maryam

مادرزادی هیپوتیروییدی درمان و بالینی عالیم

دهنده :ارایه

زاده ولی مجید دکتر

References:

• Up to date 2009 (17.3)• .

Thyroid Embryology Derived from

endodermal tissue at base of tongue

Embryonal remnants form Thyroglossal duct; pyramidal lobe; lingual thyroid

Fuse with C-cells (neural crest origin), derived from the the 5th branchial arch

C-cells scattered through posterior/superior lobes

Major causes of congenital hypothyroidism, approximate frequency

• Thyroid dysgenesis - ectopia, aplasia, or hypoplasia (1:4500)

• Inborn errors of thyroxine synthesis (dyshormonogeneses) (1:30,000)

• Maternal antibody-mediated hypothyroidism (1:25,000-1:100,000)

• Central hypothyroidism (1:25,000-1:100,000)

• Transient hypothyroidism (1:100 Europe)

Lingual thyroid

CLINICAL MANIFESTATIONS • More than 95

percent asymptomatic– umbilical cord

serum T4 concentrations are about 25 to 50 %

– inadequate, functioning thyroid tissue

Figure 15-7. Brain neurologic development relative to thyroid function in the rat and human. TH, thyroid hormones; dpc, days postconception; dpn, days postnatal. (From Porterfield and Hendrich, with permission.)

Clinical manifestations:

• Birth length and weight • head circumference • other congenital anomalies ↑

CLINICAL MANIFESTATIONS• Lethargy• slow movement• hoarse cry • feeding problems• constipation• macroglossia• umbilical hernia

• large fontanels • hypotonia• dry skin• hypothermia• prolonged jaundice• A few with thyroid

dyshormonogenesis : a palpable goiter

Figure 15-12. Ten year old female with severe 1° hypothyroidism due to primary myxedema before (A) and after (B) treatment. Presenting complaint was poor growth. Note the dull facies, relative obesity and immature body proportions prior to treatment. At age 10 years she had not lost a single deciduous tooth. After treatment was initiated (indicated by the arrow in Panel C), she lost 6 teeth in 10 months and had striking catch up growth. Bone age was 5 years at a chronologic age of 10 years. TSH receptor blocking antibodies were negative. 

Treatment:

Figure 15-4. Postnatal TSH, T4, T3, and rT3 secretion in the full-term and premature infant in the first week of life (modified from Fisher DA: Disorders of the thyroid in the newborn and infant. In: Sperling M (ed) Pediatric Endocrinology, WB Saunders Co., Philadelphia, 51, 1996).

Low T4 and Elevated TSH Values• Low T4 + TSH > 40 :is considered to have

primary hypothyroidism (Iran: TSH> 5 )• examination (immediately ) + confirmatory

serum testing to verify the diagnosis.• screening TSH concentration is only slightly

elevated but < 40 mU/L, another filter-paper specimen should be obtained for a second newborn screening.

Low T4 + high TSH

• 10% Hypothyroids ( TSH : 20-40)• It is important that age appropriate

normative values be used.• Range for TSH for the most common

time of TSH re-evaluation (between 2 and 6 weeks of age) is 1.7 to 9.1 mU/L.

Normal T4 and Elevated TSH Values ( Hyperthyrotropinemia)• Etiology :1) transient or permanent thyroid

abnormality 2) delayed maturation of the hypothalamic-

pituitary axis.3) Inactivation mutations in the TSH-R

cause compensated, mild (subclinical) primary hypothyroidism in the neonatal period.

There is controversy regarding the need for TH therapy in this setting.

High TSH + normal T4

• Most physicians would consider a persistent basal TSH concentration higher than 10 mU/L (after the first 2 weeks of age) to be abnormal.

• If such infants are not treated, measurement of FT4 and TSH should be repeated in 2 and 4 weeks, and treatment should be initiated promptly if the FT4 and TSH concentrations have not normalized.

High normal TSH

• The management of infants with TSH elevations between 6 and 10 mU/L that persist after the first month of life is even more controversial.

• A TSH range of 1.7 to 9.1 mU/L has been reported for children 2 to 20 weeks of age

• if a decision is made to treat such children , a trial off therapy at 3 years of age should be performed.

Low T4 and Normal TSH Values• 2 SDs below the mean for the reference range for

age , usually < 10 µg/dL in the newborn infant1) Hypothalamic immaturity2) during illness3) protein-binding disturbances such as TBG

deficiency(1 in 5000)4) central hypothyroidism (l in 25 000 to l in 50 000

newborn infants)5) primary hypothyroidism and delayed TSH

elevation (l in 100 000 newborn infants).• Transient hypothyroxinemia is seen to some extent

in many preterm infants

Figure 15-4. Postnatal TSH, T4, T3, and rT3 secretion in the full-term and premature infant in the first week of life (modified from Fisher DA: Disorders of the thyroid in the newborn and infant. In: Sperling M (ed) Pediatric Endocrinology, WB Saunders Co., Philadelphia, 51, 1996).

Hypothyroxinemia

• Take no further action, to follow-up with serial filter-paper screening tests until the T4 value becomes normal, or to request second blood sample for measurement of FT4 and TSH concentration.

• Most infants with low T4 and normal TSH have normal FT4 values, and subsequent thyroid function test results are normal

Transient TSH Elevation

• Intrauterine exposure to maternal anti thyroid drugs, maternal TRBAbs

• Heterozygous thyroid oxidase 2 deficiency• Germ-line mutations in the TSH-R, endemic• Iodine deficiency• Prenatal or postnatal exposure to excess

iodides ( povidone iodine, iodinated contrast materials)

CLINICAL MANAGEMENT OF NEWBORN INFANTS WITH LOW T4 AND ELEVATED TSH VALUES

• Infants with low T4 and elevated TSH concentrations have CH until proven otherwise.

