Congenital hypothyroidism Jo.pptx

1. CONGENITAL
HYPOTHYROIDISM
Dr Jo Martin Kuncheria
Pediatrics

2. Congenital Hypothyroidism
• Incidence is 1 in approx 1000 Indian Newborns
• Thyroid dysgenisis or dyshormonogenesis
• Severily affected manifest features by
1wk,milder may not be evident for months
• Most common preventable causes of
intellectual disability

3. FETAL DEVELOPMENT
Fetal thyroid arise from foramen cecum
Thyroglobulin synthesis occurs from 4wks
Iodine trapping occurs by 8-10 wks
Thyroxine(T4&to a lesser extent T3) Synthesis and
secretion occurs by 12 wks
Hypothalamic neurones synthesize thyrotropin releasing
hormone,TSH after 12 wks

4. STEPS IN THYROID HORMONE SYNTHESIS
Iodine trapping
Synthesis & secretion of thyroglobulin
Oxidation of iodides
Organification of iodide
Coupling reaction
Storage & secretion

6. Etiology
• Primary hypothyroidism
Thyroid dysgenesis
Dyshormonogenesis
Defect in TSH responsiveness
Iodine deficiency
Iodine excess
Maternal medications
• Secondary hypothyroidism
Isolated TSH deficiency
Multiple pituitary hormone
deficiencies

7. Congenital hypothyroidism may be :-
• Permanent (thyroid aplasia, hypoplasia, ectopia
or dyshormonogenesis).
• Transient (due to maternal blocking antibodies,
iodine excess or deficiency, or some types of
dyshormonogenesis).

8. Thyroid dysgenesis
• 80-85% cases of congenital hypothyroidism
• 66% hypoplasia or in ectopic location(from the base
of tongue to normal position),33% agenesis.
• F:M -2:1
• Genetic defects in transcription factors NKX2 ,
FOXE1 ,PAX8
• TSHR mutations

9. Thyroid dyshormonogenesis
• Defect in the biosynthesis of thyroid hormone
• 15% cases
• Most are recessive ;25% risk of recurrence in siblings
• Because the thyroid gland responds normally to elevated TSH
stimulation, a Goiter is almost always present.
• When the synthetic defect is incomplete, the onset of
hypothyroidism may be delayed for years.

10. Thyroid dyshormonogenesis cont…
• Defective Iodide Transport, Defects of Iodine
Organification, Defects of Thyroglobulin Synthesis, Defects in
Deiodination
• Most common defect –abnl TPO activity →→→impaired
organification with iodine.
• Pendred syndrome - Autosomal recessive ; mutaton of gene
SLC26A4 ;mild organification defects with sensorineural
deafnes. but hypothyroidism rarely occurs in newborn period.

11. TSH RESISTANCE
• Mutation of TSH receptors
• Rarely due to loss of function mutation of GS-alpha (
Hereditary Albright Osteodystrophy).
• Clinically- small gland
• T4 - normal or low
• TSH - high( depending on degree of resistance and
severity of hypothyroidism)

12. CENTRAL( HYPOTHALAMIC –PITUITARY )
HYPOTHYROIDISM
• Less common than primary hypothyroidism
• Incidence 1 in 25000
• Usually associated with other pituitary hormone defects.
• Other signs of pituitary dysfunction maybe present-
hypoglycemia ,microphallus, midline facial abnormalities .
• Need to assess cortisol and GH level and need MRI to
assess hypothalamus and pituitary

13. Transient congenital hypothyroidism
Anti thyroid drugs
Iodine excess
Iodine deficiency
TSH receptor blocking antibodies
Transient hypothyroxinemia of prematurity

14. Transient hypothyroxinemia of prematurity
• The cord blood T4 concentration is decreased in proportion
to gestational age and birthweight.
• The postnatal TSH surge is reduced, and very premature or
very LBW infants experience a decrease in serum T4 (total)
in the 1st wk of life, in contrast to term infants in whom T4
increases.
• The serum T4 gradually increases to the range observed in
term infants by about 6 wk of life.

15. Transient hypothyroxinemia of prematurity
-Mechanism
Immaturity of the hypothalamic-pituitary-thyroid axis
Loss of the maternal contribution of thyroid hormone
normally present in the 3rd trimester
Severe illness and complications of prematurity
Exposure to medications that can affect thyroid
function (e.g., dopamine and glucocorticoids).

