Transcript Slide 1

‫عالیم بالینی و درمان هیپوتیروییدی‬
‫مادرزادی‬
‫ارایه دهنده‪:‬‬
‫دکتر مجید ولی زاده‬
References:
• Up to date 2009 (17.3)
•.
Thyroid Embryology
 Derived from
endodermal tissue at
base of tongue
 Embryonal remnants
form Thyroglossal duct;
pyramidal lobe; lingual
thyroid
 Fuse with C-cells (neural
crest origin), derived
from the the 5th
branchial arch
 C-cells scattered through
posterior/superior lobes
Major causes of congenital
hypothyroidism, approximate frequency
• Thyroid dysgenesis - ectopia, aplasia, or
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hypoplasia (1:4500)
Inborn errors of thyroxine synthesis
(dyshormonogeneses) (1:30,000)
Maternal antibody-mediated hypothyroidism
(1:25,000-1:100,000)
Central hypothyroidism (1:25,000-1:100,000)
Transient hypothyroidism (1:100 Europe)
Lingual thyroid
CLINICAL
MANIFESTATIONS
• More than 95 percent
asymptomatic
– umbilical cord serum
T4 concentrations are
about 25 to 50 %
– inadequate,
functioning thyroid
tissue
Figure 15-7. Brain neurologic development relative to thyroid function in the rat and human. TH,
thyroid hormones; dpc, days postconception; dpn, days postnatal. (From Porterfield and Hendrich,
with permission.)
Clinical manifestations:
• Birth length and weight
• head circumference
• other congenital anomalies ↑
CLINICAL
MANIFESTATIONS
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Lethargy
slow movement
hoarse cry
feeding problems
constipation
macroglossia
umbilical hernia
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large fontanels
hypotonia
dry skin
hypothermia
prolonged jaundice
A few with thyroid
dyshormonogenesis :
a palpable goiter
Figure 15-12. Ten year old female with severe 1° hypothyroidism due to primary myxedema before (A) and after
(B) treatment. Presenting complaint was poor growth. Note the dull facies, relative obesity and immature body
proportions prior to treatment. At age 10 years she had not lost a single deciduous tooth. After treatment was
initiated (indicated by the arrow in Panel C), she lost 6 teeth in 10 months and had striking catch up growth. Bone
age was 5 years at a chronologic age of 10 years. TSH receptor blocking antibodies were negative.
Figure 15-4. Postnatal TSH, T4, T3, and rT3 secretion in the full-term and
premature infant in the first week of life (modified from Fisher DA: Disorders of the
thyroid in the newborn and infant. In: Sperling M (ed) Pediatric Endocrinology, WB
Saunders Co., Philadelphia, 51, 1996).
Low T4 and Elevated TSH
Values
• Low T4 + TSH > 40 :is considered to have
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primary hypothyroidism (Iran: TSH> 5 )
examination (immediately ) + confirmatory
serum testing to verify the diagnosis.
screening TSH concentration is only slightly
elevated but < 40 mU/L, another filter-paper
specimen should be obtained for a second
newborn screening.
Low T4 + high TSH
• 10% Hypothyroids ( TSH : 20-40)
• It is important that age appropriate
normative values be used.
• Range for TSH for the most common time
of TSH re-evaluation (between 2 and 6
weeks of age) is 1.7 to 9.1 mU/L.
Normal T4 and Elevated TSH
Values ( Hyperthyrotropinemia)
• Etiology :
1) transient or permanent thyroid abnormality
2) delayed maturation of the hypothalamicpituitary axis.
3) Inactivation mutations in the TSH-R cause
compensated, mild (subclinical) primary
hypothyroidism in the neonatal period.
There is controversy regarding
the need for TH therapy in this
setting.
High TSH + normal T4
• Most physicians would consider a persistent
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basal TSH concentration higher than 10 mU/L
(after the first 2 weeks of age) to be
abnormal.
If such infants are not treated, measurement
of FT4 and TSH should be repeated in 2 and
4 weeks, and treatment should be initiated
promptly if the FT4 and TSH concentrations
have not normalized.
High normal TSH
• The management of infants with TSH
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elevations between 6 and 10 mU/L that
persist after the first month of life is even
more controversial.
A TSH range of 1.7 to 9.1 mU/L has been
reported for children 2 to 20 weeks of age
if a decision is made to treat such children , a
trial off therapy at 3 years of age should be
performed.
Low T4 and Normal TSH Values
• 2 SDs below the mean for the reference range for
age , usually < 10 µg/dL in the newborn infant
1) Hypothalamic immaturity
2) during illness
3) protein-binding disturbances such as TBG
deficiency(1 in 5000)
4) central hypothyroidism (l in 25 000 to l in 50 000
newborn infants)
5) primary hypothyroidism and delayed TSH elevation
(l in 100 000 newborn infants).
• Transient hypothyroxinemia is seen to some extent
in many preterm infants
Figure 15-4. Postnatal TSH, T4, T3, and rT3 secretion in the full-term and
premature infant in the first week of life (modified from Fisher DA: Disorders of the
thyroid in the newborn and infant. In: Sperling M (ed) Pediatric Endocrinology, WB
Saunders Co., Philadelphia, 51, 1996).
Hypothyroxinemia
• Take no further action, to follow-up with
serial filter-paper screening tests until the
T4 value becomes normal, or to request
second blood sample for measurement of
FT4 and TSH concentration.
• Most infants with low T4 and normal TSH
have normal FT4 values, and subsequent
thyroid function test results are normal
Transient TSH Elevation
• Intrauterine exposure to maternal anti
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thyroid drugs, maternal TRBAbs
Heterozygous thyroid oxidase 2 deficiency
Germ-line mutations in the TSH-R, endemic
Iodine deficiency
Prenatal or postnatal exposure to excess
iodides ( povidone iodine, iodinated contrast
materials)
CLINICAL MANAGEMENT OF NEWBORN
INFANTS WITH LOW T4 AND
ELEVATED TSH VALUES
• Infants with low T4 and elevated TSH
concentrations have CH until proven
otherwise.