1) Consultation with a endocrinologist is recommended to facilitate diagnostic evaluation and optimal management.

Clinical management...

2) A complete history, including prenatal thyroid status (maternal drugs and medications) and family history should be obtained, and physical examination should be performed.

3) Serum should be obtained for confirmatory measurements of TSH and FT4.

Clinical management...

4) Education of parents by trained personnel using booklets or visual aids is highly desirable.

5) Optional diagnostic studies include - -thyroid ultrasonography

-iodine 123 (123I)- sodium technetium 99m pertechnetate (99mTc) thyroid uptake -and/or scan to identify functional thyroid tissue.

Treatment

• Treatment Should Begin As Soon As Possible, Preferably Within The First Two Weeks of Life

Treatment

The Goal Of Treatment To Ensure Normal Growth

&DevelopmentT4 10 To 16 µg/dlTSH Around 1 mIu/L

Treatment :

• The goal of therapy is to normalize T4 within 2 weeks and TSH within 1 month.

• An initial dosage of 10 to 15 g/kg of L-T4 (depending on the severity of the initial hypothyroidism)

• Administration of L-T4 is the treatment of choice.

Treatment :

• The pill should be crushed and suspended in a few milliliters of formula, breast milk, or water.

• Only T4 tablets should be used• T4 is expected to increase to more than

10 µg/dL• FT4 is expected to increase to more than 2

ng/dL by 2weeks after initiating therapy• TSH should normalize by 1 month.

Treatment :

• The L-T4 dose should be adjusted according to the infant’s clinical response and serum FT4 and TSH concentrations.

• During therapy, the serum total T4 or FT4 should and might be in the upper half of the reference range (target values depend on the assay method used [T4: 10–16 g/dL (130–206 nmol/L); FT4: 1.4 –2.3 ng/dL (18–30 pmol/L)]) during the first 3 years of life with a low normal serum TSH.

• The latter may sometimes be delayed because of relative pituitary resistance.

• Between 1 and 5 days of life, the normal range for serum total T4 concentrations is about 10 to 22 µg/dL

• Between 1 and 4 weeks of life, the normal range for serum total T4 concentrations is 7 to 16 µg/dL

Delay in normalization of TSH:• Normal or increased serum (→ or↑ )

T4 and an inappropriately high TSH concentration, the T4 value is used to titrate the dose.

• Nonadherence to the treatment is the most common cause of persistent TSH elevation and should be excluded.

Target of treatment:

• TSH levels should be maintained between 0.5 and 2.0 mU/L during the first 3 years of life

• During TH therapy, 4 or more episodes of insufficiently suppressed TSH (5 mU/L) after the age of 6 months were the most important variables associated with school delay

DIAGNOSTIC STUDIES

• venipuncture to confirm• If the diagnosis of hypothyroidism is

confirmed– thyroid radionuclide uptake and imaging– Ultrasonography– serum thyroglobulin assay– thyroid autoantibodies– urinary iodine excretionThese tests usually do not alter

treatment

Recommended follow-up

• At 2 and 4 weeks after the initiation of T4 treatment

• Every 1 to 2 months during the first year of life

• Every 2 to 3 months between 1 and 3 years of age

• Every 3 to 12 months thereafter until growth is complete

Two weeks after any change in dosage

Other neurologic sequelae • gross and fine motor incoordination

– ataxia,– increased or decreased muscle tone– short attention span– speech defects– strabismus

• Studies before the initiation of newborn screening reported that up to 20 percent of children had sensorineural hearing loss

Figure 15-11. (Left panel) Infant with severe, untreated congenital hypothyroidism diagnosed prior to the advent of newborn screening. (Right panel) Infant with congenital hypothyroidism identified through newborn screening. Note the striking difference in the severity of the clinical features.

PROGNOSIS

• If treated at appropriate time In general, these infants grow and develop normally

Untreated CH Patients at Risk for Severe Mental Retardation

Klein et al, J Pediatr 81:912-915, 1972

IQ of CH patients is normal if treatment early and adequate

NECHC. Lancet 2:1095-1098, 1981

But small differences in T4 dose have enormous impact on IQ

90

95

100

105

110

115

120

125

MDI

10 ug7 ug

MDI- Mental Development Index

T4 dose

Bongers-Shokking JJ et al, J Pediatr 136:292-297,2000

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Thyroid hormones effects

• Growth & development ( skeletal & nervous system)

• General metabolism (↑ oxidation)• Protein metabolism• Lipid metabolism• Carbohydrate metabolism

Thyroid Hormones

Hypothalamus TRH (Thyrotropin releasing

hormone)

Pituitary TSH (Thyroid stimulating

hormone)

Thyroid

T4 thyroxine T3 thyronineiodine

Permissive role: Allow for normal cell function &

growthInduce N retention for protein

synthesisStimulate growth H releaseIncreases metabolic rate

Roles

• Metabolic Rate• BMR• ↑ heat production

• Newborns• Stress

• Weight regulation• SNS Activity

• ↑ -receptors• ↑ Heart rate• Brain activity, muscle activity

• Brain development and body growth• Stimulates GH release

Congenital hypothyroidism

• approximately 1:4000 newborns• the most common treatable cause of

mental retardation• inverse relationship between age at

diagnosis and intelligence quotient (IQ) later in life