16. CLINICAL MANIFESTATIONS
IN NEWBORN
• Asymptomatic at birth, even if there is complete agenesis
of the thyroid gland.
• Due to transplacental passage of maternal T4, which
provides fetal levels that are approximately 33% of normal
at birth.
• Normal birth weight and length; Head size slightly higher
due to brain myxedema
• Large fontanels and wide sutures
• Macroglossia

17. CLINICAL MANIFESTATIONS
IN NEWBORN cont…
• Skinented abdomen with umbilical hernia
• Rough dry skin
• Skin cold with mottling
• Sensori neural deafness
• Other congenital anomalies

18. CLINICAL MANIFESTATIONS cont…
• Sluggish feeding, choking episodes
• Constipation
• Lethargic
• Sleep more ,needs to be awakened to feed
• Hoarse cry
• Hypothermia

19. CLINICAL MANIFESTATIONS cont…
• Cardiomegaly
• Murmurs
• Asymtomatic pericardial effusion
• Macroytic anemia ,hypotonia with slow reflexes
• Prolonged physiological jaundice

20. CLINICAL MANIFESTATIONS cont…
Delay of physical and mental development
Becomes more severe over time
3-6 mo of age the clinical picture is fully developed.

21. DIAGNOSIS
Primary hypothyroidism- low serum T4 &T3 and elevated
TSH Value
Free T4& Free T3 are more specific
TSH is extremely sensitive index of primary hypothyroidism
Radiographic studies –significant delay in skeletal maturation
,epiphyseal dysgenesis
Secondary hypothyroidism –TSH levels low or undetectable
with sub normal levels of T3& T4 as well as free T4 &T3 and
associated deficiency of other pituitary hormones

22. RADIOLOGICAL FINDING
Retardation of osseous development
Absence of distal epiphysis of femur and proximal epiphysis
of tibia- indicates severe CH and correlates with later
intelligence and motor scores.
Epiphyseal dysgenesis
Deformity (beaking) of 12 th thoracic or 1st or 2nd lumbar
vertebra
Skull show large fontanels and wide sutures

23. Newborn screening
Commonest cause of preventable mental retardation
Satisfies all the criteria for being included in a newborn
screening (NBS) program
Congenital hypothyroidism may be permanent (thyroid
aplasia, hypoplasia, ectopia or dyshormonogenesis)
Transient (due to maternal blocking antibodies, iodine excess
or deficiency, or some types of dyshormonogenesis)

24. Newborn screening cont….
• The crucial point to remember when screening for
CH is the neonatal surge of TSH and T4 .
• The TSH surge starts 30 min after birth (T4 some
hours later), is most marked for the next 24 h.
• TSH surge persist for 48 to 72 h. Thus, cord blood
is largely spared of the neonatal surge.

25. Newborn screening cont….
• The screen sample should therefore be taken either
from the cord (placental end, immediately after
delivery) or postnatally after 72 hrs of life.
• If the hospital stay is shorter, it may be taken after
48hrs of life.

26. Newborn screening cont….
• Cord blood NBS for CH is an effective
strategy to reduce missed opportunities for
screening due to early discharge.

27. Newborn screening cont….
Postnatal samples offer the advantage of screening
for other treatable inborn errors of metabolism like –
-Congenital adrenal hyperplasia
-Biotidinase deficiency
-Dependent on feeding (Galactosemia, PKU)

28. Advantages and disadvantages of cord blood vs. postnatal sampling
Cord blood
• Painless
• Large quantity blood
available
• Early results available
• Not affected by Neonatal
surge
• Other metabolic disorders not
addressed
• Round the clock trained staff
• Result affected by perinatal
factors like birth asphyxia
NBS
• Can be done in babies
delivered at home
• Morning staff to be trained
• CAH, PKU , Galactosemia
–etc addressed
• Neonatal surge affects results
• Pain to baby
• Special assay for DBS

29. Screening with TSH vs T4
• Primary T4 testing helps to identify patients
with primary and secondary (central) CH.
• However, it misses neonates with compensated
forms of CH (normal T4 with high TSH, which
is commonly seen in ectopic thyroid).

30. Screening with TSH vs T4 cont…
• There is a high rate of false positive results, whether
done from cord blood or postnatal day 3–5 sample.
• These include infants with thyroid-binding globulin
(TBG) deficiency and preterm and sick neonates .
• Hence, low T4 values must be followed by backup
TSH on the same DBS.

