CONGENITAL HYPOTHYROIDISM

ANIS YATIM

CONTENTS• Thyroid physiology• Incidence• Classification• Causes• Diagnosis & screening• Follow up of screening• Treatment & monitoring• Prognosis

DEFINITION• Congenital hypothyroidism is inadequate thyroid hormone production

in newborn infants. It can occur because of an anatomic defect in the gland, an inborn error of thyroid metabolism, or iodine deficiency.

An infant with cretinism. Note the hypotonic posture, coarse facial features, and umbilical hernia.

PHYSIOLOGY AND DEVELOPMENT

Thyroid function develops in three stages: 1ST, 2ND. 3RD Trimester

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• Hypothalamic-pituitary-thyroid axis becomes functional in 2nd trimester

Thyrotropin-releasing hormone (TRH), a tripeptide synthesized in the hypothalamus, stimulates the release of pituitary thyroid-stimulating hormone (TSH).

7• Peripheral metabolism of thyroid hormones matures in 3rd

trimester

Neonatal physiology

• 30 minutes after delivery- an abrupt 3 to 6-fold increase in circulating T3 and T4 level , coincident with increase of serum TSH concentration.

• TSH surge -stimulation of the neonatal thyroid gland, hence increase circulating TH.

• However, the TSH surge is short lived, and TSH hormone will decline after 72-96 hour of life due to feedback inhibition by T4 either the hypothalamic or the pituitary level(or both).

• 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…

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Normal level of thyroid hormones

Age TSH (mIU/L) Free T4 (pmol/L)Birth-D3 OL <21 26-65

D4-D30 0.51-10.8 12-30

D31-1yr 0.39-7 9-16.1

≥ 1 yr 0.4-6 13.2-22.2

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Functions of thyroid hormonesTarget tissue Mechanism

Nervous system Promote normal brain development

Heart • Increase number, affinity of beta adrenergic receptors• Enhance responses to circulating catecholamine

Muscle Increase protein breakdown

Bone Promote normal growth and skeletal development

Gut Associated with carbohydrate absorption

Adipose tissue Stimulate lipolysis

Lipoprotein Stimulate formation of LDL receptors

Other • Stimulate oxygen consumption by metabolically active tissues• Increase metabolic rates• Promote development of reproductive system • Maturation of fetal lungs

INCIDENCE• Incidence of congenital hypothyroidism

worldwide is 1:2500 - 4000 live births

• In Malaysia, it is reported as 1:3666

• It is the commonest preventable cause of mental retardation in children

Screening• Well established in developed countries• Malaysia - Started in october 1998 by Ministry of health• In kelantan – May 1999 (HRPZ2)• Why screening

• Cannot be detected at birth• Most common cause of mental retardation• Late presentation 2-6 months

Malaysian’s strategy• Cord Blood TSH level is measured primarily

supplemented by T4 for determination of borderline TSH level

• Infants with elevated TSH values & with borderline TSH and low T4 are recalled for re-testing

Why Cord Blood TSH?• Much higher coverage for infants• Can be done together with established newborn cord

blood screening for G6PD deficiency.• Cord blood sample is simple, non invasive and offers the

earliest postnatal diagnosis and treatment.

• Missed, insufficient, clotted, BBA casesshould be taken only after the 3rd day of life (4th day)-to avoid the TSH surge that occur from ½ H of life to about 72 H of life.

CAUSES OF CH:THYROID DYSGENESIS (85%)

1. Athyreosis (30%)2. Hypoplasia (10%)3. Ectopic thyroid (60%)

OTHERS(15%)

1. Inborn error of thyroid hormone

2. Hypothalamo-pituitary defect

3. Peripheral resistance to thyroid hormone

4. Transient neonatal hypothyroidism

5. Endemic cretinism

1.Thyroid dysgenesis

• 85% of cases.• aplasia, hypoplasia, and dysplasia; • thyroid dysgenesis -genetic abnormality in one of the

transcription factors necessary for thyroid gland development

• no goitre • 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, • 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

• 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.• If central hypothyroidism is suspected, cortisol and

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

4.Central (hypothalamic–pituitary) hypothyroidism

5. Transient hypothyroidism

• This accounts for 10% of cases and is usually related to either maternal medications, eg carbimazole, or to maternal antibodies.

