بررسی اختلالات تیروئید در نوزادان

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Evaluation of Thyroid Disorders in Neonates Fereidoun Azizi Research Institute for Endocrine Sciences ات ‎Science‏ Tehran, I.R.Iran TEL Rd ‏ا‎ 

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Agenda * Definitions * Congenital hypothyroidism oPrevalence oScreening management * Neonatal thyrotoxicosis 

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TRANSITIONS FROM EUTHYROIDISM TO YPOTHYROIDISM OR HYPERTHYROIDISM Overt hyperthyroidism T3-toxicosis Subclinical hyperthyroidism Euthyroidism Subclinical hypothyroidism Mild hypothyroidism Overt hypothyroidism 1 1 N=normal, !=decreased, 1 = increaseq 

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Causes of Congenital Hypothyroidism Developmental defects ~ 1 every 4000 newborns; In Iran >1/1000 ~ Complete absence of thyroid tissue ~ Failure of thyroid to descend properly during embryologic development - Route of descent (foramen caecum at the junction of anterior ti thirds and posterior third of tongue to normal site or below) Biosynthetic defects in the thyroid Pituitary or hypothalamic failure Family with mutation in gene coding TSH [ ‏الیو‎ 

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‎on <a ge‏ سا ‎approximate prevalence in the PR ‏لا ااال‎ ‏100 ‏| ‏همهاء۳ ‎ ‏درج ور مسرم و ارات ‎ae oo‏ رو ها و یتخس زر ۷ ‎ ‎۱۱۷۱۱۵۰۹۱۵۱۱ Cott ‘Thyroid-stimulating hormone unresponsiveness Iodide trapping defect Organification defect Dann C iy Iodotryrosine deiodinase deficiency ‎Transient hypothyroidism 1:40 ] 0 0 Trent tte Grey ra ‎ ‎Hypothalamic-pituitary hypothyroidism 1:100,000 ‏ااتقصمصة تسمغتستم-عتسمتقط) م مور‎ 0 Isolated thyroid-stimulating hormone deficiency Thyroid hormone resistance ‎ 

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Differential diagnosis of transient congenital hypothyroidism Primary hypothyroidism Prenatal or postnatal iodine deficiency or excess ‏صمناه»ن0عصد 0تمحوطاناصه اعصمهه۳‎ ۱ ‏ای ل ا‎ Secondary or tertiary hypothyroidism ete ‏عونتم حوطاه روط تمه هه ما‎ Prematurity (particularly <27 weeks’ gestation) Drugs Steroids ‏ترا‎ Miscellaneous Isolated TSH elevation Pee Ro ‏ومد‎ ۷ Prematurity Undernutrition Low-T3 syndrome 

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Importance of iodine in brain development ¢ 50,000 brain cells produced/second in developing ‏لل لكا‎ ۰ 100 ‏لل‎ ‎cells in adult * One million billion connections between these brain Cot OH ‏كلكا‎ 

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90 % of human brain development occurs between 3™ month of pregnancy & 3" year of life (Critical period) 

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dian urinary iodine excretion in 4 national surveys in LRuran 1 لقدممصمعنم لتمصوط] .5 تعتعم 

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00 ee el] ‏سللامت جامعه ایرانی‎ ۱ ‏ا ا‎ 1 tee eS eee] Spb Ceara Ree ayer (۱۲۰۰۰۰۰۰۰ یورو) در هزینه های بهداشتی درمانی 

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ل ا ا كت ‎ee esr‏ يه ‏* انجمن متخصصین غدد درون ریز و متابولیسم ایران * انجمن علمی متخصصین زنان و مامایی و نازایی ایران ‏** انجمن آسیب شناسی ایران ‎OO cee a SS aCe arc ae ‎۱۳۹ 

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Likely insults to the CNS in: LL a severe iodine deficiency Gestational age in months ey Pe Ly 

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CH Screening * Since 1975 * Highly sensitive immunoassay methods * Direct measurement of serum thyroxine and TSH ¢ Filter paper blood spots * Gurantee detection and treatment ‏ماهر‎ TR) oH) MT * Majority of children who were treated early experienced normal growth and neurologic development and normal- range IQ values 

