2. ➢Synthesis of thyroid hormones
➢Regulation of thyroid hormones
➢Normal thyroid physiology in fetus and
newborn
➢Classificationof congenital hypothyroidism
➢Manifestationsof congenital hypothyroidism
➢Diagnosis of congenital hypothyroidism
➢Treatment of congenital hypothyroidism
4. Thyroglobulin Synthesis
• Endoplasmicreticulum and Golgi apparatusin
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
6. 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
8. 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
9. Transport of Iodine into Follicular Cavity
SYNTHESIS OF THYROID HORMONES-
STEP 3
10. 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
12. 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
14. 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
18. 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.
19. 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
20. 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
22. Copyrights apply
SERUM BINDING PROTEINS
% of thyroid
hormones in
bound form
T4 T3
TBG 75 80
TTR 10 5
Albumin 12 12
Lipoprotein 3 3
23. Copyrights apply
SERUM BINDING PROTEINS
It is the serum free T4 and T3 concentrationsthat
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.
26. 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
27. 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.
28. Gilbert ME et al, Neurotoxicology,2012; 33:842-52
THYROID PHYSIOLOGY IN THE FETUS
AND NEWBORN
30. 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
32. 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 concentrationsalso 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.
33. 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
Trendsin incidence rates of congenitalhypothyroidismrelatedto select demographicfactors:
data from the United States, California, Massachusetts, New York, and Texas. 2010
34. CONGENITAL HYPOTHYROIDISM
• Incidence more common in infants with
Trisomy 21, congenital heart disease, other
congenital malformationslike cleft palate,
renal, skeletal and GI anomalies
35. 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
36. Inverse relationship between age at
treatment initiationand IQ
Klein, A. H., Meltzer, S., and Kenny, F. M. (1972); 81:912-5
37. 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.
40. 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
41. 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
42. TSH resistance
• Mutations in TSH receptors- AD or AR
• May be a/w pseudohypoparathyroidism
(mutations are maternal in origin)
43. TSH resistance
TOTAL T4 FREE T4 TSH THYROGLOBULIN IMAGING
N or ↓ N or ↓ ↑ ↓
Normal or
small
• In such cases, hypothyroidism is mild and, despite
thyroid hormone treatment, linear growth slows,
accompaniedby 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
44. Central hypothyroidism
TOTAL T4 FREE T4 TSH THYROGLOBULIN IMAGING
↓ ↓ N or ↓ ↓ Normal
• Hypothalamic-pituitaryhypothyroidism
• 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
45. Central hypothyroidism
• associatedwith other congenital syndromes,
particularly midline defects such as optic nerve
hypoplasia/septo-optic dysplasiaor 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
47. 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
↓ ↓ ↑ N or ↑
Normal or
large
48. Iodine excess
• Antenatal or perinatal or neonatal exposure to
high levels of iodine.
❖Infants of mothers treated with Amiodarone
❖iodine-containingantiseptic compoundsare used
in mothers or infants
❖after amniofetography with an iodinated
radiographiccontrast agent
❖Mothers who ingest large amounts of iodine-
consumptionof seaweed – iodine is secreted in
breastmilk
49. 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
50. 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
51.
52. UNICEF. UNICEF Data: Monitoring the situation of children and women.
http://data.unicef.org/nutrition/iodine
53. UNICEF. UNICEF Data: Monitoring the situation of children and women.
http://data.unicef.org/nutrition/iodine
54. 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
55. TSH receptor-blocking antibodies
• Maternal autoimmune thyroid disease
• Transplacental transfer
• 1:180,000newborns
• IgG antibodies-t1/2 ~2 weeks
• Neonatal hypothyroidism persists for ~2-3 months
TOTAL T4 FREE T4 TSH THYROGLOBULIN IMAGING
↓ ↓ ↑ ↓
Normal or
small
56. 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
57. 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
58. TOTAL
T4
FREE T4 TSH TG IMAGING TREATMENT
DYSGENESIS ↓ ↓ ↑ ↓
Absent/
small/
ectopic
✓
DYSHORMONOGENESIS ↓ ↓ ↑ ~
Normal/
large
✓
TSH RESISTANCE N/↓ N/↓ ↑ ↓
Normal/
small
Depends on
severity
CENTRAL
HYPOTHYROIDISM
↓ ↓ N/↓ ↓ Normal ✓
Causes of Permanent CH
59. TOTAL
T4
FREE T4 TSH TG IMAGING TREATMENT
MATERNAL
ANTITHYROID
MEDICATION
↓ ↓ ↑ ↑
Normal/
large
Not usually
TSH RECEPTOR
BLOCKING ANTIBODIES
↓ ↓ ↑ ↑
Normal/
small
✓
HYPOTHYROXINEMIA
OF PREMATURITY
↓ ↓ N N Normal Controversial
IODINE DEFICIENCY ↓ ↓ ↑ ↑
Normal/
large
✓
IODINE EXCESS ↓ ↓ ↑ ↑
Normal/
large
✓
LIVER HEMANGIOMA ↓ ↓ ↑ ↑ Normal ✓
TBG DEFICIENCY
↓ N N N Normal No
Causes of Transient CH
60. 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
62. Asymptomatic
• ~95% newbornswith CH are asymptomatic
• WHY?
