Download Thyroid Gland Development

Thyroid Gland Development
Commitment towards a thyroid-spesific
phenotype as well as the growth and descent
of the thyroid anlage into the neck results
from the coordinate action of a member of
novel, recently cloned transcription factors:
- Thyroid transcription factor (TTF) -1
- TTF -2
- Pax 8
TT1 : İmportant for the development of
both T4 producing follicular cells and
parafollicular or calcitonin (C) -secreting cells
Pax8 : Involved only in thyroid follicular
cell development.
Embiyogenesis in man is largely complete by
10-12 weeks of gestation. Despite the fact that
iodide uptake by the thyroid can be
demonstrated at 10-11 weeks gestation, the
capacity of the fetal thyroid to reduce iodide
trapping in response to excess iodide (The WolffChaikoff Effect), does not appear until 36-40
weeks‘ gestation
→
Premature infans are much more likely
to develop hypotyroidism when exposed to
excess iodine than are full-term babies
Maturation of the hypothalamopituitary- thyroid axis
-TSH : First identified by the pituitary gland by
10-12 wks : detectable in fetal serum at levels
of 3-4 mIU/L at gestational age 12 wks
Increases over the last trimesters to
level of 6-8 mIU/L + fetal thyroid radioiodine
uptake ↑ + progressive increase in the serum
concentrations of both total T₄ and freeT₄.
-FreeT₄/TSH ↑:
• Changes in both the sensitivity of the
pituitary thyrotroph to the (-) feedback effect
of thyroid hormones and the thyroid follicular
cell sensitivity to TSH.
Onset of FTF : Onset of secretion of the
iodothyronines by the fetal thyroid (≈ 18 – 22
weeks )
Fetal serumT₃ : Low during gestation
( immaturity of the type 1 deiodinase )
Maturation of thyroid hormone
metabolism
Activity of the type 1 deiodinase (seleno enzyme) is low : circulating T₃ ↓ ( to avoid tissue
thermogenesis, to potentiate the anabolic state
of the fetus )
Type II and III deiodinase highly expressed in
brain and pituitary , are detectable at midgestation
→ Fetal brain T₃ levels are 60-80 ℅ those of
the adult by fetal age 20-26 weeks.
In fetal hypothroidism, type II deiod.
activity↑,type III and type I ↓ : preservation of
normal brain T₃ levels (providing that maternal T₄
levels are maintained at normal concentrations )
Maturation of thyroid hormone action
Thyroid hormone influences in the brain
• Neurogenesis and neural cell migration (5-24
wks)
• Neuronal differentiation
• Dendritic – axonal growth
• Synaptogenesis
• Gliogenesis ( Late fetal – 6 months postpartum)
• Myelination ( second trimester to 24mo)
• Neurotransmitter enzyme synthesis
The role of the placenta
Under normal circumstances, the placenta
has only limited permeability to thyroid hormone
and the fetal hypothalamic -pituitary- thyroid
system develops independent of maternal
influence.
The relative impermeability of the human
placenta to thyroid hormone is due primarily to
the presence of type III and to type II deiodinase
which serve to inactivate most of the thyroid
hormone presented from the maternal or fetal
circulation . The iodide released in this way can
then be used for fetal thyroid hormone synthesis.
But T₄ is found in first trimester coelamic
fluid from the earliest date studied ( 6 wks of
GA ) in concentrations that correlate
significantly with maternal circulating levels –
fT₄ concentrations are comparable with those
that are biologically effective in adults.
Nuclear TR (receptors) are present in the
brain of 10 week old fetuses increasing rapidly by
16 weeks a period of very active cortical
neurogenesis.
The number of T₃ -occupied receptors in the
whole fetal brain increases about 500 fold
between 10-18 weeks , a finding that confirms
that maternal thyroid hormone does reach the
human brain early in gestation ( de Escobar 2000
)
When the fetus is hypothyroid, there is an
increased net flux of maternal thyroid
hormone to the fetal compartment.
Infants with the complete inability to
synthesize T₄ have cord T₄ concentrations
between 20℅ and 50℅ of normal.