1) Consultation with a endocrinologist is
recommended to facilitate diagnostic
evaluation and optimal management.
Clinical management...
2) A complete history, including prenatal
thyroid status (maternal drugs and
medications) and family history should be
obtained, and physical examination should
be performed.
3) Serum should be obtained for
confirmatory measurements of TSH and
FT4.
Clinical management...
4) Education of parents by trained personnel
using booklets or visual aids is highly
desirable.
5) Optional diagnostic studies include
-thyroid ultrasonography
-iodine 123 (123I)
- sodium technetium 99m pertechnetate
(99mTc) thyroid uptake
-and/or scan to identify functional thyroid
tissue.
Treatment
• Treatment Should Begin As Soon As
Possible, Preferably Within The First Two
Weeks of Life
Treatment
The Goal Of Treatment
To Ensure Normal Growth &Development
T4 10 To 16 µg/dl
TSH Around 1 mIu/L
Treatment :
• The goal of therapy is to normalize T4
within 2 weeks and TSH within 1 month.
• An initial dosage of 10 to 15 g/kg of L-T4
(depending on the severity of the initial
hypothyroidism)
• Administration of L-T4 is the treatment of
choice.
Treatment :
• The pill should be crushed and suspended in
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a few milliliters of formula, breast milk, or
water.
Only T4 tablets should be used
T4 is expected to increase to more than 10
µg/dL
FT4 is expected to increase to more than 2
ng/dL by 2weeks after initiating therapy
TSH should normalize by 1 month.
Treatment :
• The L-T4 dose should be adjusted according to the
infant’s clinical response and serum FT4 and TSH
concentrations.
• During therapy, the serum total T4 or FT4 should and
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might be in the upper half of the reference range
(target values depend on the assay method used [T4:
10–16 g/dL (130–206 nmol/L); FT4: 1.4 –2.3 ng/dL
(18–30 pmol/L)]) during the first 3 years of life with a
low normal serum TSH.
The latter may sometimes be delayed because of
relative pituitary resistance.
• Between 1 and 5 days of life, the normal
range for serum total T4 concentrations is
about 10 to 22 µg/dL
• Between 1 and 4 weeks of life, the normal
range for serum total T4 concentrations is
7 to 16 µg/dL
Delay in normalization of TSH:
• Normal or increased serum (→ or↑ ) T4
and an inappropriately high TSH
concentration, the T4 value is used to
titrate the dose.
• Nonadherence to the treatment is the
most common cause of persistent TSH
elevation and should be excluded.
Target of treatment:
• TSH levels should be maintained between
0.5 and 2.0 mU/L during the first 3 years
of life
• During TH therapy, 4 or more episodes of
insufficiently suppressed TSH (5 mU/L)
after the age of 6 months were the most
important variables associated with school
delay
DIAGNOSTIC STUDIES
• venipuncture to confirm
• If the diagnosis of hypothyroidism is
confirmed
– thyroid radionuclide uptake and imaging
– Ultrasonography
– serum thyroglobulin assay
– thyroid autoantibodies
– urinary iodine excretion
These tests usually do not alter treatment
Recommended follow-up
• At 2 and 4 weeks after the initiation of T4
treatment
• Every 1 to 2 months during the first
year of life
• Every 2 to 3 months between 1 and 3
years of age
• Every 3 to 12 months thereafter until
growth is complete
 Two weeks after any change in dosage
Other neurologic sequelae
• gross and fine motor incoordination
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ataxia,
increased or decreased muscle tone
short attention span
speech defects
strabismus
• Studies before the initiation of newborn
screening reported that up to 20 percent
of children had sensorineural hearing loss
Figure 15-11. (Left panel) Infant with severe, untreated congenital hypothyroidism
diagnosed prior to the advent of newborn screening. (Right panel) Infant with
congenital hypothyroidism identified through newborn screening. Note the striking
difference in the severity of the clinical features.
PROGNOSIS
• If treated at appropriate time In general,
these infants grow and develop normally
Untreated CH Patients at Risk
for Severe Mental Retardation
Klein et al, J Pediatr 81:912-915, 1972
IQ of CH patients is normal if
treatment early and adequate
NECHC. Lancet 2:1095-1098, 1981
But small differences in T4 dose
have enormous impact on IQ
125
120
115
T4 dose
110
10 ug
7 ug
*
105
100
MDI- Mental Development Index
95
90
MDI
Bongers-Shokking JJ et al, J Pediatr 136:292-297,2000
Thyroid hormones effects
• Growth & development ( skeletal &
nervous system)
• General metabolism (↑ oxidation)
• Protein metabolism
• Lipid metabolism
• Carbohydrate metabolism
Thyroid Hormones
Hypothalamus
 TRH (Thyrotropin releasing hormone)
Pituitary
 TSH (Thyroid stimulating hormone)
Thyroid

T4 thyroxine  T3 thyronine
iodine
Permissive role:
Allow for normal cell function & growth
Induce N retention for protein synthesis
Stimulate growth H release
Increases metabolic rate
Roles
• Metabolic Rate
•  BMR
• ↑ heat production
• Newborns
• Stress
• Weight regulation
• SNS Activity
• ↑ -receptors
• ↑ Heart rate
• Brain activity, muscle activity
• Brain development and body growth
• Stimulates GH release
Congenital hypothyroidism
• approximately 1:4000 newborns
• the most common treatable cause of
mental retardation
• inverse relationship between age at
diagnosis and intelligence quotient (IQ)
later in life