Congenital hypothyroidism
- 2. CONTENTS • Thyroid physiology • Incidence • Classification • Causes • Diagnosis & screening • Follow up of screening • Treatment & monitoring • Prognosis
- 3. DEFINITION • Congenital hypothyroidism is inadequate thyroid hormone production in newborn infants. It can occur because of an anatomic defect in the gland, an inborn error of thyroid metabolism, or iodine deficiency. An infant with cretinism. Note the hypotonic posture, coarse facial features, and umbilical hernia.
- 4. PHYSIOLOGY AND DEVELOPMENT Thyroid function develops in three stages: 1ST, 2ND. 3RD Trimester
- 5. The gland descends to its definitive position in the anterior lower neck by the end of the first trimester. Embryogenesis begins on the floor of the primitive oral cavity. 5
- 6. 6 • Hypothalamic-pituitary-thyroid axis becomes functional in 2nd trimester Thyrotropin-releasing hormone (TRH), a tripeptide synthesized in the hypothalamus, stimulates the release of pituitary thyroid- stimulating hormone (TSH).
- 7. 7 • Peripheral metabolism of thyroid hormones matures in 3rd trimester
- 8. Neonatal physiology • 30 minutes after delivery- an abrupt 3 to 6-fold increase in circulating T3 and T4 level , coincident with increase of serum TSH concentration. • TSH surge -stimulation of the neonatal thyroid gland, hence increase circulating TH. • However, the TSH surge is short lived, and TSH hormone will decline after 72-96 hour of life due to feedback inhibition by T4 either the hypothalamic or the pituitary level(or both).
- 9. • 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…
- 10. Normal level of thyroid hormones Age TSH (mIU/L) Free T4 (pmol/L) Birth-D3 OL <21 26-65 D4-D30 0.51-10.8 12-30 D31-1yr 0.39-7 9-16.1 ≥ 1 yr 0.4-6 13.2-22.2 10
- 11. Functions of thyroid hormones Target tissue Mechanism Nervous system Promote normal brain development Heart • Increase number, affinity of beta adrenergic receptors • Enhance responses to circulating catecholamine Muscle Increase protein breakdown Bone Promote normal growth and skeletal development Gut Associated with carbohydrate absorption Adipose tissue Stimulate lipolysis Lipoprotein Stimulate formation of LDL receptors Other • Stimulate oxygen consumption by metabolically active tissues • Increase metabolic rates • Promote development of reproductive system • Maturation of fetal lungs 11
- 12. INCIDENCE • Incidence of congenital hypothyroidism worldwide is 1:2500 - 4000 live births • In Malaysia, it is reported as 1:3666 • It is the commonest preventable cause of mental retardation in children
- 13. Screening • Well established in developed countries • Malaysia - Started in october 1998 by Ministry of health • In kelantan – May 1999 (HRPZ2) • Why screening • Cannot be detected at birth • Most common cause of mental retardation • Late presentation 2-6 months
- 14. Malaysian’s strategy • Cord Blood TSH level is measured primarily supplemented by T4 for determination of borderline TSH level • Infants with elevated TSH values & with borderline TSH and low T4 are recalled for re-testing
- 15. Why Cord Blood TSH? • Much higher coverage for infants • Can be done together with established newborn cord blood screening for G6PD deficiency. • Cord blood sample is simple, non invasive and offers the earliest postnatal diagnosis and treatment.
- 16. • Missed, insufficient, clotted, BBA cases should be taken only after the 3rd day of life (4th day) -to avoid the TSH surge that occur from ½ H of life to about 72 H of life.
- 19. CAUSES OF CH: THYROID DYSGENESIS (85%) 1. Athyreosis (30%) 2. Hypoplasia (10%) 3. Ectopic thyroid (60%) OTHERS(15%) 1. Inborn error of thyroid hormone 2. Hypothalamo-pituitary defect 3. Peripheral resistance to thyroid hormone 4. Transient neonatal hypothyroidism 5. Endemic cretinism
- 20. 1.Thyroid dysgenesis • 85% of cases. • aplasia, hypoplasia, and dysplasia; • thyroid dysgenesis -genetic abnormality in one of the transcription factors necessary for thyroid gland development • no goitre • 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)
- 21. 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, • 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
- 22. • 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. • If central hypothyroidism is suspected, cortisol and growth hormone measured and (MRI) scan done to visualize the hypothalamus and pituitary gland 4.Central (hypothalamic–pituitary) hypothyroidism
- 23. 5. Transient hypothyroidism • This accounts for 10% of cases and is usually related to either maternal medications, eg carbimazole, or to maternal antibodies. • Maternal antithyroid drugs can cause decreased neonatal thyroid hormone synthesis which lasts for a few days to two weeks after birth. • Maternal antithyroid antibodies can cross the placenta and block the TSH receptor in the neonatal thyroid. This effect can last up to 3 to 6 months after birth as maternal antibody levels fall
- 24. Clinical diagnosis • Most infants are asymptomatic at birth. • Most infants with the disease have no obvious clinical manifestations at birth, therefore neonatal screening of thyroid function should be performed on all newborns. Subtle clinical features occurred during early weeks of life: • Prolonged neonatal jaundice • Constipation • A quiet baby • Enlarged fontanelle • Respiratory distress with feeding • Dry skin • Absence of one or both epiphyses on X-ray of left knee (lateral view).
- 25. The infant on the left with CH demonstrate absence of the distal femoral and proximal tibial epiphyses, while in normal infant on the right the distal femoral epiphysis is present.