When both maternal and fetal
hypothyroidism occur, there is significant
impairment in neurointellectual development
despite the initiation of early and adequate
postnatal thyroid replacement.
Maternal hypothyroxinemia ( in iodine
deficient areas ) alone may be sufficient to
result in mild cognitive and/or motor delay in
the fetus: Children of women with fT₄ levels
below the 5th and 10th percentiles at 12
weeks’ gestation had significantly lower scores
on the Bayley psychomotor developmental
Index (PDI) scale at 10 months of age
compared to children of mothers with higher
fT₄ values (Pop1999 )
Overt maternal hypothyroidism in severe
iodine deficient areas is associated with
severely impaired neuological development of
the offspring.
In contrast to thyroid hormone , the
placenta is freely permeable to TRH and to
iodide, to certain drugs (antithyroid) ,to Ig’s of
the IgG class(TSH receptor Ab’s)
Maternal TSH does not cross the placenta .
Thyroid function in the full term and premature
neonate in the infant and during childhood:
At the time of birth: there is an abrupt
increase in serum TSH within 30’ of delivery
reaching concentrations of 60-70 mU/L →
℅50 increase in serum T₄ + 3-4 x increase in
the serum T₃ within 24h. The marked increase
in T3 is due not only to the increase in TSH but
also to an increase in the type I deiodinase
activity.
The premature infant:
After delivery there is a surge in T₄ and TSH
analogous to that observed in term infants but
the magnitude of the increase is less in
prematures neonates and there is a more
dramatic fall in the T₄ conc. over the
subsequent 1-2 wks. Serum rT₃ ↑ T₃ ↓ ←
immature type 1 deiodinase system.
Infants and children :
There is a slow and progressive decrease in
T₄ ,free T₄, T₃ and TSH during infancy and
childhood. The most important aspect of
thyroid physiology in the infant and child is
the markedly higher T₄ turnover in this age
group relative to that in the adult . In infants ,
T₄ production rates are estimated to be in the
order of 5-6 microg/kg/day , decreasing slowly
over the first few years of life to about 2-3
microg/kg/day at 3-9 years.
Size of the thyroid :
1 gr → +1 gr per year until age 15 (adult
size : 15-20 gr)
Hypothyroidsm : Congenital and acquired
Congenital : hypothyroidism present at
birth or even during fetal life (neonatal)
Acquired : (juvenile )
When congenital anomalies of thyroid
development or function are minor ( e.g. large
ectopic thyroid glands ), minor congenital dejects
in thyroid hormonogenesis or in some cases of
resistance to thyroid hormones , the
development of hypothyroidism can be delayed
until adolescence or even adulthood :it appears
clinically an acquired hypothyroidism.
Conversely severe hypothyroidism can
occasionally be acquired during early postnatal
life (pre-and postnatal iodine overload) and be
expressed as neonatal hypothyroidism.
Congenital hypothyroidism: thyroid
failure detected by neonatal screening.
Acquired hypothyroidism : a state of
thyroid failure not detected by screening.
Worldwide the most common cause of CH
is iodine deficiency . In severely iodine
deficient areas , CH is endemic ( endemic
cretenism ) and is characterized by mental
retardation , short stature, deaf-mutism and
neurological abnormalities
In iodine-sufficient areas and in areas of
borderline iodine deficiency CH is usually
sporadic.
Treatment must be initiated soon after
birth before affected infants are recognizable
clinically. A normal outcome is possible as long
as treatment is started sufficiently early and is
adequate.
Differential diagnosis of permanent
congenital hypothyroidism :
1.
2.
3.
4.
Thyroid dysgenesis: Aplasia,hypoplasia+/- ectopy
Inborn errors of thyroid hormonogenesis
Secondary and/or tertiary hypothyroidism
Thyroid hormone resistance
Transient congenital hypotyroidism
(most common in premature infants)
1- Primary hypothyroidism :
a.
b.
c.
