Download Evaluation of thyroid disorders in Neonates

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.