congenital hypothyroidism

3. SYSTEM FUNCTION
CVS heart rate
force of cardiac contractions
cardiac output
Peripheral vasodilation
GIT appetite
"digestive juices"
gastric motility
CNS Normal brain development (cerebellar growth and nerve myelination)
Emotional stability in adults
Normal intellectual development in infants
PHYSIOLOGICAL EFFECTS OF THYROID HORMONE

4. SYSTEM FUNCTION
Blood Erythropoiesis
Respiratory Lung development
Surfactant production
rate and depth of respirations
Metabolic Oxidative metabolism
Oxygen consumption(except the brain, gonads and spleen)
Heat production
Synthesis and degradation of carbohydrate, fat, and protein
Skin Growth and maturation(epidermis and hair follicles)
Skeletal
Bone formation
Tooth development and eruption
Skeletal maturation

5. SYNTHESIS OF THYROID HORMONES

8.  High in hyperthyroidism
 Low in hypothyroidism
 T3 is less sensitive and less specific than decrease in
free T4
 Measurement of free T3 is preferable to total T3.
SERUM TRIIODOTHYRONINE (T3)

9.  Measure free T4, not total T4
 Free T4 is biologically active
◦ Pregnancy raises total T4
◦ Chronic liver failure lowers total T4
 High in hyperthyroidism
 Low in hypothyroidism
SERUM THYROXINE (T4)

10.  TSH is LOW in hyperthyroidism
 TSH is HIGH in hypothyroidism
 TSH- Sensitive screening test for hyperthyroidism and
primary hypothyroidism
SERUM THYROTROPIN(THYROID STIMULATING
HORMONE;TSH)

11. Hypothyroidism -insufficient circulating thyroid hormone
Caused by
1- Thyroid gland itself (primary hypothyroidism)
2-Reduced thyrotropin (TSH) stimulation (central or secondary
hypothyroidism).
Hypothyroidism Type
-Congenital
-Acquired,
REFERENCE FROM NELSON 21 EDITION

12. Congenital caused by -
 Thyroid dysgenesis
 Dyshormonogenesis
Detected by newborn screening program(NBS) in 1st few wk after birth.

13. Incidence -1 in 4,000 infants worldwide.
Incidence in India = 1:1,000 to 1:1,500 live
birth
Epidemiology

15.  Neonates-asymptomatic
 Birth weight and length-normal but increased head
circumference (Myxedema)
 Anterior and Posterior Fontanelle: wide open
 Prolonged jaundice(Indirect Hyperbilirubinemia)
 Cry little,sleep much
 Poor appetite
 Sluggish
 Feeding difficulty
CLINICAL MANIFESTATIONS

16.  Respiratory difficulties ( macroglossia-apneic
episodes,noisy respirations and nasal obstruction
 Constipation
 Abdomen -large and umbilical hernia
 Subnormal Temperature( <35 degree celcius)
 Skin: Cold and mottled
 External genitalia: Edema
 Pulse : Slow
 CVS: Heart murmurs, cardiomegaly and pericardial effusion

17. Approx 10% : congenital anomalies(Cardiac anomalies )
NKX-2 mutation-CH,respiratory distress and ataxia or
choreoathetosis
FOXE1 mutation-CH, spiky or curly hair and cleft palate
PAX-8 -CH and genitourinary anomalies , renal agenesis

18. Untreated Congenital hypothyroidism?
 Stunted growth
 Large anterior fontanel and posterior
 Depressed nasal bridge, eyes far apart
 Mouth : kept open and broad tongue
protrudes
 Delayed dentition
 Short and thick neck

19. Primary Hypothyroidism

20. 1.Thyroid Dysgenesis
 80-85% cases of permanent hypothyroidism.
 Includes aplasia, hypoplasia and dysplasia.
 Dysplasia (failure to descend) – Ectopy
 Sporadic, no risk siblings.
 2:1 female to male preponderance.