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Algorithm for evaluating abnormal thyroid ‏انیت‎ tests Pesta gin Soa ۲4 a Normal/Low TSH Sere ۲ 2 i 14 14 iF Normal Low Normal or low ۳۳۹ a eee ‏د‎ scan Nt) pees Due ‏نك‎ 1 ۱ ۳ ‏رب‎ 1 220 oeaTll ۳ 00 =) aaa / Normal LowNotmal Low 1 i Nae 81 TG Deficiency cin BU ented 7 perenne! ‏لمر ۳6۷ 4عاهامور‎ 1 8 ‏تن‎ Deficiency Sesh ‏تا كذ‎ a TBG ١ \ ۱ ‏همم‎ ‏ل ور‎ kes MEST e corer! Central CH CH Antithyroid Drugs Iodine Trapping Defect ‏عصنقه1‎ 00۵06 

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1 rel ا ا ۱9| ‎Ea alee‏ ما ا ا 00 ا ۱ شد. با ل مکسن تحقیقات غدد درونریسن دانشگاه علوم ‎tee Ler Teaee‏ اا ا ا اال ۱ انرژسی اتمی مجددا نامه غربالگرری کم‌کاری مادرزادی قيرروئید را از سال در بعضبی از بیمارستان‌های شهر تهرران و سپس شبکه دماوند اجرا کرد . 

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نتايج مطالعات مركز تحقيقات غدد دانشكاه شهيد بيشتى و مطالعه شيراز شيوع بالاى كمكارى مادرزادی نوزادان در کشور را نشان می‌دهد. این ‎US ICeree Tete‏ 510 ‎oat alo oe ee Deed‏ ات ‎bgp G1} ,2b0‏ ۱ ا 

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High prevalence of consanguineous and congenital ۱ Incidence: 1: 1403 live births Dyshormonogenesis: 20%, (1: 5010) Parental Odds ratio consanguinity: 9 (95% CI) Control: ‏خرص‎ Permanent 47.1 2.75 (1.17- CH 6.47) Ordookhani A. et al. J Pediatr Endocrinol Metab 2004; 17: 1201 

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| اجرای آزمایشی (پایلوت) در ۳ استان: سال ۱۳۸۳ 

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اجزای تشکیل دهنده برنامه غربالگری نوزادان - آموزش (پرسنل بهداشتی درمانی و اجرائی, والدین, عموم جامعه. سياستكذاران) 0 Cen nCy LS acy SU ‏ال م‎ !- ييكيرى اوليه (فراخوان موارد مشكوى) 030 Nee TOE ‏ا‎ ee eer ste ssi 

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هدف اصلی برنامه ۱ 1 بازده نهایی اجرای برنامه كاهش هزينه هاى اقتصادى ناشى از بيمارى ‎RR sere ee ae‏ " ارتقا کیفیت زندگی بیماران و خانواده آنها ارتقا ميانكين ضريب هوشى افراد جامعه ازطريق بيشكيرى از كاهش ضريب هوشى مبتلايان 

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۱ Oe 1 ۱ : تعداد بیماران شناسایی شده: بیش از ۲۰۰۰۰ بیمار كك نوع گذرای بیماری - ۲۹ درصد ۰ بروز بیماری: ۱در 1۰۰ نوزاد غربالگری شده 

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زمان شروع درمان برحسب سن نوزاد | کمتر از ۲۸روز روز 40-28 ۰ 71% 18% | 5% :© شاخص زمان شروع فرمان فر بيماران شناسابى شدده 48 درصد ذر زمان مثانسب 

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ل ‎POS acer nt‏ در برنامه کشوری ‎BS esp lee 52111111 ere‏ ۳-۷ روزه كك ۸ روزه - ۵ ماهگی 5018 تاه 10 191۲2 روزه ‏هروس 00 ‏فراخوان به موقع نوزاد خوب ۱-۳ روزه 515 ۱-۰ روزه 

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Signs and Symptoms of Hypothyroidism الال 0ن 0 ی ۱ ۱ OC eran C MC n a Ceuta rte ‏(طتودع1 تقححدمم‎ During Early Infancy * decreased muscle tone, lethargy, poor feeding * ‏متسحع طامموط‎ ‏ا‎ ‎* prolonged jaundice * abdominal distension, umbilical hernia ‏کر‎ ‎* macroglossia * hoarse cry ** myxedematous appearance 

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Algorithm for the diagnostic evaluation of an infant with suspected congenital hypothyroidism. 