✓Maternal thyroxine (T4) crosses the placenta :
umbilical cord serum T4 concentrationsare
~25-50% of those of normal infants
✓Many infants with CH have some, albeit
inadequate, functioning thyroid tissue
63. 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
64. Symptomatic
• symptoms and signs: develop over the first few
months of life
• Prenatal ultrasound-goiter
• Goiter may be clinically noticed later in life
65. • Lethargy
• Hoarse cry
• Feeding problems
• Often needing to be
awakened to nurse
• Constipation
• Puffy (myxedematous)
and/or coarse facies
• Macroglossia
• Umbilical hernia
• Large fontanels
• Hypotonia
• Dry skin
• Hypothermia
• Prolonged jaundice
(primarily unconjugated
hyperbilirubinemia)
Symptomatic
66.
67. 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
69. 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
70.
71.
72. Which sample?
ADVANTAGE DISADVANTAGE
CORD
BLOOD
SAMPLE
•Easy to draw
•No extra prick
•Suitable during early
discharge
•Sample can be processed
at any local lab
•Other disorders cannot be
screened
•Staff needs to be trained to
collect sample immediately at
delivery
•Not feasible for home
deliveries
HEEL
PRICK
•Can be used to screen
multiple disorders
•Only morning shift staff
needs to be trained
•Can be done for home
deliveries
•Needs special assay and
reliable central lab
•Adequate training required to
ensure error free blood spots
73. Which sample?
• Postnatal peripheral venous sample is
acceptable if filter paper sample is not
feasible.
75. 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 newbornsin NICU, sample should be
collected before 7 days of age, or before
discharge, whichever is earlier
78. Approaches to Screening
ADVANTAGE DISADVANTAGE
Primary TSH →
backup T4
•Cost effective
•Most sensitive for
primary CH
Likely to miss central
CH, TBG deficiency,
hypothyroxinemia
with delayed
evaluation of TSH
Primary T4 → backup
TSH
Sensitive for central
CH
•Likely to miss milder
subclinical CH
•Higher false positive
results
Concomitant T4 &
TSH
Ideal approach Higher cost
79. Approach to Screening
• Indian Society of Pediatric and Adolescent
Endocrinology (ISPAE) guidelines recommend
primary TSH assay for screening of CH (2018)
80. Interpretation of Results
Cord blood/heel
prick TSH
<20mU/L
(<34mU/L in 24-
48h sample)
Normal screen
20-40mU/L 40-80mU/L >80mU/L
Repeat TSH &
FT4/T4 at 7-10
DOL
Repeat TSH &
FT4/T4 urgently
within 72 h
Repeat TSH &
FT4/T4 &
immediately
start treatment
without waiting
for results
s/o CH
Start treatment
Not s/o CH
Normal screen
s/o CH
Start treatment
Not s/o CH
Normal screen
TSH >20 in <2wk
TSH >10 in ≥2wk
83. Scenario A (borderline
high TSH with normal T4)
↓
Retest after 2 weeks
↓
Treat if TSH >10 after 3 weeks
of life even with normal T4
Scenario B (low T4 with
normal TSH)
↓
R/O hypothyroxinemia of
pregnancy, sick euthyroid,
TBG deficiency, pituitary
defects
↓
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
Interpretation of Borderline Thyroid function
86. 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
91. 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
92. Follow up
• A re-evaluation of the thyroid axis is
warrantedat 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.
93. 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
94.
95. Follow up
• In those babies with proven agenesis or
ectopic thyroid there is no need for
reevaluation
96. • 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
98. 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