31. Screening with TSH vs T4
• Primary TSH screen is more sensitive and specific
for the diagnosis of primary CH compared to T4
screen.
• Primary TSH screening may miss infants with
delayed rise of TSH most often seen in preterm
babies due to immaturity of the hypothalamic-
pituitary-thyroid (HPT) axis.

32. Screening with TSH vs T4
• It also fails to detect cases of central CH; however,
detection of this rare disorder is not the target of
mass NBS.
• Overall, primary TSH-based CH screening is more
practical and cost-effective.

33. 1. TSH >20 mIU/L (serum units) is recommended as the cut-off for
recall for cord blood and postnatal screen samples after 48 h of age.
2Age-related TSH cut-off (>34 mIU/L) is suggested for screen samples
taken between 24 to 48 h of age
3. Screen TSH >40 mIU/L is recommended for defining screen positive
cases for immediate recall for venous confirmatory test, whereas those
with mildly elevated TSH from 20 to 40 mIU/L should have a second
TSH screen at 7 to 10 d of age.
TSH Cut offs

34. BY HEEL PRICK OR CORD BLOOD ON FIRST SCREEN
TSH >80 -take confirmatory sample and start levo thyroxine immedietly
without delay
TSH >40 -Take confirmatory sample for TSH and FT4 /T4 after 72 hrs of
age
TSH 20-40 or ( 34-40 in 24 to 48 hrs of life) –rept at 7-10 days of life (
TSH,,FT4/T4)
Venous TSH>20 mIU/L before age 2 wk and, >10 mIU/L after age 2 wk
with serum T4<10 μg/dL (<128 nmol/L) and FT4<1.17 ng/dL (< 15
pmol/L) is indicative of primary CH and needs treatment initiation.
tion.

35. CONFIRMATORY VENOUS SAMPLE AFTER 72 HRS OF LIFE
Normal T4 ,high TSH Low T4
Elevated TSH for age (>20 for <2 wks OR
> 10 for > 2 wks
Repeat TSH at 2 weeks
if TSH <10 –Normal
TSH >10 –after the age of 3 wks
with normal T4/FT4
start treatment
Low FT4 (<1.1ng/dl) or low T 4
(<8mcg/dl) irrespective of TSH
OR
FT4 < 1.17, or T4 < 10mcg/dl and TSH
>20 (>10 for >2weeks)
start treatment

36. CRITERIA FOR INITIATION OF LEVOTHYROXINE
THERAPY IN TERM NEWBORNS
Low T4 (<100 nmol/L or 8 μg/dL) or low FT4 (<12 pmol/L or <1.1
ng/dL) irrespective of TSH.
Mild low T4 (<128 nmol/L or 10 μg/dL) or low FT4 (<15 pmol/L or 1.17
ng/dL) in the presence of elevated venous TSH >20mIU/L if age is <2 wk
and >10 mIU/L if age is >2 wk.
Normal T4/FT4 with persistently elevated TSH >10 mIU/L at age>3 wk.

37. Decision Making for Borderline Thyroid
Function
• After 3 wks of age, if TSH remains persistently >10
mIU/L with normal range of T4/FT4, levothyroxine
treatment may be started to avoid insult to the
developing brain.
• Low T4/FT4 with normal TSH levels.
• Thyroid imaging to get a definitive diagnosis.
• Referral to a pediatric endocrinologist is helpful.
• Reevaluation is recommended after 3 y of age

38. Recommendation for preterm /LBW
1. As for all newborns, preterm and LBW/VLBW infants
should undergo routine screening for CH at 48–72 h postnatal
age.
2. Sick neonates should be screened at least by 7 d of age.
3. High risk neonates such as preterm, LBW and VLBW
babies, ill neonates admitted to NICU and multiple births
(particularly same sex twins) may have a second screen at 4
wk of age (or at 2 wk of age if discharged early)

40. Imaging in CH
• Thyroid imaging should be done to identify the
etiology.
• Etiological diagnosis helps in identification of
temporary vs. permanent CH and guides the
course of LT4 treatment.

41. Imaging in CH
• Those with transient CH will not need lifelong
therapy.
• Imaging of the thyroid gland by either
ultrasonography or nuclear imaging
(scintigraphy) or both is recommended in
various guidelines to confirm the etiology.

42. Imaging in CH
• Imaging should never be the reason to delay
initiation of therapy in CH.
• Scintigraphy may be done as long as the TSH is
still high, i.e.,safely within 7days of initiation of
therapy.
• Ultrasonography maybe done weeks or even
months after treatment is initiated.