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Congenital Hypothyroidism: Outcome Disease-Related Variables: - Etiology of hypothyroidism ‏«اتساحص لحاع‌امی(ه‎ ۷1 - Age at onset of therapy Starting dose - Time to achieve normalization - Subsequent treatment and out - Compliance and treatment ‏اتلك‎ | Gender Social, genetic and environmental factors 

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Thyroid function, physical development and intelligence quotient in various types Ectopy (@=3) 40 tity 5.8 0.79 +3.30 112 68* 0.39 12.3 الملا *1.00 stig Athyroidis m (@m=45) ين !1 *0.19 1:31 +1.21- -7.15* وم of congenital hypothyroidism BAe mts tel Hypoplasia (n=31) ماطمنع ۷ تطضاط عم ‎Serum TSH (mU/L)‏ ۱ ‎Serum Tg (ng/mL)‏ ‎At age 4.8-14.2 y:‏ Target Ht SDS, ‏تفت‎ Bone-chronological Peace) ۱ tls Cord 

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Intelligence and Achievement Test Result by Etiology in Congenital Hypothyroidism ‏زم‎ ‎100 te a ‏تس تمه‎ 5 ۱: ao 40 Pi) 00 005 Bue ‏اللي اك‎ Full Performance IQ Arithmetic Reading ~~ WISC-III 0 01376 ماعط بتقطعظ :ه12 .لد ا وده لتتصمه5 

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Congenital Hypothyroidism: Outcome Disease-Related Variables: - Etiology of hypothyroidism Skeletal maturity BUCO ‏ی رت ار ور‎ b - Age at onset of therapy Starting dose - Time to achieve normalization - Subsequent treatment and outc 5 ‏07د ا 16 ان‎ Gender Social, genetic and environmental factors 

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Reference intervals for TSH of 

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Age-related reference values for fT4 (both sexes) 

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Percentiles tor [SH (mU/L) oF children And adolescents Upper limit (97.5) 16.9 10.2 6.9 6.3 5.4 4.6 4.3 Mean 3.5 3.5 28 3 2.3 2.1 ۳ poeta (2.5) ۳ ۳0 1.1 08 08 ۳ 0.5 تن 1-7 days 8-30 days 1-12 months 1-5 years 6-10 years 11-14 years 15-18 ‏كنوع‎ Kapelari K, et al. BMC Endocrine Disorders 2008; 8: 15-25 

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Effect of Delay Treatment on Eventual 10 ٠ Klein et al: A 5-6 month delay in treatment with an average IQ approximately 70 * Loss of 5-6 IQ points pey manibps (linear effect) ¢ Bonger-Schoking et al: Delay treatment in early weeks * Most impact * Lower IQ several points BRL) 

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Congenital Hypothyroidism: Outcome Disease-Related Variables: - Etiology of hypothyroidism Skeletal maturity Thyroid hormone levels at diag1 3 - Age at onset of therapy Starting dose - Time to achieve normalization - Subsequent treatment and outc - Compliance and treatment ‏ينين‎ | Gender Social, genetic and environmental factors 

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Congenital Hypothyroidism: Outcome Disease-Related Variables: - Etiology of hypothyroidism - Skeletal maturity - Thyroid hormone levels at diag - Age at onset of therapy - Starting dose ۲۱۱۱۱ ‏ایو وتا‎ - Subsequent treatment and out - Compliance and treatment ‏فيك‎ | Gender Social, genetic and environmental factors 

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Congenital Hypothyroidism: Outcome Disease-Related Variables: - Etiology of hypothyroidism Skeletal maturity BURG Mie ‏الاك ا ل ا‎ - Age at onset of therapy be Starting dose Time to achieve normalization Subsequent treatment and out: Compliance and treatment ade ll Gender Social, genetic and environmental factors 

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CH: Treat Children But ‏و0‎ erat Cc ae Mey Parents * Evaluate the IQ development in CH children detected by neonatal screening in an Flac mcm Canam ‏ا ل‎ vice the IQ development * Three educational-affective attitudes in the ۱۱۹ ۱ ‏الت اللا ل ل ا ل‎ distress ° 2) 51% reacted with anxiety resulting in overstimulation of the child 0 50 1 ‏اا ال تا ل‎ ۱9 ‏كأسعسدم 04 مستلاء كفداقء! لمع زات 1[ ار‎ 

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Management of Congenital ‏ال ةا‎ Medications 1-14: 10-15 ‏ترلتقك ععصه طتامصص ترط وعا/وير‎ Monitoring Recheck T4, TSH Pee ecm Nt eac toe Oe Tt tty Every 1-2 mo in the first 6 mo Every 3-4 mo between 6 mo and 3 y of age Every 6-12 mo from 3 y of age to end of growth Goal of therapy Normalize TSH and maintain T4 and FT4 in upper half of reference range Assess permanence of CH If initial thyroid scan shows ectopic/absent gland, CH is permanent If initial TSH is 50 mU/L and there is no increase in TSH after newborn period, then trial off therapy at 3 y of age a eter Roan cy NaC Cm ental E Pee a ne ee ee EAL 