21.  No goiter, low total and free T4 levels, elevated TSH, and normal
TBG.
 Thyroglobulin (TG) - low in aplasia and hypoplasia.
 Diagnosis: Ultrasound and/or thyroid scintiscanning (
Radioactive iodine (RAI) or Pertechnetate - 99mT c)

22.  2–5% thyroid dysgenesis caused by genetic defects in-
 transcription factors-thyroid morphogenesis and differentiation,
NKX2.1 (TTF1), FOXE1 (TTF2), and PAX8.
 NKX2.1- thyroid, lung, and central nervous system,
 Cause- thyroid dysgenesis, respiratory distress, and neurologic
problems (chorea and ataxia)

23. FOXE1 -thyroid dysgenesis, spiky or curly hair, cleft palate, and
choanal atresia and bifid epiglottis (Bamforth-Lazarus syndrome).
PAX8-thyroid and kidney and cause thyroid dysgenesis and
kidney and ureteral malformations.

24. Bamforth-Lazarus syndrome

25.  CH-infants with pseudohypoparathyroidism type 1a.
 Somatic inactivating mutations - G-protein stimulatory α-subunit
Gsα (GNAS).
 Impaired signaling of the TSH receptor.

26.  10-15 % cases of permanent hypothyroidism.
 Defects in thyroid hormone production.
Abnormal thyroid peroxidase activity - impaired oxidation and
organification of iodine.
Autosomal Recessive inheritance, 25% increased risk in
subsequent siblings.
2.Defects in Thyroid Hormone Synthesis
(Dyshormonogenesis)

27.  Thyroglobulin (TG) - low in TG synthetic defects
 Imaging: Normally placed thyroid gland-normal size or
enlarged.
 Partial deficiency-signs and symptoms delayed.

28.  Mutations in sodium-iodide symporter.
 Mechanisms for concentrating iodide are defective in thyroid and salivary
glands.
 Uptake of radioiodine and pertechnetate is low.
 Eutopic and normal or enlarged gland on sonography.
Consanguinity -30% of cases.
3.Defective Iodide Transport

29.  Reduced saliva:serum ratio of I123-support diagnosis, confirmed by
mutation in the NIS gene.
 Responds to large doses of potassium iodide, but treatment with
levothyroxine .

30.  Pendred syndrome -autosomal recessive disorder composed of
sensorineural deafness and goiter.
 Pendred syndrome -mutation in chloride–iodide transport protein
pendrin (SLC26A4)
 Expressed in thyroid gland and cochlea.
 Impaired iodide organification and a positive perchlorate discharge
test.
Pendred syndrome

32.  Most common type of thyroid hormone synthetic defects.
 Iodide oxidized to reactive iodine
 Incorporated into tyrosine residues on thyroglobulin.
 Reactions catalyzed by enzyme thyroperoxidase (TPO)- H2O2 and
hematin (a cofactor).
4.Defects of Iodine Organification

33.  Enzyme dual oxidase 2 (DUOX2) produces H2O2 required for iodide
organification.
 DUOX2 mutations cause permanent or transient congenital
hypothyroidism.

34. CH with goiter and absent or low levels of circulating thyroglobulin.
5.Defects of Thyroglobulin Synthesis

35.  Monoiodotyrosine and diiodotyrosine released from thyroglobulin
with thyroxine (T4) and triiodothyronine (T3).
 IYD gene (DEHAL1) encodes thyroidal enzyme iodotyrosine
deiodinase.
 Deiodinates intermediates and allows liberated iodide- recycled
into thyroid hormone synthesis..
6.Defects in Deiodination

36.  Mutations transporter MCT8 (SLC16A2), located on X-chromosome,
impair movement of T4 and T3 into cells.
 Cause-
 Profound developmental delay,
 reduced muscle mass,
 dysarthria,
 athetoid movements
 Hypotonia
 spastic paraplegia (Allan-Herndon Dudley syndrome).
7.Defects in Thyroid Hormone Transport

38.  Maternal TSHR– blocking antibodies (TRBAbs)-2% CH
 Detected by neonatal screening programs (1 in 50,000-100,000
infants).
 Transplacentally-maternal TRBAb inhibits binding of TSH to
receptor in neonate.
8.Thyrotropin Receptor–Blocking
Antibodies

39. Maternal autoimmune thyroid disease.
Includes-
 chronic lymphocytic thyroiditis or
Graves disease,
maternal hypothyroidism, or
transient congenital hypothyroidism in previous
siblings.

