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Evaluation of Thyroid Disorders in Neonates Fereidoun Azizi Research Institute for Endocrine Sciences Shahid Beheshti University of Medical Science Tehran, I.R.Iran بیست و هشتمین همایش بین املللی بیماری های کودکان 1395 آبان ماه2 مهر تا29 Agenda • Definitions • Congenital hypothyroidism oPrevalence oScreening management • Neonatal thyrotoxicosis TRANSITIONS FROM EUTHYROIDISM TO HYPOTHYROIDISM OR HYPERTHYROIDISM Serum TSH Serum FT4 Serum FT3 Overt hyperthyroidism ↓ ↑ ↑ T3-toxicosis ↓ N ↑ Subclinical hyperthyroidism ↓ N N Euthyroidism N N N Subclinical hypothyroidism ↑ N N Mild hypothyroidism ↑ ↓ N Overt hypothyroidism ↑ ↓ ↓ N = normal, ↓=decreased, ↑ = increased کم کاری تيروييد نوزادان 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 two 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 β subunit Thyroid disorders and their approximate prevalence in the neonatal period Thyroid dysgenesis >1:1000-1:4000 Agenesis Hypogenesis Ectopia Thyroid dyshormonogenesis 1:40,000 Thyroid-stimulating hormone unresponsiveness Iodide trapping defect Organification defect Defect in thyroglobulin Iodotryrosine deiodinase deficiency Transient hypothyroidism 1:40,000 Drug induced Maternal antibody induced Idiopatic Hypothalamic-pituitary hypothyroidism Hypothalamic-pituitary anomaly Panhypopituitarism Isolated thyroid-stimulating hormone deficiency Thyroid hormone resistance 1:100,000 Differential diagnosis of transient congenital hypothyroidism Primary hypothyroidism Prenatal or postnatal iodine deficiency or excess Maternal antithyroid medication Maternal TSH receptor blocking antibodies Secondary or tertiary hypothyroidism Prenatal exposure to maternal hyperthyroidism Prematurity (particularly <27 weeks’ gestation) Drugs Steroids Dopamine Miscellaneous Isolated TSH elevation Low T4 with normal TSH Prematurity Undernutrition Low-T3 syndrome Importance of iodine in brain development • 50,000 brain cells produced/second in developing fetal brain • 100 billion brain cells in adult • One million billion connections between these brain cells: Determine IQ Importance of iodine in brain development 90 % of human brain development occurs between 3rd month of pregnancy & 3rd year of life (Critical period) Goiter has been known since the days of Lord Buddha and before Earliest evidence of goiter: 3000 BC Cretinism, Tip of the Iceberg 1% - 10% Cretinism 5% - 30% Some brain damage 30% - 70% Loss of energy due to hypothyroidism World wide prevalence of goiter Median urinary iodine excretion in 4 national surveys in the I.R.Iran Median urinary iodine (µg/L) 250 200 150 100 50 0 1989 Before 1996 2001 2007 After iodine supplementation Total goiter rate in 4 national surveys in the I.R. Iran Azizi F. Thyroid International 2009;4:1 تاثیر حذف كمبود يد در سالمت جامعه ايراني • پيشگیري از بروز گواتر در بيش از 25ميليون متولدين 23سال اخیر • افزايش 66،000،000ضريب هوش ي در كودكان و نوجوانان • صرفه جويي 17،500،000،000،000ريال ( 12،000،000،000يورو) در هزينه هاي بهداشتي درماني راهنمای تشخیص و درمان بیماریهای تیروئید در بارداری و پس از زایمان انجمن متخصصین غدد درون ریز و متابولیسم ایران انجمن علمی متخصصین زنان و مامایی و نازایی ایران انجمن آسیب شناس ی ایران انجمن علمی دکترای علوم آزمایشگاهی تشخیص طبی ایران 1394 CH Screening • Since 1975 • Highly sensitive immunoassay methods • Direct measurement of serum thyroxine and TSH • Filter paper blood spots • Gurantee detection and treatment