Congenital Hypothyroidism
Congenital Hypothyroidism
Congenital Hypothyroidism
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
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
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
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
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
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
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
↓ ↓ 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
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
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
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)
↓ ↓ 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
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.
↓ ↓ ↑ ↑ 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
↓ 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
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
<20mU/L
(<34mU/L in 24- 20-40mU/L 40-80mU/L >80mU/L
48h sample)
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