40.  Ultrasonography -normally positioned but small thyroid gland;
 Thyroid tissue not detected by scintigraphy with technetium
pertechnetate or 123I -impaired TSHR function suppresses thyroidal
iodine uptake.
 Serum thyroglobulin levels are also low.
 Treatment with levothyroxine -initially,
 Remission of hypothyroidism occurs in 3-6 mo-TRBAb are cleared from
infant circulation.

41.  Neonatal hypothyroidism-radioiodine used as treatment for Graves
disease or thyroid cancer to a mother during pregnancy.
 Fetal thyroid -capable of trapping iodide by 70-75 days of gestation.
 Pregnancy test -performed in woman of childbearing age before
131I is given.
 Radioactive iodine to lactating women- contraindicated because
excreted in breast milk.
9.Radioiodine Administration

42.  CH from fetal exposure to excessive iodides.
 Perinatal exposure-iodine antiseptic to prepare skin for caesarian
section or to paint cervix before delivery.
 Hypothyroidism -exclusively breastfed infants born to mothers-
 consume large amounts of iodine daily (up to 12 mg) in form of
nutritional supplements
 consume large quantities of iodine-rich seaweed.

43.  Iodine-induced hypothyroidism is transient.
 Neonate, with low birthweight (LBW), topical iodine-containing
antiseptics used in nurseries and perioperatively-transient
hypothyroidism.
 Detected by newborn screening tests.
 Older children, excess iodine -preparations used to treat asthma or
in amiodarone, an antiarrhythmic drug with high iodine content.
10.Iodine Exposure

44.  Iodine deficiency or endemic goiter is most common cause of CH
worldwide.
 Recommended iodine in adults is 150 μg daily to 220 μg daily
during pregnancy.
 Borderline iodine deficiency -problems in preterm infants
 Depend on a maternal source of iodine for normal thyroid
hormone production
 Receive insufficient dietary iodine from common preterm infant
formulas (low in iodine).
11.Iodine Deficiency (Endemic Goiter)

45. Central (Secondary) Hypothyroidism

46.  Deficiency of TSH and central hypothyroidism can occur with
developmental defects of the pituitary or hypothalamus.
 1 in 16,000-30,000 infants.
 Not detected by neonatal screening programs,
 75% infants have multiple pituitary hormone deficiencies.
 Present with hypoglycemia,
 persistent jaundice, micropenis or cryptorchidism (in males), or
midline cleft lip or palate or midface hypoplasia.
1.Thyrotropin and Thyrotropin-Releasing
Hormone Deficiency

47. NEW BORN SCREENING

48. WHY?
 Asymptomatic
 Window to initiate treatment is 2 weeks
The concept of NBS with dried blood spot
(DBS) was first conceived by Prof. Guthrie
in 1960 for phenylketonuria
To this, screening for CH was added in
1965

49. NEW BORN SCREENING
 When? : 48-72 hours. If sick neonates
, preterm – by 7 days
 What ? : Capillary blood sample from
heel
prick versus cord blood sample
 How? : Specialized filter paper , dried
at room temperature , sent to central
lab

50. Cord blood sample Postnatal sample
Advantages  It is painless
 Larger quantity of blood allows the use of
locally available serum TSH assay
 Not affected by neonatal surge
 Ensures NBS for early discharged cases
 Report is usually ready before discharge
 Can counsel parents if repeat testing needed
• Other disorders can be tested like CAH and
those dependent on feeding
(e.g.galactosemia, PKU)
• Training or logistics needed only for
morning shift
• Recommended for NBS in special situation
• Can be done for babies delivered at home
Disadvantages  Metabolic disorder which
depend on feeding may not
be tested
 Round the clock personnel
need to be trained, not
just morning shift
 Result may be affected by
perinatal factors
 Neonatal surge of TSH
(half hour after birth,
settles after 48 to 96 h)
and false positive screen
in case of early discharge
 Pain to the baby
 Need special assay system
Advantages and disadvantages of cord blood vs. postnatal
sampling for newborn screening (NBS)

