Binding Inhibitory Immunoglobulin) are
documented in infant, treatment should be started if T4 is low
and continued for 3-6 months.
 If it is not possible to document TBII, continue treatment till the
age of 3 years and then give a trial off therapy for 6 weeks
followed by retesting of T4 and TSH to determine the need for
continuation of therapy. If they are normal, monitor TSH
annually.

Prognosis
 It depends on age of onset of treatment, starting dose of l-
Thyroxine & severity of hypothyroidism.
 Age of onset of treatment : In infants in whom treatment was
started between birth and 3 months of age, the mean IQ was
89; between 3 and 6 months of age, the mean IQ was 71; while
if treatment did not start until after 6 months of age, the mean
IQ dropped to 54.
 Starting done of l-Thyroxine : Outcome is better in children a
“high” dose 10.1-15 mcg/kg/day than “low” dose 6-8
mcg/kg/day and “intermediate” dose 8.1-10.0 mcg/kg/day.
 Severity of hypothyroidism : Neonates having complete
athyreosis, very low pre-treatment T4 levels and presenting with
epiphyseal dysgenesis have poorer outcome.

Key messages
 Congenital hypothyroidism is quite common in Indians and is the
most common reversible congenital cause of mental retardation.
 Early identification and intervention is important as Thyroid
dependent brain development is complete by 3 years of age.
 Universal screening is ideal as most cases are sporadic.
 Positive cases on screening by filter paper test should be confirmed by
serum levels estimation.
 Serum Thyroid hormone levels are of primary importance in
diagnosing and managing this condition, other investigations are
ancillary.
 Age based reference values must be followed in interpreting the
results.
 Timely monitoring (serum hormone levels, compliance, growth &
development) and adequate counseling of care givers are key in
managing this condition. Dr Naveen Kumar Cheri

Thank you

Congenital Hypothyroidism

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