Iodine deficiency and iodine excess (prenatal,postnatal)
Reported sources of iodine
Drugs ( e.g . Potassium iodide , amiodarone)
Radiocontrast agents ( e.g. for i.v. pyelogram, oral
cholesistogram or amniofetography)
Antiseptic solutions(povidone iodine)
Maternal thyrotropin receptor abs
(Maternal TSH receptor – blocking Abs)
Maternal antithyroid medication (PTU, MMI or carbimazole )
2. Secondary or tertiary hypothyroidism :
a. Prenatal exposure to maternal
hypothyroidism
b. Prematurity
c. Drugs (Dopamine)
3- a ) Isolated hyperthyrotropinemia
Most common in premature infants
b ) Hypothyroxinemia ( Normal TSH ).
Most commonly in premature infants.
Abnormalities in thyroid-binding
proteins(TBG,transthyretin)
c ) Low T₃ syndrome
SCREENING METHODS
Primary TSH measurements supplemented
by T₄ determinations for those infants with
elevated TSH values.
TBG deficiency
Missed Hypothyroxinemia with delayed TSH elevation
Secondary or tertiary hypothyroidism
Primary T₄/ back up TSH
Detect
Primary hypothyroidism (low or low normal T₄ + TSH ↑)
TBG deficiency ( ⅟₅₀₀₀-₁₀̦₀₀₀ )
Secondary or tertiary hypothyroidism
Hyperthyroxinemia
Low T₄ but delayed rise in TSH
Netherlands 2001
* will miss compensated hypothyroidism
< -0.8 ( 25 th percentile ) → TSH
< -1.6 → + TBG
Combined primary T₄ and TSH measurements
Ideal screening approach
Results from specimens collected in the first
24- 48 hrs may lead to false-positive TSH
elevations.It is highly desirable that the blood
be collected when the infant is between 2-6
days age.Accurate screening results depend
on good quality blood spots:
- Should be collected on approved filter paper
norms(SS903)
- Dried at room temperature
- Not subjected to excessive heat
- The blood should completely saturate the
filter paper and be applied to one side only.
Prof. Grüters
TSH > 15 mU/L
TSH > 50
TSH > 15
< 50
2nd filter paper sample
TSH > 15
TSH,T₄(fT₄) in serum
Diagnostic procedure in confirmed CH
US , Serum Tg , Serum T₄
Athyreose: Tg low
Ectopy: Tg normal
T₄ very low
T₄ low
No thyroid
No Thyroid
Defects of biosynthesis: Tg normal
T4 very low
thyroid (+)
Antibodies, urinary iodine
Inborn errors of hormonogenesis (aut. recessive)
- Decreased TSH responsiveness
- Failure to concentrate iodide
- Defective organification of iodide due to an
abnormality in the TPO enzyme or in the H₂O₂
generating system
- Defective Tg synthesis or transport
- Abnormal iodothyrodine deiodinase activity
Pendred syndrome : organification defect +
sensorineural deafness
Eutopic thyroid gland may be increased in size
at birth (except in decreased TSH
responsiveness)
Clinical manifestations :
Large tongue
Hoarse cry
Facial puffiness
Umbilical hernia
Hypotonia
Mottling
Cold hands and feet
Lethargy
Unconjugated hyperbilirubinemia
Gestation > 42 wks
Feeding difficulties
Delayed passage of stools
Hypothermia
Resp. distress in an infant over > 2.5 kg
A large anterior fontanelle and/or a posterior
fontanelle >0.5 cm
Lab. evaluation :
• TSH , T₄
• Bone age x – ray
• A radio nuclide scan (¹²³I or [ ⁹⁹ Tc ]
pertechnetate) ¹²³I preferred (organified)
• Ultrasound (to confirm absence of thyroid
tissue )
• Urinary iodine measurment
• Serum Tg
Treatment :
An initial dose of 10 – 15 microg/kg is
recommended to normalize the T₄ as soon as
possible
To repeat T₄ and TSH at 2-4 wks after initiation
of treatment
Every 1-2 months during the first year of life
Every 2-3 months between 1-3 years of age
Every 3-12 months until growth is complete
Trial off replacement therapy can be
initiated after 3 years of age
Premature : < 27 weeks with a low T₄ +/elevated TSH. 8 microg/kg/day