51.  All newborns, preterm and LBW /VLBW infants-routine
screening for CH at 48-72 hours of post natal age
 Sick neonates -screened by atleast 7 days of age
 High risk neonates -preterm, LBW and VLBW babies , ill
neonates admitted to NICU and multiple births-second screen
at 4 weeks of age (or 2 weeks of age if discharged early)
New born screening: Recommendations

52.  Serum T4
 Serum T3
 TSH
 Anti-thyroid antibodies
 Thyroid stimulating Immunoglobulins
 Thyroid uptake and scan
 Thyroid Ultra sound
LABORATORY EVALUATION AND
IMAGING STUDIES

53. Imaging (ultrasound and
scintigraphy) should be done
after CH is biochemically
confirmed. Scintigraphy can
be done up to 7 days after
start of levothyroxine (if TSH
is high)
APPROACH TO CONGENITAL
HYPOTHYROIDISM

54.  I-123
 I-131
 Technetium 99
 *Radiotracer:
 Injectable IV: Technetium (15 min
later: scan)
 Oral: 131 I and 123 I;(24 h later:
scan/uptake)
 Scan: structure
 Uptake: function
 Obtain pregnancy test before the test
THYROID UPTAKE AND SCAN

55.  Painless, quick, no contrast
material, no radiation
 Can be used in pregnancy, while
on L- thyroxine therapy, after
exogenous iodine exposure
 Can detect thyroid nodules as small
as 2-3 mm and provide guidance
for FNAbiopsy.
THYROID ULTRASONOGRAPHY

56. • Thyroid antibody study- autoimmune thyroiditis.
• Sec./Tertiary hypothyroidism- TSH levels low or
undetectable with subnormal levels of T3 & T4 as well as
free T4 & T3 and associated deficiency of other pituitary
hormones.

57.  Low serum T4 & T3 and elevated TSH values
 Free T4 and free T3 are more specific
 TSH is sensitive index of primary hypothyroidism.
 Radiographic studies- significant delay in skeletal maturation,
epiphyseal dysgenesis.
DIAGNOSIS

58.  Retardation of osseous development
 Absence of distal epiphysis
 Epiphyseal dysgenesis
 Deformity (beaking) of 12th thoracic or 1st or 2nd lumbar vertebra
 Skull show large fontanels and wide sutures
RADIOLOGICAL FINDINGS

60. REFERENCE FROM IAP 2022

61. • Thyroid replacement should be started.
• In central hypothyroidism, cortisol replacement precede thyroid
replacement.
• Thyroxine (T4) is initiated at a dose of 10-15μg/kg/day.
• Transient hypothyroidism is suspected-treatment can be stopped
safely after the age of 3 years followed by further evaluation.
• Mental retardation and short stature are common outcomes.
MANAGEMENT

62.  CH is the commonest cause of preventable mental retardation.
 NBS for CH should be done for every NB in India.
 Either cord blood or post natal, day 3 to day 5 samples should be
used for screening for CH
 Primary TSH assay should be done for CH
 TSH >20mIU/L – cut off for recall
 Screen TSH >40mIU/L – screen positive cases for immediate
recall for venous confirmatory test.
SUMMARY

63. Screen TSH 20-40mIU/L - should have a second TSH
screen at 7 to 10 d of age.
All newborns, preterm and LBW/VLBW infants should
undergo routine screening for CH at 48–72h postnatal
age.
 Sick neonates should be screened at least by 7 d of age.
High risk neonates such as preterm, LBW and VLBW
babies, ill neonates and multiple births (particularly same
sex twins) : second screen at 4 wk of age (or at 2 wk of
age if discharged early).

64. REFERENCE FROM
1.NELSON 21 EDITION
2.IAP GUIDELINES FOR HYPOTHYROIDISM 2022