43. Imaging in CH
If the gland is eutopic or thyroid scan is normal, it indicates
the possibility of temporary CH.
A re- assessment should be done in such cases after the age of
3 y after stopping treatment for 4 wk and repeating the
thyroid function test.
If scintigraphy was not done at the time of diagnosis it may
be done at three years of age when permanence of CH is
established prior to restarting treatment.

45. Treatment and monitoring
Start L Thyroxine at 10-15mcg/kg /day
In severe cases with very low T4, the initial dose should be on the higher
side.
Initiating treatment as soon as the diagnosis is made, as early as possible
within the first 2 wk of life, is essential for optimal neurodevelopmental
outcome
Goal of therapy - T4 level should be normalise with in 2 week & TSH level with in
one month of starting therapy.
The dose should be titrated to maintain the T4/FT4 values in the upper half of normal
range for age

46. Treatment and monitoring
• For the first 6 months, while the baby is on exclusive
breastfeeding, the tablet should be soaked in a cup in a
few ml of breast milk and crushed with a spoon.
• After 6 mo of age, it can be given with water in the
same manner.
• Levothyroxine should be given separate from a feed
so that the entire medicine is ingested.

47. Treatment and monitoring
• Concurrent administration of iron, calcium and soya
are to be avoided as these are known to hinder
absorption of LT4.
• Levothyroxine is to be administered daily,
administration at a consistent time of the day is more
important than administration on an empty stomach.

48. Treatment and monitoring
• TSH is a very good indicator of the hypothyroid state and
the goal of therapy is to keep TSH in the adult normal
range for the laboratory.
• There could be transient elevated TSH levels despite
optimal FT4/T4 levels which reflects transient pituitary
thyroid hormone resistance which improves with age.

49. Treatment and monitoring
If the FT4/T4 levels are in the upper normal range,
one should not aggressively pursue normalization of
TSH level.
If financial constraints are present, TSH alone may be
monitored beyond infancy.

50. FOLLOW UP
• First follow up - TFT should be done 2wk after starting
treatment (normalization of FT4/T4 expected)
• If the levels are low ,slight increase in the dose is required
• Repeat the test after 1 month - T4/FT4 and TSH
(normalization of TSH expected).
• Dose should not be reduced,if a single value of T4 found
above the normal range

51. FOLLOW UP cont…
• Further follow up –every 2 months in early infancy
till 6 months age
• Every 3 months in 6 months - 3years
• Every 3-6 months there after till growth &
development completed

52. FOLLOW UP cont….
Compliance issues or abnormal thyroid functions --
further follow up should be done early and more
frequently to ensure attainment of euthyroid status
Any dose change is followed by a biochemical
evaluation after 4 weeks.

53. FOLLOW UP cont….
• Regular clinical and thyroid profile evaluation, and
periodic assessment of compliance, are essential.
• Even a moderate degree of under treatment has been
shown to result in abnormalities in IQ and specific
fields.
• Overtreatment has also been found to be associated
with impairment of cognitive outcomes

54. FOLLOW UP cont….
• Universal hearing screen and regular hearing
assessment throughout childhood.
• As there is an increased incidence of other congenital
anomalies in children with CH especially cardiac
anomalies, a thorough clinical examination should be
done.
• During each follow-up visit, anthropometric
measurements and development should be
documented.

55. Genetic counselling
• Any etiology of CH is associated with increased risk
of recurrence in the next sibling.
• Dyshormonogenesis disorders have the highest risk,
being autosomal recessive in inheritance.
• Thus, genetic counseling forms an important part of
the care, in a family with a newborn diagnosed with
CH.

56. Re-evaluation cont…
• Re-evaluation at the completion of 3 years in babies
in whom the possibility of transient CH exists
• 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 weeks and repeating the thyroid function tests
and thyroid scan.

57. Re-evaluation cont..
• Alternatively, if the permanence of CH is to be confirmed
without etiological diagnosis, the dose may be tapered by
one-third for 2–3 weeks 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.

58. Re-evaluation cont…
In those babies with proven agenesis or ectopic
thyroid there is no need for re evaluation .

59. Prognosis
• With prompt diagnosis and treatment – outcome is
excellent.
• Subtle defects in visuo spatial process, memory,
sensory motor function maybe seen in severe CH

60. THANK YOU