CONGENITAL HYPOTHYROIDISM

Dr. Ravindra K Sharma

Pediatric Specialist, FUJAIRAH HOSPITAL, UAE

drravindrakr@gmai.com

ReferenceManual of Neonatal Care , Cloherty ; Seventh edition,2012

(AAP 2006)

AAP guidelines 2007

Australian pediatric endocrine group

Guideline for CH in Scotland-NHS 2010

Abu Dhabi Newborn Screening program manual 2009

Layout of presentation

Thyroid physiology

Incidence

Classification

Causes

Diagnosis & screening

Follow up of screening

Treatment & monitoring

Prognosis

Physiology in fetus & Newborn

fetal HPT axis develops independent of the mother due to the high placental concentration of D3(inactivates T4 from mother)

embryogenesis is complete by 10 to 12 weeks’ gestation,

T3 levels remain low, but brain and

pituitary T3 levels are higher because of

type 2 deiodinase (D2) enzyme, which

converts T4 to the active isomer T3

Physiology in fetus & Newborn contd….

TSH from fetal pituitary gland increases from mid-gestation.

negative feedback mechanism of HPT axis starts to mature by 26 weeks

Circulating levels of TRH are high in the fetus relative to the mother

Ability of gland to adapt to exogenous iodine not mature until 36 to 40 weeks’ gestation

Neonatal physiology

30 minutes after delivery-dramatic surge in TSH, with peak at 6 hours of life, followed by a rapid decline over 24 hours,

TSH surge -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

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…

CONGENITAL HYPOTHYROIDISM

most common preventable

causes of mental retardation.

USA-1:2500

Male:Female=1:2

More commom in Trisomy 21, CHD & other congenital anomaly

UAE-350 thyroid gland deficiency between 2005-2012 (1:1914)

Incidence

Classification

Permanent

Transient

Hypothyroxinemia with delayed TSH rise

Causes of permanent CH

Thyroid dysgenesis

Defects in thyroid hormone synthesis and secretion (Thyroid dyshormonogenesis)

TSH resistance

Central (hypothalamic–pituitary) hypothyroidism

1.Thyroid dysgenesis

85% of cases.

aplasia, hypoplasia, and dysplasia;

thyroid dysgenesis -genetic abnormality

no goiter,

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)

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,

and 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

3.TSH resistance

mutations in the TSH receptor gene.

loss-of-function mutation in the G-stimulatory subunit that links TSH binding to action

thyroid gland is small.

T4 is normal or low and TSH is elevated

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.

cortisol and growth hormone measured

(MRI) scan done to visualize the hypothalamus and pituitary gland

4.Central (hypothalamic–pituitary) hypothyroidism

Causes of transient CH

Antithyroid drugs

Iodine excess.

Worldwide, iodine deficiency

Transient hypothyroxinemia of prematurity

TSH receptor-blocking IgG antibodies

Large liver hemangiomas

1.Antithyroid drugs

intrauterine exposure to PTU or MMI

typically resolves within 1 week and does not require treatment

2.Worldwide, iodine deficiency

• most common cause of transient

hypothyroidism, particularly

in preterm

3.Iodine excess.

exposed to excess iodine in the perinatal and/or neonatal period.

Preterm infants –susceptible to thyroid suppressing effects of excess iodine

through breast milk and in mothers who ingest large amounts of seaweed (e.g., in Japan).

Goiter may be present.

T4 is low and TSH is elevated.

RAI or 99mTc uptake is blocked by excess iodine,

Ultrasound -normally positioned thyroid gland

m/c <31 weeks’ gestation.

hypothalamic–pituitary immaturity (< 27 weeks’ gestation), acute illness, and medications (e.g., dopamine, steroids).

TSH is inappropriately “normal.”

total T4 is more affected than free T4

neonatal death, intraventricular hemorrhage, periventricular leukomalacia, cerebral palsy, intellectual impairment, and school failure.

Tx controversial but beneficial to infants <27 weeks’ gestation.

4.Transient hypothyroxinemia of prematurity

5.TSH receptor-blocking IgG antibodies

1% to 2%

known maternal autoimmune thyroid disease.

half-life 2 weeks.

Both stimulating and blocking antibodies present

Hypothyroidism persists for 2 to 3 months

Goiter is not present.

T4 is low, TSH is elevated, and TBG is normal.

