Congenital Hypothyroidism

Congenital Hypothyroidism

Dr.Shivani Bansal

Thyroid glandThyroid is an endocrine gland situated at the root of the neck on either side of the trachea.It has 2 lobes,which are connected in the middle by isthmus.

Hormones of thyroid gland-It secretes 3 hormones-Tetraiodothyronine or T4(thyroxine)Tri-iodothyronine or T3Calcitonin

Function - Increase BMR - stimulates growth in children - increase oxygen consumption - stimulate protein synthesis - affect the carbohydrate ,lipid and vitamin metabolism

Thyroid development and physiologyFetal Development-the fetal thyroid bilobed shape is recognised by 7 weeks of gestation.Characterstic thyroid follicle cells and colloid formation is seen by 10 weeksThyroglobulin synthesis occurs from 4 weeksIodine trapping occurs by 8-10 weeksThyroxine (t4) and triiodothyronine (t3) synthesis and secretion occur from 12 weeks of gestation

Hypothalamic neurons synthesise thyrotropin releasing hormone (TRH) by 6 to 8 weeks.Pitutary portal vessel system begins development by 8 to 10 weeks.Thyroid stimulating hormone (TSH) secretion is evident by 12 weeks of gestation.Thyroid Physiology- the main function of thyroid gland is to synthesise t4 and t3.The only known physiologic role of iodine is in the synthesis of these hormonesThe recommended dietary allowance of iodine is 30 ug/kg/24 hour for infants,90-120 ug/24 hour for children,and 150 ug/24 hour for adolescent and adults

Synthesis of thyroid hormones

The metabolic patency of t3 is 3 to 4 times that of t4In adults thyroid produces approx 100 ug of t4 and 20 ug of t3 dailyOnly 20% of circulating t3 is secreted by thyroidThe remainder is produced by de-iodination of t4 in liver,kidney and other peripheral tissues by type I 5 deiodinase.

Thyroid regulation

Hypothyroidism

Results from deficient production of thyroid hormone or a defect in thyroid hormone receptor activitydisese may manifest from birth or acquired

Congenital Hypothyroidism-

Congenital hypothyroidism (CH) is defined as thyroid hormone deficiency present at birthmost cases of congenital hypothyroidism are not herediatory and result from thyroid dysgenesisSome cases may be famalial,usually caused by one of the inborn errors of thyroid hormone synthesis and may be associated with goiter.Incidence1: 4,000 newborns worldwideHispanic, American Indian/Alaska Native people (1:2,000 newborns)Black 1:3,2000 in black Americans

EtiologyCommon form of thyroid dysgenesisAplasiaHypoplasiaEctopic gland (66%)Cause of thyroid dysgenesis is unknown (85% sporadic, 15% hereditary)MutationsInborn errors of T4 synthesis, secretion, or utilization (2/3 heritable cases)Transient HypothyroidismMaternal Autoimmune thyroiditisMaternal medication for Graves diseaseEndemic cretinism from iodine deficiency

Etiologic classificationCentral or (Hypopitutary hypothyroidism)PIT 1 mutations-deficiency of TSH,GH and prolactinPROP 1 mutations-deficiency of TSH, GH, prolactin ,LH ,FSH +_ ACTHTRH defeciencyTRH unresponsivenessTSH defeciencyMultiple pitutary defeciency ex cranio pharyngiomaTSH unresponsivenessPrimary hypothyroidismDefect of fetal thyroid development-aplasia,hypoplasia,ectopiaDefect in hormone synthesis-Iodine transport defect, thyroid peroxidase defect,Thyroglobulin synthesis defectDefect in thyroid hormone transportIodine defecincy-neurological type ,myxedematous typeMaternal antibodies-thyrotropine receptor antibodyMaternal medications-radio iodine ,iodide,amiodarone

