CONGENITAL

HYPOTHYROIDISM

Presented by
Dr. Aja Patel
Under guidance of
Dr. Somashekhar Nimbalkar sir
➢Synthesis of thyroid hormones
➢Regulation of thyroid hormones
➢Normal thyroid physiology in fetus and
newborn
➢Classification of congenital hypothyroidism
➢Manifestations of congenital hypothyroidism
➢Diagnosis of congenital hypothyroidism
➢Treatment of congenital hypothyroidism
 SYNTHESIS OF THYROID HORMONES
• SITE?
➢Thyroid follicle
• SUBSTRATES?
➢Tyrosine, Iodine
• WHEN?
➢Continuous process
SYNTHESIS OF THYROID HORMONES-
STEP 1
Thyroglobulin Synthesis
• Endoplasmic reticulum and Golgi apparatus in
the follicular cells of thyroid gland synthesize
and secrete thyroglobulin continuously.
• Thyroglobulin molecule is a large glycoprotein
containing 140 molecules of amino acid
tyrosine.
• After synthesis, thyroglobulin is stored in the
follicle.
SYNTHESIS OF THYROID HORMONES-
STEP 1

Thyroglobulin Synthesis
SYNTHESIS OF THYROID HORMONES-
STEP 2
Iodide Trapping
• Iodide is actively transported from blood into
follicular cell, against electrochemical gradient.
• Iodide is transported into the follicular cell along
with sodium by Na/I symport pump, which is also
called iodide pump (secondary active transport)
• Normally, iodide is 30 times more concentrated in
the thyroid gland than in the blood.
SYNTHESIS OF THYROID HORMONES-
STEP 2

Iodide Trapping
SYNTHESIS OF THYROID HORMONES-
STEP 3
Transport of Iodine into Follicular Cavity
• From the follicular cells, iodine is transported
into the follicular cavity by an iodide-chloride
pump called pendrin.
SYNTHESIS OF THYROID HORMONES-
STEP 3
Transport of Iodine into Follicular Cavity
SYNTHESIS OF THYROID HORMONES-
STEP 4
Iodination of Tyrosine (organification of
thyroglobulin)
• Combination of iodine with tyrosine is known as
iodination.
• It takes place in thyroglobulin.
• Iodination process is accelerated by the enzyme
iodinase, which is secreted by follicular cells.
• Iodination of tyrosine occurs in several stages.
• Tyrosine is iodized first into monoiodotyrosine
(MIT) and later into di-iodotyrosine (DIT).
• MIT and DIT are called the iodotyrosine residues
SYNTHESIS OF THYROID HORMONES-
STEP 4
Iodination of Tyrosine
(organification of
thyroglobulin)
SYNTHESIS OF THYROID HORMONES-
STEP 5
Coupling reactions
• Tyrosine + I = Monoiodotyrosine (MIT)
• MIT + I = Di-iodotyrosine (DIT)
• DIT + MIT = Tri-iodothyronine (T3)
• MIT + DIT = Reverse T3
• DIT + DIT = Tetraiodothyronine or Thyroxine
(T4)
SYNTHESIS OF THYROID HORMONES-
STEP 5
Coupling reactions
 SYNTHESIS OF THYROID HORMONES-
STEP 6
Release of thyroid hormones
• The thyroid hormones cross the follicular cell
membrane towards the blood vessels by an
unknown mechanism.
• It was believed that diffusion is the main means of
transport, but recent studies indicate
that monocarboxylate transporter (MCT) 8 and 10
play major roles in the efflux of the thyroid
hormones from the thyroid cells.
• Approximately 100 mcg of thyroglobulin is
released from the thyroid each day.
SYNTHESIS OF THYROID HORMONES-
STEP 6
Release of thyroid hormones
 SYNTHESIS OF THYROID HORMONES