• Maternal antithyroid drugs can cause decreased neonatal thyroid hormone synthesis which lasts for a few days to two weeks after birth.

• Maternal antithyroid antibodies can cross the placenta and block the TSH receptor in the neonatal thyroid. This effect can last up to 3 to 6 months after birth as maternal antibody levels fall 

Clinical diagnosis • Most infants are asymptomatic at birth. • Most infants with the disease have no obvious clinical

manifestations at birth, therefore neonatal screening of thyroid function should be performed on all newborns.

Subtle clinical features occurred during early weeks of life: • Prolonged neonatal jaundice • Constipation • A quiet baby • Enlarged fontanelle • Respiratory distress with feeding

• Dry skin • Absence of one or both epiphyses on X-ray of left knee (lateral

view).

The infant on the left with CH demonstrate absence of the distal femoral and proximal tibial epiphyses, while in normal infant on the right the distal femoral epiphysis is present.

• If left untreated, overt clinical signs will appear by 3 - 6 months: • coarse facies• dry skin• Macroglossia• hoarse cry• umbilical hernia• Lethargy• slow movement• Hypotonia• delayed developmental milestones.

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• Infant with congenital hypothyroidism. A - 3 month old infant with untreated CH; picture demonstrates hypotonic posture, myxedematous facies, macroglossia, and umbilical hernia. B - Same infant, close up of face, showing myxedematous facies, macroglossia, and skin mottling. C - Same infant, close up showing abdominal distension and umbilical hernia.

TREATMENT• Timing: Should begin immediately after diagnosis is

established. If features of hypothyroidism are present, treatment is started urgently.

• Duration: Treatment is life long except in children suspected of having transient hypothyroidism where re-evaluation is done at 3 years of age.

• Preparation: There are currently no approved liquid preparations.• Only L-thyroxine tablets should be used. The L-thyroxine tablet should be crushed, mixed with breast milk, formula, or water and fed to the infant.

• Tablets should not be mixed with soy formulas or any preparation containingiron (formulas or vitamins), both of which reduce the absorption of T4.

GOALS OF THERAPY• To restore the euthyroid state by maintaining a normal

serum FT4 level at the upper half of the normal age-related reference range. Ideally, serum TSH levels should be between 0.5-2.0 mU/L.

• Serum FT4 level usually normalise within 1-2 weeks, and then TSH usually become normal after 1 month of treatment.

• Some infants continue to have high serum TSH concentration (10 - 20 mU/L) despite normal serum FT4 values due to resetting of the pituitary-thyroid feedback threshold. However, compliance to medication has to be reassessed and emphasised.

FOLLOW UP• Monitor growth parameters and developmental assessment.• The recommended measurements of serum FT4 and TSH by

American Academy of Pediatrics are according to the following schedules: - • At 2 and 4 weeks after initiation of T4 treatment. • Every 1 to 2 months during the first 6 months of life.• Every 3 to 4 months between 6 months and 3 years of age. • Every 6 to 12 months thereafter until growth is completed. • After 4 weeks if medication is adjusted. • At more frequent interval when compliance is questioned or abnormal values are obtained.

• Ongoing counseling of parents is important because of the serious consequences of poor compliance.

Follow up• Mental and cognitive function – IQ test• Symptoms over and under treatment• Hearing test• Bone age – normalisation by 1-2 years

Re-evaluation of patients likely having transient hypothyroidism• This is best done at age 3 years when thyroid dependent

brain growth is completed at this age.• Stop L-thyroxine for 4 weeks then repeat thyroid function

test: FT4, TSH. • Imaging studies: Thyroid scan, Ultrasound of the thyroid. • If the FT4 is low and the TSH value is elevated,

permanent hypothyroidism confirmed and life-long L-thyroxine therapy is needed.

• All newborns of mothers with thyroid diseases should be evaluated for thyroid dysfunction, followed up and treated if necessary.

• Compulsory screening without any miss or error• Repeat test if any doubt• Congenital hypothyroidism – screening, treat to prevent

MR• Patient education and compliance to treatment/follow up

Early treatment-Excellent recovery

Take Home Message

REFERENCES• Paediatrics protocol 3rd edition. • Congenital hypothyroid screening using cord blood TSH

January 1999, journal.• Nelson paediatrics 6th edition.