congenital hypothyroidism
TRANSCRIPT
CONGENITAL HYPOTHYROIDISM
Dr. Ravindra K Sharma
Pediatric Specialist, FUJAIRAH HOSPITAL, UAE
ReferenceManual of Neonatal Care , Cloherty ; Seventh edition,2012
(AAP 2006)
AAP guidelines 2007
Australian pediatric endocrine group
Guideline for CH in Scotland-NHS 2010
Abu Dhabi Newborn Screening program manual 2009
Layout of presentation
Thyroid physiology
Incidence
Classification
Causes
Diagnosis & screening
Follow up of screening
Treatment & monitoring
Prognosis
Physiology in fetus & Newborn
fetal HPT axis develops independent of the mother due to the high placental concentration of D3(inactivates T4 from mother)
embryogenesis is complete by 10 to 12 weeks’ gestation,
T3 levels remain low, but brain and
pituitary T3 levels are higher because of
type 2 deiodinase (D2) enzyme, which
converts T4 to the active isomer T3
Physiology in fetus & Newborn contd….
TSH from fetal pituitary gland increases from mid-gestation.
negative feedback mechanism of HPT axis starts to mature by 26 weeks
Circulating levels of TRH are high in the fetus relative to the mother
Ability of gland to adapt to exogenous iodine not mature until 36 to 40 weeks’ gestation
Neonatal physiology
30 minutes after delivery-dramatic surge in TSH, with peak at 6 hours of life, followed by a rapid decline over 24 hours,
TSH surge -stimulation of the neonatal thyroid gland.
Serum T3 and T4 levels increase sharply and peak within 24 hours of life, followed by a slow decline
preterm infant-TSH surge is less marked, and the T4 and T3 responses are blunted.
<31 weeks’ gestation no surge seen and, instead T4 fall for 7 to 10 days.
Neonatal physiology contd…
CONGENITAL HYPOTHYROIDISM
most common preventable
causes of mental retardation.
USA-1:2500
Male:Female=1:2
More commom in Trisomy 21, CHD & other congenital anomaly
UAE-350 thyroid gland deficiency between 2005-2012 (1:1914)
Incidence
Classification
Permanent
Transient
Hypothyroxinemia with delayed TSH rise
Causes of permanent CH
Thyroid dysgenesis
Defects in thyroid hormone synthesis and secretion (Thyroid dyshormonogenesis)
TSH resistance
Central (hypothalamic–pituitary) hypothyroidism
1.Thyroid dysgenesis
85% of cases.
aplasia, hypoplasia, and dysplasia;
thyroid dysgenesis -genetic abnormality
no goiter,
low total and free T4 levels, elevated TSH, and
normal TBG.
Thyroglobulin (TG) -low in aplasia and hypoplasia
Confirmed absence by USG and/or thyroid scintiscanning with radioactive iodine (RAI) or pertechnetate (99mTc)
2.Defects in thyroid hormone synthesis and secretion (Thyroid dyshormonogenesis)
10% to 15%
25% recurrence risk -siblings.
synthetic defect is abnormal thyroid peroxidase activity
Pendred syndrome –goiter +sensorineural deafness
Goiter present.
Total and free T4 levels are low, TSH is elevated,
and TBG is normal.
serum TG, low in TG synthetic defects and high in other thyroid hormone synthetic defects.
Imaging reveals a normally placed thyroid gland
3.TSH resistance
mutations in the TSH receptor gene.
loss-of-function mutation in the G-stimulatory subunit that links TSH binding to action
thyroid gland is small.
T4 is normal or low and TSH is elevated
other signs of pituitary dysfunction, -hypoglycemia, microphallus, and midline facial abnormalities.
Septo-optic dysplasia -important cause of central hypothyroidism.
Goiter is not present.
Total and free T4 are low, TSH is low or inappropriately normal,
TBG is normal.
cortisol and growth hormone measured
(MRI) scan done to visualize the hypothalamus and pituitary gland
4.Central (hypothalamic–pituitary) hypothyroidism
Causes of transient CH
Antithyroid drugs
Iodine excess.
Worldwide, iodine deficiency
Transient hypothyroxinemia of prematurity
TSH receptor-blocking IgG antibodies
Large liver hemangiomas
1.Antithyroid drugs
intrauterine exposure to PTU or MMI
typically resolves within 1 week and does not require treatment
2.Worldwide, iodine deficiency
• most common cause of transient
hypothyroidism, particularly
in preterm
3.Iodine excess.
exposed to excess iodine in the perinatal and/or neonatal period.
Preterm infants –susceptible to thyroid suppressing effects of excess iodine
through breast milk and in mothers who ingest large amounts of seaweed (e.g., in Japan).
Goiter may be present.
T4 is low and TSH is elevated.
RAI or 99mTc uptake is blocked by excess iodine,
Ultrasound -normally positioned thyroid gland
m/c <31 weeks’ gestation.
hypothalamic–pituitary immaturity (< 27 weeks’ gestation), acute illness, and medications (e.g., dopamine, steroids).