2
3

5
6
 Recycling of Iodide
• The iodotyrosines liberated from thyroglobulin
are deiodinated by iodotyrosine deiodinase.
• Most of the iodide is then recycled for thyroid
hormone synthesis.
• Homozygous mutations in DEHAL1, the gene
that encodes iodotyrosine deiodinase, result
in iodotyrosine deiodinase deficiency with
hereditary and sometimes severe
hypothyroidism and goiter.
 T3 production
• Only 20 percent of T3 is directly produced in
thyroid gland
• Remaining 80 percent of the T3 produced is
formed by 5'-deiodination of T4 in
extrathyroidal tissue – EXTRATHYROIDAL T3
PRODUCTION
• Sites: liver, kidney
• Other sites: muscle, brain, pituitary, skin,
placenta
 SERUM BINDING PROTEINS
More than 99.95% of T4 and 99.5% of the T3 in
serum are bound to several serum proteins:
• thyroxine-binding globulin (TBG)
• transthyretin (TTR, formerly called thyroxine-
binding prealbumin [TBPA])
• albumin
• lipoproteins
 SERUM BINDING PROTEINS

Copyrights apply
 SERUM BINDING PROTEINS
% of thyroid
hormones in T4 T3
bound form

TBG 75 80

TTR 10 5

Albumin 12 12

Lipoprotein 3 3
Copyrights apply
 SERUM BINDING PROTEINS

It is the serum free T4 and T3 concentrations that

determine the hormones' biological activity.
The binding proteins serve to maintain the serum
free T4 and T3 concentrations within narrow
limits, yet ensure that T4 and T3 are
immediately and continuously available to
tissues.
These proteins, therefore, have both storage and
buffer functions.

Copyrights apply
REGULATION OF THYROID HORMONES
REGULATION OF THYROID HORMONES
 NORMAL THYROID PHYSIOLOGY IN
THE FETUS
• First half of pregnancy- T4 in fetus is of
maternal origin
• Second half of pregnancy – T4 production
switches over from maternal to fetal origin
 NORMAL THYROID PHYSIOLOGY IN
THE FETUS
• Maternal T4 partially protects a hypothyroid
fetus in-utero.
• The fetus is dependent on maternal iodine
intake, and iodine is transferred across the
placenta for fetal thyroid hormone
production.
THYROID PHYSIOLOGY IN THE FETUS
AND NEWBORN

Gilbert ME et al, Neurotoxicology, 2012; 33:842-52

THYROID PHYSIOLOGY IN THE FETUS
AND NEWBORN

UpToDate
 POSTNATAL THYROID FUNCTION IN
TERM INFANTS
• Serum TSH concentrations rise abruptly to 60 to
80 mU/L within 30 to 60 minutes after delivery in
healthy term babies
• This rise is associated with stress during labor,
exposure of the infant to a colder environment
and clamping of the umbilical cord.
• The serum TSH concentration then decreases
rapidly to approximately 20 mU/L 24 hours after
delivery and then more slowly to 6 to 10 mU/L at
one week
POSTNATAL THYROID FUNCTION IN
TERM INFANTS

Brook’s Pediatric Clinical Endocrinology, 6th Edition

 POSTNATAL THYROID FUNCTION IN
TERM INFANTS
• The initial surge in TSH stimulates thyroidal T4
secretion, so that serum total and free T4
concentrations rise to a peak at 24 to 36 hours
of life
• Serum T3 concentrations also rise
concomitantly
• The increase in serum T3 is a result of
increases in both thyroidal secretion and
conversion of T4 to T3 in peripheral tissues.
 CONGENITAL HYPOTHYROIDISM
• Incidence- 1:1200 in Asian Indian infants
• 1:2000 to 1:4000 - United States, Canada,
European countries, Israel, Australia, New
Zealand, Japan
• twin births - 1:900
• multiple births - 1:600
• consanguinity further increases the risk
• female:male :: 2:1
Trends in incidence rates of congenital hypothyroidism related to select demographic factors:
data from the United States, California, Massachusetts, New York, and Texas. 2010
 CONGENITAL HYPOTHYROIDISM
• Incidence more common in infants with
Trisomy 21, congenital heart disease, other
congenital malformations like cleft palate,
renal, skeletal and GI anomalies
 CONGENITAL HYPOTHYROIDISM
• It is one of the most common preventable
causes of intellectual disability
• There is an inverse relationship between age at
treatment initiation and intelligence quotient
(IQ) later in life, so that the longer the
condition goes undetected and untreated, the
lower the IQ
 Inverse relationship between age at
treatment initiation and IQ

Klein, A. H., Meltzer, S., and Kenny, F. M. (1972); 81:912-5

 Primary hypothyroidism
• Inadequate thyroid hormone production in
the gland itself.

