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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