Congenital Hypothyroidism: Early Detection and Treatment Prevents Mental Retardation
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Congenital Hypothyroidism: Early Detection and Treatment Prevents Mental Retardation
- 1. CONGENITAL HYPOTHYROIDISM Dr. Ravindra K Sharma Pediatric Specialist, FUJAIRAH HOSPITAL, UAE drravindrakr@gmai.com
- 2. Reference Manual 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
- 3. Layout of presentation Thyroid physiology Incidence Classification Causes Diagnosis & screening Follow up of screening Treatment & monitoring Prognosis
- 4. 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
- 5. Physiology in fetus & Newborn contd…. TSH from fetal pituitary gland increases from midgestation. 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
- 6. 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
- 7. Neonatal physiology contd… 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.
- 8. CONGENITAL HYPOTHYROIDISM most common preventable causes of mental retardation.
- 9. Incidence 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)
- 11. Causes of permanent CH Thyroid dysgenesis Defects in thyroid hormone synthesis and secretion (Thyroid dyshormonogenesis) TSH resistance Central (hypothalamic–pituitary) hypothyroidism
- 12. 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)
- 13. 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
- 14. 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
- 15. 4.Central (hypothalamic–pituitary) hypothyroidism 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
- 18. Causes of transient CH Antithyroid drugs Iodine excess. Worldwide, iodine deficiency Transient hypothyroxinemia of prematurity TSH receptor-blocking IgG antibodies Large liver hemangiomas
- 19. 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
- 20. 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
- 21. 4.Transient hypothyroxinemia of prematurity 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.
- 22. 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
- 23. 6.Large liver hemangiomas refractory hypothyroidism due to expression of D3 activity by the hemangioma present after the newborn period as the hemangioma enlarges. Tx- Large doses of L-thyroxine resolves as the hemangioma regresses
- 24. 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
- 27. Diagnosis & Screening method Over 95% of newborns with CH are asymptomatic at birth, but universal newborn screening allows for early diagnosis and treatment
- 28. 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
- 29. Diagnosis & Screening method contd… 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
- 30. 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
- 31. Follow-up of newborn screening for CH in hospitalized preterm 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
- 32. Follow-up of newborn screening for CH in hospitalized preterm contd… TG level + US and/or scanning Differentiate 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
- 34. Treatment and monitoring 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
- 35. Preparation of L-Thyroxine 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
- 36. Preterm suspected of transient hypothyroxinemia of prematurity Trials failed to demonstrate benefits of routine Lthyroxine 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,
- 37. Suspected transient CH 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
- 38. 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
- 39. Take Home Message 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
- 40. Thank You!
Editor's Notes
- The fetal Hypothalamuspitutary thyroid axis develops relatively independent of the mother due to the high placental concentration of D3, which inactivates most of the T4 presented from the maternal circulation .Thyroid embryogenesis is complete by 10 to 12 weeks’ gestation, by which time the fetal thyroid gland starts to concentrate iodine and synthesize and secrete T3 and T4 .Circulating T3 levels remain low, although brain and pituitary T3 levels are considerably higher as a result of a local intracellular type 2 deiodinase (D2) enzyme, which converts T4 to the active isomer T3
- . TSH from the fetal pituitary gland increases from mid-gestationThe negative feedback mechanism of the HPT axis starts to mature by 26 weeks of gestationCirculating levels of TRH are high in the fetus relative to the mother, although the physiologic significance is unclear. The ability of the thyroid gland to adapt to exogenous iodine does not mature until 36 to 40 weeks’ gestation. Thus, premature infants are more sensitive than are full-term infants to the thyroid suppressing effects of exogenous iodine
- Within 30 minutes after delivery, there is a dramatic surge in serum TSH, with peak levels as high as 80 mU/L at 6 hours of life, followed by a rapid decline over 24 hours, then a slower decline over the first week of lifeThe TSH surge causes marked stimulation of the neonatal thyroid glandSerum T3 and T4 levels increase sharply and peak within 24 hours of life, followed by a slow decline
- In the preterm infant, the pattern of postnatal thyroid hormone change is simi-lar to the pattern seen in the full-term infant, but the TSH surge is less marked, and the T4 and T3 responses are blunted. In very preterm infants (<31 weeks’ gestation), no surge is seen and, instead, the circulating T4 level may fall for the first 7 to 10 days.
- Thyroid dysgenesis includes aplasia, hy-poplasia, and dysplasiathyroid dysgenesis is associated with a genetic abnormality in one of the transcription factors necessary for thyroid gland development
- Defects in thyroid hormone synthesis and secretion (thyroid dyshormono-genesis) are responsible for most of the remaining 10% to 15% of permanent CH cases and generally carry a 25% recurrence risk in subsequent siblingsThe most common synthetic defect is abnormal thyroid peroxidase activity, which results in impaired oxidation and organification of iodinePendred syndrome is characterized by a goiter due to an underlying mild organification defect. It is an important cause of sensorineural deafness, but hypothyroidism rarely occurs in the newborn period
- . TSH resistance is usually caused by mutations in the TSH receptor gene. Rarely, it is due to a loss-of-function mutation in the G-stimulatory subunit that links TSH binding to The severity of the hypothyroidism depends on the degree of resistance
- Affected infants may have other signs of pituitary dysfunction, such as hypoglycemia, microphallus, and midline facial abnormalities. Septo-optic dysplasia is an important cause of central hypothyroidism. Goiter is not pres-entIf central hypothyroidism is suspected, cortisol and growth hormone levels should be measured and a magnetic resonance imaging (MRI) scan done to visualize the hypothalamus and pituitary gland
- ., intrauterine exposure to PTU or MMI can cause transient hypothyroidism that typically resolves within 1 week and does not require treatment. The elimination half-life of PTU is 1.5 to 5 hours and of MMI is 4 to 6 hours
- Neonates may be exposed to excess iodine in the perinatal and/or neonatal period. Preterm infants are particularly susceptible to the thy-roid suppressing effects of excess iodine (, such as from topical antisep-tic solutions (e.g., povidine iodine), radiographic contrast solutions, and drugs (e.g., amiodarone). Iodine is also passed through breast milk and can be exces-sive in mothers who ingest large amounts of seaweed (e.g., in Japan).