Central hypothyroidism
• Defects in the production of TSH due to either
hypothalamic or pituitary dysfunction.
 Permanent hypothyroidism
• Thyroid dysgenesis
• Thyroid dyshormonogenesis
• TSH resistance
• Central hypothyroidism

Transient hypothyroidism
• Antithyroid drugs
• Iodine excess
• Iodine deficiency
• Transient hypothyroxinemia of prematurity
• TSH receptor blocking antibodies
• Large liver hemangiomas
Permanent hypothyroidism
 Thyroid dysgenesis
• Abnormal thyroid gland development :
agenesis, hypoplasia, or ectopy
• Accounts for 70% cases of permanent CH
• Sporadic

TOTAL T4 FREE T4 TSH THYROGLOBULIN IMAGING

Absent, small,
↓ ↓ ↑ ↓
ectopic
 Thyroid dyshormonogenesis
• Defects in thyroid hormone synthesis and secretion
• Accounts for remaining ~30% cases of permanent
CH
• 25% recurrence in siblings
• m/c- abnormal TPO (thyroid peroxidase) activity
• Other : defects in TG synthesis, iodine trapping,
hydrogen peroxidase generation, iodotyrosine
deiodination

TOTAL T4 FREE T4 TSH THYROGLOBULIN IMAGING

Normal or
↓ ↓ ↑ ~
large
 TSH resistance
• Mutations in TSH receptors- AD or AR
• May be a/w pseudohypoparathyroidism
(mutations are maternal in origin)
 TSH resistance
• In such cases, hypothyroidism is mild and, despite
thyroid hormone treatment, linear growth slows,
accompanied by excessive weight gain
• Screening for hypocalcemia and elevated PTH levels
to confirm PTH resistance should be done.
• Severity of symptoms depends on degree of TSH
resistance

TOTAL T4 FREE T4 TSH THYROGLOBULIN IMAGING

Normal or
N or ↓ N or ↓ ↑ ↓
small
 Central hypothyroidism
• Hypothalamic-pituitary hypothyroidism
• May be missed on primary TSH NB screen
• Affected infants usually have other signs of
pituitary dysfunction
• If suspected, cortisol, GH should be measured
• MRI – to visualize hypothalamus and pituitary

TOTAL T4 FREE T4 TSH THYROGLOBULIN IMAGING

↓ ↓ N or ↓ ↓ Normal
 Central hypothyroidism
• associated with other congenital syndromes,
particularly midline defects such as optic nerve
hypoplasia/septo-optic dysplasia or midline cleft
lip and palate defects and may follow birth trauma
or asphyxia
• May be caused by insufficient treatment of
maternal Graves hyperthyroidism during
pregnancy. This form of central hypothyroidism
may persist beyond six months of age, especially
when maternal thyrotoxicosis occurred before 32
weeks gestation
Transient hypothyroidism
 Antithyroid drugs
• Intrauterine exposure to Methimazole or
Propylthiouracil
• Can cross the placenta
• Resolves within 1 week after birth without any
treatment

TOTAL T4 FREE T4 TSH THYROGLOBULIN IMAGING

Normal or
↓ ↓ ↑ N or ↑
large
 Iodine excess
• Antenatal or perinatal or neonatal exposure to
high levels of iodine.
❖Infants of mothers treated with Amiodarone
❖iodine-containing antiseptic compounds are used
in mothers or infants
❖after amniofetography with an iodinated
radiographic contrast agent
❖Mothers who ingest large amounts of iodine-
consumption of seaweed – iodine is secreted in
breastmilk
 Iodine excess
• At risk population: premature infants (<36 weeks
more susceptible to thyroid suppressing effects of
iodine), preterm or term infants with congenital
heart defects or other anomalies (due to exposure
to iodine through the skin and/or in contrast
media used for cardiac catheterization or
lymphangiography)
• ↑ urinary iodine