from the first weeks of life • Majority of children who were treated early experienced normal growth and neurologic development and normal-range IQ values Algorithm for evaluating abnormal thyroid screening tests Positive screening test Serum T4, TSH High TSH Normal/Low TSH T4 T4 Low Normal Normal or low Scan FT4 Normal Ectopic Gland Low Thyroid U/S TG TBG Normal Prematurity GH/Cortisol Low Normal Low Isolated TSH Deficiency TBG Deficiency Central CH No uptake Normal scan No Thyroid Absent Normal/High TG Deficiency TBII Positive Negative Transient Goitrous CH CH Antithyroid Drugs Agenesis Thyroid Negative TSH Resistance Iodine Trapping Defect Iodine Blockade Normal TBII Positive Transient CH تاريخچه غربالگري CHدرايران اولين اقدام براي غربالگري كمكاري مادرزادي نوزادان در سال 1366توسط دفتر تحقيقات غدد دانشگاه علوم پزشكي شهيد بهشتي انجام گرفت ولي به دليل فراواني ميزان فراخوان (به علت كمبود يد در كشور) اين مطالعه پس از دو سال متوقف شد .با رفع كمبود يد در كشور ،مركز تحقيقات غدد درونريز دانشگاه علوم پزشكي شهيد بهشتي با همكاري سازمان انرژي اتمي ايران و آژانس بيناملللي انرژي اتمي مجددا برنامه غربالگري كمكاري مادرزادي تيروئيد را از سال 1376در بعض ي ازبيمارستانهاي شهرتهران و سپس شبكه دماوند اجرا كرد . نتايج مطالعات مركز تحقيقات غدد دانشگاه شهيد بهشتي و مطالعه شیراز شيوع باالي كمكاري مادرزادي نوزادان در كشور را نشان ميدهد .اين شيوع به ترتيب يك در 914و 1433تولد گزارش شده بود .مطالعه ديگري شيوع بسيار باالي كمكاري مادرزادي تیروئيد برابر يك در 370نوزاد در اصفهان را گزارش نمود. High prevalence of consanguineous and congenital hypothyroidism in Iran Incidence: 1: 1403 live births Dyshormonogenesis: 20%, (1: 5010) Parental consanguinity: % Control: 28.6 Permanent CH Ordookhani A. et al. J Pediatr Endocrinol Metab 2004; 17: 1201 47.1 Odds ratio (95% CI) 2.75 (1.17-6.47) تاريخچه برنامه – طراحي برنامه :سال 1382 – اجراي آزمايش ي (پايلوت) در 3استان :سال 1383 – ادغام درسيستم سالمت كشور :مهرماه 1384 اجزای تشکيل دهنده برنامه غربالگری نوزادان آموزش (پرسنل بهداشتی درمانی و اجرائی ،والدين ،عموم جامعه، سياستگذاران) آزمون غربالگری (اصول نمونه گیری ،نوع آزمون غربالگري ،انتقال نمونه ها، انجام آزمون غربالگری ،گزارش دهی ) پيگيری اوليه (فراخوان موارد مشكوك) تشخيص بيماري مراقبت (درمان ،پيگیري هاي الزم و مشاوره هاي تخصص ي الزم) ارزشيابی برنامه (داخلي و خارجي) هدف اصلی برنامه شناسايی و کنترل متابوليك نوزادان مبتال به بيماری کم کاری تيروييد ،درمان و پيشگيری ازعوارض آن بازده نهايی اجراي برنامه کاهش هزينه های اقتصادی ناش ی ازبيماری کاهش ناتوانيهای حاصل ازبيماری ارتقا کيفيت زندگی بيماران و خانواده آنها ارتقا ميانگين ضريب هوش ی افراد جامعه ازطريق پيشگيری از کاهش ضريب هوش ی مبتاليان شاخص هاي اجرايي برنامه پوشش برنامه درسطح ملي 97.3 :درصد تعداد نوزادان غربالگري شده 8 :ميليون تعداد بيماران شناسايي شده :بيش از 20000بيمار (گذرا و دائمی) نوع گذرای بیماری = 29درصد بروزبيماري1 :در 600نوزاد غربالگري شده شاخص هاي اجرايي برنامه ... زمان انجام نمونه گيری برحسب سن نوزاد 5 -3روز 78% 21-6روز 20% 22و بيشتر 2% زمان شروع درمان برحسب سن نوزاد كمتر از 28روز 28-40روز 41و بيشتر 77% 18% 5% شاخص زمان شروع درمان دربيماران شناسايي شده 95 :درصد درزمان مناسب در 77درصد بيماران شروع درمان درسن قبل از 28روزگي (مطلوب) در 18درصد بيماران شروع درمان درسن قبل از 29تا 40روزگي (قابل قبول) حدود غیرطبیعی آزمایش های تیروئید نوزادان در برنامه کشوری نمونه پاشنه پا در کاغذ فیلتر نمونه وریدی TSH≥ 10 mU/L 7-3روزه ≥ 4.9 mU/L 8روزه – 5ماهگی TSH≥ 10 mU/L 14-7روزه T4<6.5 µg/dl فراخوان به موقع نوزاد خوب 13-11روزه متوسط 20-14روزه Signs and Symptoms of Hypothyroidism At Birth