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Facts and Recommendations for neuropsychological » IQ scores ‏لالن‌کرد‎ y bets ack a tests in almost all adequately treated CH children. » Selected tests of motor proficiency are indicated at 3 and 5 years of age. » Language performances are at particular risk in CH children, and language achievements should be regularly reevaluated at 6-month intervals and, Sim CM TCM rem CM Lo ac Mm 267 should receive specific rehabilitation treatment. OCR iam ‏تا ا الل ل ل‎ warranted in CH children with normal tests at age 5 5. 

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Health care professionals must both remain alert to parents’ perceptions, which may be different than those of their affected children, and promote the need for patient adherence to treatment throughout life, 1 confirmed to have permanent CH, using a standard clinical protocol Leger J, et al. JCEM 2011; 96: 1771. 

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4 Hyperthyroidi 

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Clinical manifestations of neonatal hyperthyroidism » Low birth, prematurity » Microcephaly, frontal bossing, triangular facies » Irritablelity, fever, diarrhea 00117 15ت ردعتزء :ا اعستسساممرط ع » Tachycardia, bonding pulses » Cardiomegaly, EHF, arrhythmias » Jaundice, hepatosplenomegaly, thrombocytopenia » Accelerated skeletal maturation 

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Management Of thyrotoxicosis in Confirm diagnosis 14 160 nancy Start ‏ا ا ا الل ۸۸۱۱ ی‎ in ‏ل ع انا‎ trimester 11 ‏ا 061 تدع‎ euthyroid: continue with low-dose ATD up to and during labor and postpartum Monitor thyroid function: Res metal me UMP Lae Clot ame) ‏صتع‌اصته‎ T4 at upper level of normal ]9 tel ۱۰۱۰۱ aPC POA e TATA atte * effect on patient * effect on fetus « breast feeding Inform obstetrician and pediatrician Review postpartum-check for exacerbation 

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WHAT IS THE VALUE OF TSHRAB MEASUREMENT IN THE EVALUATION OF A PREGNANT WOMAN WITH GRAVES’ HYPERTHYROIDISM? - If the patient has a past or present history of Graves’ disease, a maternal serum measure of TSHRAb should be obtained at 24-28 weeks gestation. 1 Cree B VC PLEO} Se eee gamete Neo ty Ree ee) ‏قنمعرط؟ .له ۵ ۱ ملهه‌ههمه۹ -وهاه نه:‎ 2009, 19: 6612 

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TSH receptor antibody in 0 ‏ل‎ si el UY Colette لا ا ¢ Euthyroid or hypothyroid GD patients may still DEN mre MMe Uy * High TRAb is more common after radioiodine ‏لعا‎ ¢ Fetal and neonatal thyrotoxicosis occur in 1- 5% of mothers with current or past GD. ٠ TRAb is the best predictor (predictive value BarM2%@ et al. J Clin Endocrinol Metab 2013; 98: 2247. Kamijo K. Endocr J 2007;54:619-624, ‎OD MUU BSAA EPL LLY)‏ ل 1ك 

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UNDER WHAT CIRCUMSTANCES SHOULD ADDITIONAL FETAL ULTRASOUND MONITORING FOR GROWTH, HEART RATE, AND GOITER BE PERFORMED IN WOMEN WITH GRAVES’ HYPERTHYROIDISM IN PREGNANCY? » Fetal surveillance should be performed in women who have uncontrolled hyperthyroidism or who have _ highly elevated TSHRAb titers. Such monitoring may include ultrasound monitoring for heart rate, growth, and fetal goiter. Sees ee ese eer 

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freatment Of neonatar hyperthyroidism * Methimazole (not PTU) 0.25-1 mg/kg/d ¢ Propanolol 2 mg/kg/d ¢ Lugol’s solution or potassium iodide on ipanoic acide 100-200 mg/d ٠ Glucocorticoids, in severe cases * Digoxine, if needed Barbesino G, et al. J Clin Endocrinol Metab 2013; 98: 2247. Kamijo K. Endocr J 2007;54:619-624. Laurberg P, et al. Eur J Endocrinol 2009; 160: 1-8. 

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