TOTAL T4 FREE T4 TSH THYROGLOBULIN IMAGING

Normal or
↓ ↓ ↑ ↑
large
 Iodine deficiency
• Low maternal dietary iodine intake- recommended
iodine intake during pregnancy - 250 to 300 mcg/day
• more common in preterm infants
• ↓ urinary iodine

TOTAL T4 FREE T4 TSH THYROGLOBULIN IMAGING

Normal or
↓ ↓ ↑ ↑
large
UNICEF. UNICEF Data: Monitoring the situation of children and women.
http://data.unicef.org/nutrition/iodine
UNICEF. UNICEF Data: Monitoring the situation of children and women.
http://data.unicef.org/nutrition/iodine
 Transient hypothyroxinemia of
prematurity
• m/c- infants born before 31 weeks gestation
• Hypothalamic-pituitary immaturity
• Precipitating factors – acute illness, medications
(dopamine, steroids)
• Adverse outcomes: NND, IVH, PVL, CP, intellectual
impairment, school failure
• Treatment- ?? (infants <27 weeks gestation may
benefit from L-thyroxine supplementation)

TOTAL T4 FREE T4 TSH THYROGLOBULIN IMAGING

↓ ↓ N N Normal
 TSH receptor-blocking antibodies
• Maternal autoimmune thyroid disease
• Transplacental transfer
• 1:180,000 newborns
• IgG antibodies- t1/2 ~2 weeks
• Neonatal hypothyroidism persists for ~2-3 months

TOTAL T4 FREE T4 TSH THYROGLOBULIN IMAGING

Normal or
↓ ↓ ↑ ↓
small
 Large liver hemangiomas
• a/w severe refractory primary hypothyroidism due to
massive expression of thyroid hormone inactivating
D3 by the hemangioma
• "consumptive hypothyroidism"
• Treatment- large doses of L-thyroxine and often T3
• The hypothyroidism usually resolves as the
hemangioma regresses.

TOTAL T4 FREE T4 TSH THYROGLOBULIN IMAGING

↓ ↓ ↑ ↑ Normal
 TBG deficiency
• Hereditary – Hereditary TBG deficiency is an X-linked
recessive disorder
• Hormonal abnormalities – high doses of androgens
• Nephrotic syndrome – Urinary loss of TBG
• Drugs – L-asparaginase, danazol, and niacin lower
serum TBG by decreasing TBG production.
• Starvation, poor nutrition

TOTAL T4 FREE T4 TSH THYROGLOBULIN IMAGING

↓ N N N Normal
 Causes of Permanent CH

TOTAL
FREE T4 TSH TG IMAGING TREATMENT
T4

Absent/
DYSGENESIS ↓ ↓ ↑ ↓ small/ ✓
ectopic

Normal/
DYSHORMONOGENESIS ↓ ↓ ↑ ~ ✓
large

Normal/ Depends on
TSH RESISTANCE N/↓ N/↓ ↑ ↓
small severity

CENTRAL
↓ ↓ N/↓ ↓ Normal ✓
HYPOTHYROIDISM
 Causes of Transient CH
TOTAL
FREE T4 TSH TG IMAGING TREATMENT
T4
MATERNAL
Normal/
ANTITHYROID ↓ ↓ ↑ ↑ Not usually
large
MEDICATION
TSH RECEPTOR Normal/
↓ ↓ ↑ ↑ ✓
BLOCKING ANTIBODIES small
HYPOTHYROXINEMIA
↓ ↓ N N Normal Controversial
OF PREMATURITY
Normal/
IODINE DEFICIENCY ↓ ↓ ↑ ↑ ✓
large
Normal/
IODINE EXCESS ↓ ↓ ↑ ↑ ✓
large