TSH is inappropriately “normal.”
total T4 is more affected than free T4
neonatal death, intraventricular hemorrhage, periventricular leukomalacia, cerebral palsy, intellectual impairment, and school failure.
Tx controversial but beneficial to infants <27 weeks’ gestation.
4.Transient hypothyroxinemia of prematurity
5.TSH receptor-blocking IgG antibodies
1% to 2%
known maternal autoimmune thyroid disease.
half-life 2 weeks.
Both stimulating and blocking antibodies present
Hypothyroidism persists for 2 to 3 months
Goiter is not present.
T4 is low, TSH is elevated, and TBG is normal.
High concentrations of TSH receptor-blocking antibodies present in maternal and neonatal serum.
thyroid scintiscanning, uptake absent,
thyroid gland seen on ultrasound
6.Large liver hemangiomas
refractory hypothyroidism due to expression of D3 activity by the hemangioma
present after the newborn period as the hemangiomaenlarges.
Tx- Large doses of L-thyroxine
resolves as the hemangioma regresses
Hypothyroxinemia with delayed TSH elevation (atypical CH)
due to recovery from sick euthyroid syndrome
infants < 1,500 g
critically ill newborns including congenital heart disease.
Delayed TSH elevation may be missed on the initial screen, particularly in primary TSH screening programs.
repeat testing at 2 to 6 weeks of age
Diagnosis & Screening method
Over 95% of newborns with CH are asymptomatic at birth, but universal newborn
screening allows for early diagnosis and treatment
Newborn screening for CH
Some programs measure T4 for the primary screen, followed by TSH when T4 is low,
other programs measure TSH as the primary screen (UAE)
advantages and disadvantages to each approach.
Few measure both T4 and TSH in
the initial screen for all newborns
filter paper spot - 48 to 72 hours of age
discharged <48 hours - sent before discharge
discharged < 24 hours of age -retested at 48 to72 hours
if transferred other hospital, receiving hospital should send
<1,500 g repeat specimens at 2, 6, and 10 weeks of age due to the risk of delayed TSH elevation
Diagnosis & Screening method contd…
If signs of hypothyroidism tests immediately, even if the initial screen was normal.
screening programs can miss cases of CH
TSH screening programs may miss infants with central (pituitary) hypothyroidism.
Acquired hypothyroidism -missed on newborn screening
Diagnosis & Screening method contd….
abnormal screening result- evaluated without delay
Maternal and family history should be reviewed +physical examination
TFT Repeated within 24 hours.
Initial TSH level > 50 mU/L-permanent CH.
TSH is 20 to 40 mU/L, the CH may be transient.
TSH level is not elevated, the TBG level should be measured to exclude TBG deficiency
Follow-up of newborn screening for CH in hospitalized preterm
TG level + US and/or scanningDifferentiate dysplasia from defects, and transient from permanent conditions.
if transient hypothyroxinemia of prematurity is suspected- test not needed
Thyroid scanning -detect dysplastic or ectopic thyroid tissue
Treatment not be delayed to perform thyroid scanning.
If not done within 5 days of diagnosis, -deferred until 3 years at which time thyroid hormone replacement be safely discontinued
USG can be done irrespective of the TSH concentration
Bone age helpful -severity and duration of intrauterine hypothyroidism
Follow-up of newborn screening for CH in hospitalized preterm contd…
For infants with suspected transient or permanent CH,
L-thyroxine -10 to 15 mcg/kg/day,
normalize thyroid hormone,
with total T4 in the 10 to 16 mcg/dL range,
free T4 1.4 to 2.3 ng/dL,
and TSH > 0.5 to 2 mU/L
Normalise T4 within 1 week, TSH -2 weeks,.
Lab after 1 week after starting therapy, 2 weeks after any dose change, and every 1 to 2 months in first year of life
Treatment and monitoring
crushed and fed directly to the infant or mixed in a small amount of juice, water, or breast milk.
Soy-based formulas, ferrous sulfate, and fiber interfere with absorption
2 hours early
No liquid preparations
Preparation of L-Thyroxine
Trials failed to demonstrate benefits of routine L-thyroxine supplementation
Some prefer to treat <27 weeks’ gestation due to presumed hypothalamic–pituitary immaturity,
Infants with TSH concentration borderline high range (10–20 mU/L) or with a serum TSH level that is rising -treated.
starting dose of L-thyroxine is 8 mcg/kg/day,
Preterm suspected of transient hypothyroxinemia of prematurity
brief trial off medication can be attempted at 3 years of age, after thyroid hormone-dependent brain development is complete.
dose required to maintain normal thyroid function does not change with age
Suspected transient CH
Prognosis
neurodevelopmental out-come is excellent
Subtle visuospatial processing, memory, and sensorimotor defects have been reported in severe CH-significance controversial
diagnosed late may have substantial cognitive and behavioral defects
Compulsory screening without any miss or error
Repeat test if any doubt
All with low T4 and high TSH are CH until proved otherwise
Consultation with pediatric endocrinologist
Scanning should not delay Rx
Early treatment-Excellent recovery
Take Home Message
Thank You!