High concentrations of TSH receptor-blocking antibodies present in maternal and neonatal serum.

thyroid scintiscanning, uptake absent,

thyroid gland seen on ultrasound

6.Large liver hemangiomas

refractory hypothyroidism due to expression of D3 activity by the hemangioma

present after the newborn period as the hemangiomaenlarges.

Tx- Large doses of L-thyroxine

resolves as the hemangioma regresses

Hypothyroxinemia with delayed TSH elevation (atypical CH)

due to recovery from sick euthyroid syndrome

infants < 1,500 g

critically ill newborns including congenital heart disease.

Delayed TSH elevation may be missed on the initial screen, particularly in primary TSH screening programs.

repeat testing at 2 to 6 weeks of age

Diagnosis & Screening method

Over 95% of newborns with CH are asymptomatic at birth, but universal newborn

screening allows for early diagnosis and treatment

Newborn screening for CH

Some programs measure T4 for the primary screen, followed by TSH when T4 is low,

other programs measure TSH as the primary screen (UAE)

advantages and disadvantages to each approach.

Few measure both T4 and TSH in

the initial screen for all newborns

filter paper spot - 48 to 72 hours of age

discharged <48 hours - sent before discharge

discharged < 24 hours of age -retested at 48 to72 hours

if transferred other hospital, receiving hospital should send

<1,500 g repeat specimens at 2, 6, and 10 weeks of age due to the risk of delayed TSH elevation

Diagnosis & Screening method contd…

If signs of hypothyroidism tests immediately, even if the initial screen was normal.

screening programs can miss cases of CH

TSH screening programs may miss infants with central (pituitary) hypothyroidism.

Acquired hypothyroidism -missed on newborn screening

Diagnosis & Screening method contd….

abnormal screening result- evaluated without delay

Maternal and family history should be reviewed +physical examination

TFT Repeated within 24 hours.

Initial TSH level > 50 mU/L-permanent CH.

TSH is 20 to 40 mU/L, the CH may be transient.

TSH level is not elevated, the TBG level should be measured to exclude TBG deficiency

Follow-up of newborn screening for CH in hospitalized preterm

TG level + US and/or scanningDifferentiate dysplasia from defects, and transient from permanent conditions.

if transient hypothyroxinemia of prematurity is suspected- test not needed

Thyroid scanning -detect dysplastic or ectopic thyroid tissue

Treatment not be delayed to perform thyroid scanning.

If not done within 5 days of diagnosis, -deferred until 3 years at which time thyroid hormone replacement be safely discontinued

USG can be done irrespective of the TSH concentration

Bone age helpful -severity and duration of intrauterine hypothyroidism

Follow-up of newborn screening for CH in hospitalized preterm contd…

For infants with suspected transient or permanent CH,

L-thyroxine -10 to 15 mcg/kg/day,

normalize thyroid hormone,

with total T4 in the 10 to 16 mcg/dL range,

free T4 1.4 to 2.3 ng/dL,

and TSH > 0.5 to 2 mU/L

Normalise T4 within 1 week, TSH -2 weeks,.

Lab after 1 week after starting therapy, 2 weeks after any dose change, and every 1 to 2 months in first year of life

Treatment and monitoring

crushed and fed directly to the infant or mixed in a small amount of juice, water, or breast milk.

Soy-based formulas, ferrous sulfate, and fiber interfere with absorption

2 hours early

No liquid preparations

Preparation of L-Thyroxine

Trials failed to demonstrate benefits of routine L-thyroxine supplementation

Some prefer to treat <27 weeks’ gestation due to presumed hypothalamic–pituitary immaturity,

Infants with TSH concentration borderline high range (10–20 mU/L) or with a serum TSH level that is rising -treated.

starting dose of L-thyroxine is 8 mcg/kg/day,

Preterm suspected of transient hypothyroxinemia of prematurity

brief trial off medication can be attempted at 3 years of age, after thyroid hormone-dependent brain development is complete.

dose required to maintain normal thyroid function does not change with age

Suspected transient CH

Prognosis

neurodevelopmental out-come is excellent

Subtle visuospatial processing, memory, and sensorimotor defects have been reported in severe CH-significance controversial

diagnosed late may have substantial cognitive and behavioral defects

Compulsory screening without any miss or error

Repeat test if any doubt

All with low T4 and high TSH are CH until proved otherwise

Consultation with pediatric endocrinologist

Scanning should not delay Rx

Early treatment-Excellent recovery

Take Home Message

Thank You!