postmaturity macrosomia open posterior fontanel, large head circumference generalized delay in skeletal maturation (but normal or near-normal length) During Early Infancy decreased muscle tone, lethargy, poor feeding hypothermia constipation prolonged jaundice abdominal distension, umbilical hernia dry and mottled skin macroglossia hoarse cry myxedematous appearance Algorithm for the diagnostic evaluation of an infant with suspected congenital hypothyroidism. Congenital Hypothyroidism: Outcome Disease-Related Variables: - Etiology of hypothyroidism - Skeletal maturity - Thyroid hormone levels at diagnosis - Age at onset of therapy - Starting dose - Time to achieve normalization - Subsequent treatment and outcome - Compliance and treatment adequacy Gender Social, genetic and environmental factors Thyroid function, physical development and intelligence quotient in various types of congenital hypothyroidism Type of Defect Variable Athyroidism (n=45) Hypoplasia (n=31) Ectopy (n=3) Serum TSH (mU/L) 148* 68* 40 Serum FT4 (ng/dL) 0.19* 0.39 0.40 Serum Tg (ng/mL) 1.1* 12.3 9.8 Target Ht SDS, corrected -1.21 † 0.28† 0.79 Bone-chronological age (cm) -7.15* 1.00* +3.30 87† 103† 112 At birth: At age 4.8-14.2 y: Intelligence quotient * p<0.01, † p<0.05 Pniewska-Siark et al. Endocr Reg 2006; 40: 7-14 Intelligence and Achievement Test Result by Etiology in Congenital Hypothyroidism 120 Athyrotic Dyshormonogenesis Eitopic 100 80 60 40 20 0 <0.05 <0.01 <0.01 <0.01 Performance IQ Arithmetic Full Reading IQ WISC-III WRAT3 Soon-il Song et al . Dev Behav Pediatr 2001;22:376 Congenital Hypothyroidism: Outcome Disease-Related Variables: - Etiology of hypothyroidism - Skeletal maturity - Thyroid hormone levels at diagnosis - Age at onset of therapy - Starting dose - Time to achieve normalization - Subsequent treatment and outcome - Compliance and treatment adequacy Gender Social, genetic and environmental factors Reference intervals for TSH of age groups Kapelari K, et al. BMC Endocrine Disorders 2008; 8: 15-25 Age-related reference values for fT4 (both sexes) Kapelari K, et al. BMC Endocrine Disorders 2008; 8: 15-25 Percentiles for TSH (mU/L) of children And adolescents Age Lower limit Mean (2.5) Upper limit (97.5) 1-7 days 0.7 3.5 16.9 8-30 days 0.7 3.5 10.2 1-12 months 1.1 2.8 6.9 1-5 years 0.8 2.7 6.3 6-10 years 0.8 2.3 5.4 11-14 years 0.7 2.1 4.6 15-18 years 0.5 1.7 4.3 Kapelari K, et al. BMC Endocrine Disorders 2008; 8: 15-25 Effect of Delay Treatment on Eventual IQ • Klein et al: A 5-6 month delay in treatment with an average IQ approximately 70 • Loss of 5-6 IQ points per month (linear effect) J pediatr 1972 • Bonger-Schoking et al: Delay treatment in early weeks • Most impact • Lower IQ several points per week J pediatr 2000 Congenital Hypothyroidism: Outcome Disease-Related Variables: - Etiology of hypothyroidism - Skeletal maturity - Thyroid hormone levels at diagnosis - Age at onset of therapy - Starting dose - Time to achieve normalization - Subsequent treatment and outcome - Compliance and treatment adequacy Gender Social, genetic and environmental factors Congenital Hypothyroidism: Outcome Disease-Related Variables: - Etiology of hypothyroidism - Skeletal maturity - Thyroid hormone levels at diagnosis - Age at onset of therapy - Starting dose - Time to achieve normalization - Subsequent treatment and outcome - Compliance and treatment adequacy Gender Social, genetic and environmental factors Congenital