- These antibodies freely cross the pla-centa and persist in the neonatal circulation with a half-life of approximately 2 weeksBoth stimulating and blocking antibodies may be present simultane-ously and their relative proportions may change over time.
- due to expression of D3 activity by the hemangioma. Infants typically present after the newborn period as the hemangioma enlarges. Large doses of L-thyroxine are required for treatment. The hypothyroidism resolves as the hemangioma regresses
- is often due to recovery from sick euthyroid syndrome but needs to be distinguished fromtransient hypothyroidism, or from a mild form of permanent CH. This condi-tion is most common among very low birth weight infants (<1,500 g,) and low birth weight infants (<2,500 g,), and in other critically ill newborns including those with congenital heart diseaseDelayed TSH elevation may be missed on the initial screen, particularly in primary TSH screening programsSome screening programs require repeat testing at 2 to 6 weeks of age for infants at high risk for delayed TSH elevation and a few require repeat testing for all infants
- A filter paper blood spot specimen should be sent from all newborns, opti-mally at 48 to 72 hours of age but, often, this is not possible due to the practice of early discharge. For infants discharged prior to 48 hours of age, a specimen should be sent prior to discharge. Infants discharged before 24 hours of age should be retested at 48 to72 hours to minimize risk of false negative results. For infants transferred to another hospital, the receiving hospital should send a specimen if it cannot be con rmed that the hospital of birth sent one. For infants <1,500 g birth weight, repeat specimens should be sent at 2, 6, and 10 weeks of age due to the risk of delayed TSH elevation
- If clinical signs of hypothyroidism are present (prolonged jaundice, con-stipation, hypothermia, poor tone, mottled skin, poor feeding, large tongue, open posterior fontanel), thyroid function tests should be sent immediately, even if the initial screen was normalRarely, screening programs miss cases of CH as a result of early discharge, improper or no specimen collection (e.g., hospital transfers, home births, sick or premature neonates), labora-tory error, or delayed TSH elevation
- Any infant with abnormal screening results should be evaluated without delay. Consultation with a pediatric endocrinologist is recommendedMa-ternal and family history should be reviewed and a physical examination per-formed. Thyroid function tests should be repeated in serum within 24 hours. Most infants with an initial TSH level >50 mU/L have a permanent form of CH. If the initial TSH is 20 to 40 mU/L, the CH may be transient. If it is not possible to see the patient promptly, therapy should be initiated as soon as the diagnosis is confirmed. If the TSH level is not elevated, the TBG level should be measured to exclude TBG deficiency
- Measurement of TG level and thyroid ultrasound and/or thyroid scan-ning with RAI or 99mTc can help differentiate thyroid dysplasia from defects in thyroid hormone synthesis, and transient from permanent conditionsThese tests are not necessary if transient hypothyroxinemia of prematurity is suspectedThyroid scanning is useful to detect dysplastic or ectopic thyroid tissue as long as the serum TSH level is 30 mU/L at the time of scanning.Treatment should not be delayed to perform thyroid scanning. If scanning cannot be performed within 5 days of diagnosis, it should be deferred until the child is 3 years old, at which time thyroid hormone replacement can be safely discontinued for a brief period of timeUnlike thyroid scintiscan, ultrasound can be performed irrespective of the TSH concentration.c. Bone age may be helpful in assessing the severity and duration of intrauterine hypothyroidism but currently is performed less frequently than in the past
- An optimal neurodevelopmental outcome depends on early, adequate treatment of CHL-thyroxine should be initiated at 10 to 15 mcg/kg/day, with a higher dose used for infants with the lowest T4 and highest TSH levelsThe goal of treatment is to normalize thyroid hormone levels as soon as possible, 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. Ideally, the T4 level will normalize within 1 week, and the TSH level within 2 weeks, of starting therapyNoncompliance can have serious, permanent neurodevelopmental consequences for the infant and should always be considered by caregivers when thyroid function tests fail to normalize with treatment
- treatment decisions are complicated by incomplete knowledge regarding the risks and benefits of treatment. studies have found an association of a low serum T4 concentration with increased morbidity and mortality, randomized trials have failed to demonstrate a short- or long-term benefit of routine L-thyroxine supplementation for all preterm infants.Some physicians prefer to treat infants <27 weeks’ gestation due to presumed hypothalamic–pituitary immaturity, but this issue is controversial
- For infants with suspected transient CH, a brief trial off medication can be attempted at 3 years of age, after thyroid hormone-dependent brain develop-ment is complete. Usually in infants with transient hypothyroidism, the dose required to maintain normal thyroid function does not change with age
- With prompt diagnosis and treatment, the neurodevelopmental out-come is excellent for infants with CH. Subtle visuospatial processing, memory, and sensorimotor defects have been reported, particularly in those infants with severe CH, but the clinical signi cance of these differences is controversial. In contrast, infants who are diagnosed late may have substantial cognitive and be-havioral defects ranging from mild to severe, depending on the severity of the CH and the length of delay in starting treatment.