LIVER HEMANGIOMA ↓ ↓ ↑ ↑ Normal ✓

TBG DEFICIENCY
↓ N N N Normal No
 Atypical congenital hypothyroidism
• Hypothyroxinemia with delayed TSH elevation
• d/t recovery from sick euthyroid syndrome
• m/c- VLBW (1/58), LBW (1/95), newborns with
CHD
• Monozygotic twins discordant for CH – mixing
of fetal blood before birth- allows the normal
twin’s thyroid to compensate for CH of the
affected twin
 Clinical Manifestations
• Asymptomatic
• Symptomatic
• Associated congenital malformations
 Asymptomatic
• ~95% newborns with CH are asymptomatic
• WHY?
✓Maternal thyroxine (T4) crosses the placenta :
umbilical cord serum T4 concentrations are
~25-50% of those of normal infants
✓Many infants with CH have some, albeit
inadequate, functioning thyroid tissue
 Asymptomatic: subtle clues
• Birth length and weight : within the normal range
• birth weight often is at a relatively higher
percentile than birth length, owing to myxedema
• head circumference also may be increased.
• knee epiphyses often lack calcification
(M:F :: 40:28)
• reduced variability in fetal heart rate tracings
 Symptomatic
• symptoms and signs: develop over the first few
months of life
• Prenatal ultrasound- goiter
• Goiter may be clinically noticed later in life
 Symptomatic
• Lethargy • Macroglossia
• Hoarse cry • Umbilical hernia
• Feeding problems • Large fontanels
• Often needing to be • Hypotonia
awakened to nurse • Dry skin
• Constipation • Hypothermia
• Puffy (myxedematous) • Prolonged jaundice
and/or coarse facies (primarily unconjugated
hyperbilirubinemia)
 Symptomatic
• In central CH, the c/f are often related to associated
deficiencies of other pituitary hormones:
✓ hypoglycemia (growth hormone and
adrenocorticotropic hormone)
✓ micropenis (growth hormone and/or gonadotropins)
✓ undescended testes (gonadotropins)
✓ least commonly, features of diabetes insipidus
(vasopressin)
✓ Hearing loss in an infant with central hypothyroidism
may be a tip-off to a TBL1X mutation
 Associated congenital malformations
CH a/w congenital defects
✓Heart
✓Kidneys
✓Urinary system
✓Gastrointestinal tract
✓Skeleton
 Diagnosis
Newborn screening Rationale
• CH is a common disorder
• TSH is relatively cheap and easily available
• Benefit of treating is many times more than
cost of screening
 Which sample?
ADVANTAGE DISADVANTAGE

•Easy to draw •Other disorders cannot be

•No extra prick screened
CORD •Suitable during early •Staff needs to be trained to
BLOOD discharge collect sample immediately at
SAMPLE •Sample can be processed delivery
at any local lab •Not feasible for home
deliveries
•Can be used to screen •Needs special assay and
multiple disorders reliable central lab
HEEL •Only morning shift staff •Adequate training required to
PRICK needs to be trained ensure error free blood spots
•Can be done for home
deliveries
 Which sample?

• Postnatal peripheral venous sample is

acceptable if filter paper sample is not
feasible.
HEEL PRICK SAMPLE
 Timing of sample?
• Cord sample OR
• Postnatal sample at 48-72 hours (not later than
5 days)
• if early discharge is planned, sample may be
sent at 24-48 hours (but cut offs are different)
➢No difference in timing of collection for term
and preterm
➢For sick newborns in NICU, sample should be
collected before 7 days of age, or before
discharge, whichever is earlier
No infant should be sent at home
without screening for CH !
 Approaches to Screening
• Primary TSH → backup T4
• Primary T4 → backup TSH
• Concomitant T4 & TSH
 Approaches to Screening
ADVANTAGE DISADVANTAGE
•Cost effective Likely to miss central
Primary TSH → •Most sensitive for CH, TBG deficiency,
backup T4 primary CH hypothyroxinemia
with delayed
evaluation of TSH
Sensitive for central •Likely to miss milder
Primary T4 → backup
CH subclinical CH
TSH
•Higher false positive
results
Concomitant T4 & Ideal approach Higher cost
TSH
 Approach to Screening
• Indian Society of Pediatric and Adolescent
Endocrinology (ISPAE) guidelines recommend
primary TSH assay for screening of CH (2018)
 Interpretation of Results
Cord blood/heel
prick TSH