Hypothyroidism: Outcome Disease-Related Variables: - Etiology of hypothyroidism - Skeletal maturity - Thyroid hormone levels at diagnosis - Age at onset of therapy - Starting dose - Time to achieve normalization - Subsequent treatment and outcome - Compliance and treatment adequacy Gender Social, genetic and environmental factors CH: Treat Children But Don’t Forget Their Parents • Evaluate the IQ development in CH children detected by neonatal screening in an attempt to identify factors that may affect the IQ development • Three educational-affective attitudes in the parents • 1) 38% appropriate coping with emotional distress • 2) 51% reacted with anxiety resulting in overstimulation of the child • 3) 11% completely refused the disease • Psychological counselling of parents Europ J Endocrinol 1999;141: 101-104 Management of Congenital Hypothyroidism Medications L-T4: 10–15 µg/kg by mouth once daily Monitoring Recheck T4, TSH 2–4 wk after initial treatment is begun 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 If TSH increases off therapy, consider permanent CH Rose S & Brown R. Pdiatric 2006; 117: 2290 Facts and Recommendations for neuropsychological follow up in CH IQ scores are in the normal range of 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, if no spontaneous improvement is observed, they should receive specific rehabilitation treatment. No further motor and language evaluation is warranted in CH children with normal tests at age 5 years. 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, if confirmed to have permanent CH, using a standard clinical protocol Leger J, et al. JCEM 2011; 96: 1771. Neonatal Hyperthyroidism Clinical manifestations of neonatal hyperthyroidism Low birth, prematurity Microcephaly, frontal bossing, triangular facies Irritablelity, fever, diarrhea Prominent eyes, diffuse goiter Tachycardia, bonding pulses Cardiomegaly, EHF, arrhythmias Jaundice, hepatosplenomegaly, thrombocytopenia Accelerated skeletal maturation Management of thyrotoxicosis in pregnancy Confirm diagnosis Start propylthiouracil in first trimester; methimazole in the 2nd and 3nd trimester Render patient euthyroid: continue with low-dose ATD up to and during labor and postpartum Monitor thyroid function: Throughout gestation; adjust ATD if necessary to maintain T4 at upper level of normal Check TSHRAb at 26 weeks Discuss treatment with patient effect on patient effect on fetus breast feeding Inform obstetrician and pediatrician Review postpartum-check for exacerbation 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. Lution O et al. J Clin Endocrinol Metab 2005; 90: 6093 Laurberg P et al. Europ J Endocrinol 2009;160: 1-8 Zwaveling- Soonawala N et al. Thyroid 2009; 19: 661-2. TSH receptor antibody in pregnancy • A significant decrease in TRAb during pregnancy • Euthyroid or hypothyroid GD patients may still have high TRAb • High TRAb is more common after radioiodine therapy • Fetal and neonatal thyrotoxicosis occur in 1-5% of mothers with current or past GD. • TRAb is the best predictor (predictive value 42%) • Over 3 times UNL of TRAb at 24-28 weeks close follow-up of the fetus. 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. 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. Papendieck P et al. J Ped Endocrinol Metabol 2009; 22: 547 Treatment of neonatal 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 • 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.