- 26. • If left untreated, overt clinical signs will appear by 3 - 6 months: • coarse facies • dry skin • Macroglossia • hoarse cry • umbilical hernia • Lethargy • slow movement • Hypotonia • delayed developmental milestones.
- 27. 27
- 28. • Infant with congenital hypothyroidism. A - 3 month old infant with untreated CH; picture demonstrates hypotonic posture, myxedematous facies, macroglossia, and umbilical hernia. B - Same infant, close up of face, showing myxedematous facies, macroglossia, and skin mottling. C - Same infant, close up showing abdominal distension and umbilical hernia.
- 30. TREATMENT • Timing: Should begin immediately after diagnosis is established. If features of hypothyroidism are present, treatment is started urgently. • Duration: Treatment is life long except in children suspected of having transient hypothyroidism where re- evaluation is done at 3 years of age.
- 31. • Preparation: There are currently no approved liquid preparations. • Only L-thyroxine tablets should be used. The L- thyroxine tablet should be crushed, mixed with breast milk, formula, or water and fed to the infant. • Tablets should not be mixed with soy formulas or any preparation containingiron (formulas or vitamins), both of which reduce the absorption of T4.
- 33. GOALS OF THERAPY • To restore the euthyroid state by maintaining a normal serum FT4 level at the upper half of the normal age- related reference range. Ideally, serum TSH levels should be between 0.5-2.0 mU/L. • Serum FT4 level usually normalise within 1-2 weeks, and then TSH usually become normal after 1 month of treatment. • Some infants continue to have high serum TSH concentration (10 - 20 mU/L) despite normal serum FT4 values due to resetting of the pituitary-thyroid feedback threshold. However, compliance to medication has to be reassessed and emphasised.
- 35. FOLLOW UP • Monitor growth parameters and developmental assessment. • The recommended measurements of serum FT4 and TSH by American Academy of Pediatrics are according to the following schedules: - • At 2 and 4 weeks after initiation of T4 treatment. • Every 1 to 2 months during the first 6 months of life. • Every 3 to 4 months between 6 months and 3 years of age. • Every 6 to 12 months thereafter until growth is completed. • After 4 weeks if medication is adjusted. • At more frequent interval when compliance is questioned or abnormal values are obtained. • Ongoing counseling of parents is important because of the serious consequences of poor compliance.
- 36. Follow up • Mental and cognitive function – IQ test • Symptoms over and under treatment • Hearing test • Bone age – normalisation by 1-2 years
- 37. Re-evaluation of patients likely having transient hypothyroidism • This is best done at age 3 years when thyroid dependent brain growth is completed at this age. • Stop L-thyroxine for 4 weeks then repeat thyroid function test: FT4, TSH. • Imaging studies: Thyroid scan, Ultrasound of the thyroid. • If the FT4 is low and the TSH value is elevated, permanent hypothyroidism confirmed and life-long L- thyroxine therapy is needed.
- 38. • All newborns of mothers with thyroid diseases should be evaluated for thyroid dysfunction, followed up and treated if necessary. • Compulsory screening without any miss or error • Repeat test if any doubt • Congenital hypothyroidism – screening, treat to prevent MR • Patient education and compliance to treatment/follow up Early treatment-Excellent recovery Take Home Message
- 39. REFERENCES • Paediatrics protocol 3rd edition. • Congenital hypothyroid screening using cord blood TSH January 1999, journal. • Nelson paediatrics 6th edition.
Editor's Notes
- #6: Embryogenesis begins on the floor of the primitive oral cavity. The gland descends to its definitive position in the anterior lower neck by the end of the first trimester. Thyroid glands that do not reach the normal location are ectopic but may retain function; however, the glands most often become insufficient by early to mid childhood to support full thyroid secretion (a lingual or sublingual site or even tissue found in a thyroglossal duct cyst may be the only functioning thyroid gland).
- #7: Pituitary TSH is a glycoprotein that stimulates the synthesis and Thyroid-stimulating hormone (TSH) from the pituitary gland stimulates the secretion of thyroxine (T4) and triiodothyronine (T3) from the thyroid gland. These act at the pituitary gland level to control secretion of TSH by a negative feedback mechanism. In addition, T4 is metabolized to the potent T3 within the pituitary gland by a monoiodinase. Secretion of TSH is stimulated by thyrotropin-releasing hormone (TRH) from the hypothalamus and inhibited by somatostatin. Thyroid hormone acts at the hypothalamus to stimulate secretion of somatostatin (somatostatin acts as a negative signal to the pituitary secretion of TSH). CRH, corticotropin-releasing hormone; OB-R, leptin receptor. release of thyroid hormones by the thyroid gland.
- #8: T4T3 conversion mainly occurred in liver and kidneys
- #9: The TSH surge( a response to the thermal stimuli coincident after birth)n causes marked 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
- #10: 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.
- #11: TH level in newborn gradually return to adult levels by approximately 1 months of age.
- #21: Thyroid dysgenesis includes aplasia, hy-poplasia, and dysplasia thyroid dysgenesis is associated with a genetic abnormality in one of the transcription factors necessary for thyroid gland development
- #22: 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 siblings The most common synthetic defect is abnormal thyroid peroxidase activity, which results in impaired oxidation and organification of iodine Pendred 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
- #23: 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-ent If 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
- #25: Clinical features of hypothyroidism are subtle during the early weeks of life. However, prolonged neonatal jaundice (3/3), widely opened posterior fontanelle (3/3) and dry skin (3/3) were the common features in all our cases by 2-6 weeks of life.