<20mU/L
(<34mU/L in 24- 20-40mU/L 40-80mU/L >80mU/L
48h sample)

Repeat TSH & Repeat TSH & Repeat TSH &

Normal screen FT4/T4 at 7-10 FT4/T4 urgently FT4/T4 &
DOL within 72 h immediately
start treatment
Not s/o CH s/o CH Not s/o CH s/o CH without waiting
for results

Normal screen Normal screen

Start treatment

TSH >20 in <2wk Start treatment

TSH >10 in ≥2wk
Interpretation of Confirmatory sample
TSH
HIGH NORMAL

LOW HYPOTHYROIDISM SCENARIO A

FT4

NORMAL
SCENARIO B NORMAL
Interpretation of Borderline Thyroid function
Scenario B (low T4 with
normal TSH)
Scenario A (borderline ↓
high TSH with normal T4)
R/O hypothyroxinemia of
↓ pregnancy, sick euthyroid,
Retest after 2 weeks TBG deficiency, pituitary
↓ defects
Treat if TSH >10 after 3 weeks ↓
of life even with normal T4 Treat if consistent with central
CH
In other cases, repeat TFT after
2-4 weeks, and treat if
persistently low T4 or
delayed rise in TSH
Thyroid Imaging
 Treatment
• Tab L-thyroxine 10-15 mcg/kg/day with the
aim to normalize T4 levels
• Severe cases- start with highest dose
• Dissolve in ~5-10 ml of breast milk- to be fed
directly with spoon (NOT to be added to
feeding bottle)
• Avoid intake of iron/calcium/soya/vitamins
within 3-4 hours of ingestion of tablet
• Counselling
Written information
to parents in a
language which
they understand

Available on
www.ispae.org.in
 Further biochemical follow up

Follow up depends on degree of variations in TSH/FT4/T4 levels

AIIMS Protocols in Neonatology, 2nd Edition
 Follow up
• TSH & T4:
✓TSH in lower half of normal range
✓T4 in upper half of normal range
• Growth and puberty:
✓Height and weight monitoring
✓Tanner staging
• Development
✓Developmental assessment at each follow up
✓Head circumference
 Follow up
• A re-evaluation of the thyroid axis is
warranted at the completion of 3 years in
babies in whom the possibility of transient CH
exists such as those started on treatment
before complete evaluation, sick babies,
preterms, those with a normal gland on
imaging or mild dyshormonogenesis.
• This is done by temporarily stopping LT4 for a
period of 4 wk and repeating the thyroid
function tests and thyroid scan.
 Follow up
• Alternatively, if the permanence of CH is to be
confirmed without etiological diagnosis, the dose
may be tapered by one-third for 2–3 wk and the
TSH level rechecked.
• If the TSH level shows a rise of >10 mIU/L, then
permanence is confirmed and treatment
continued.
• If TSH level does not rise, the dose may be further
tapered, stopped and then retested.
• In those babies with proven agenesis or ectopic
thyroid there is no need for reevaluation
 Follow up
• In those babies with proven agenesis or
ectopic thyroid there is no need for
reevaluation
• Prevention of poor neurological and overall
outcome in CH is possible.
• Screening of high risk mothers: maintain
trimester specific desired range of TSH
• Screen all neonates
• Advocate early treatment
• Ensure regular follow up
Thank you
 References
• AIIMS Protocols in Neonatology, 2nd Edition
• Cloherty and Stark’s Manual of Neonatal Care,
8th Edition
• Nelson Textbook of Pediatrics, 21st Edition
• Indian Society for Pediatric and Adolescent
Endocrinology (ISPAE) Guidelines
• UpToDate- Anatomy and Physiology of Thyroid
gland, Congenital Hypothyroidism