Clinical ManifestationsInfants protected for 1st few wks of lifeFraction of maternal thyroid hormone crosses placenta>40 wk GAHead size Slightly higher % due to brain myxedemaLarge fontanels & wide suturesMacroglossiaDistended abdomen with umbilical herniaRough dry skinSkin cold with mottlingSensorineural deafness (10%)Other congenital anomalies (10%)

Sluggish feedingConstipationLethargic Sleep more, needs to be awakened to feed Hoarse cry HypothermiaCardiomegalyMurmurAsymptomatic pericardial effusionMacrocytic anemiaHypotonic with slow reflexesProlonged physiological jaundice

If undiagnosed at a later ageSlow linear growthLoss of IQAtaxiaGross/fine motor incordinationHypotonia & spasticitySpeech disordersAttention deficitStrabismusSensorineural deafness (10%)

Diagnosis:Primary hypothyroidism- low serum T4 & T3 and elevated TSH valuesFree T4 and free T3 are more specificTSH is extremely sensitive index of primary hypothyroidismRadiographic studies- significant delay in skl. Maturation, epiphyseal dysgenesisImaging studies (U/S, radioisotope scan)- anatomical & functional statusThyroid antibody study- autoimmune thyroiditisSec./Tertiary hypothyroidism- TSH levels low or undectable with subnormal levels of T3 & T4 as well as free T4 & T3 and associated deficiency of other pitutiary hormones

Radiological finding

Retardation of osseous developmentAbsence of distal epiphysisEpiphyseal dysgenesisDeformity (beaking) of 12th thoracic or 1st or 2nd lumbar vertebraSkull show large fontanels and wide sutures

Epiphyseal dysgenesis Shortening of long boneLarge fontanel and wide suture

ScreeningStarted in Mid-1970sMeasure T4 & TSH > 48 hrs of lifeT4 false-positive rate 0.30%TSH false-positive 0.05%Preterm infants have higher false-positiveIf + confirm thyroid US or thyroid uptake scanIf maternal autoimmune thyroid disease measure TSH-binding inhibitor IgIf iodine exposure/deficiency measure urinary iodine

Screening

Ideal is universal newborn screening at 3-4 days of age.Universal screening: Most cases are sporadic in Iodine sufficient areas and intellectual impairment can be prevented if treatment is initiated early.In the absence of universal screening, newborns with following indications must be screened:1.Having clinical features of congenital hypothyroidism or family history.2.History of thyroid disease or anti-thyroid medication intake in mother.3.Presence of other conditions like Downs syndrome, trisomy 18, neural tube defects, congenital heart disease, metabolic disorders, familial autoimmune disorders are associated with higher prevalence of congenital hypothyroidism.

Screening Approaches

Newborn screening is done using cord blood or by heel prick sample on dried blood spot filter paper at 2nd and 5th days of life.Three approaches are being used for screening:

1. Primary TSH, back upT42. Primary T4, back up TSH3. Concomitant T4and TSH

Screening Approaches

1. Primary TSH, back upT4: TSH is measured first. T4 is measured only if TSH is > 20 mu/L.2. Primary T4, back up TSH: T4is checked first If it is low (< 6.5 g/dL), then TSH is also checked. This is likely to miss milder/ subclinical cases of CH in which T4is initially normal with elevated TSH.3. Concomitant T4and TSH:It is the most sensitive approach but incurs higher cost.Abnormal values on screening should always be confirmed by a venous sample, using age appropriate cut-offs.

Approach to a newborn with positive screening test for Congenital HypothyroidismPositive screening test on filter paper sampleSerum T4/Free T4, TSHAbnormalThyroid scanEctopicEctopic thyroid glandNormalNormalAbsent uptakeSTART TREATMENT-DONT WAIT FOR SCAN

Age based reference values of thyroid hormones

Treatment

Infants with low T4 and elevated TSH should be started on L-Thyroxine as soon as the diagnosis is made.Initial dose of L-Thyroxine is 10-15 g/Kg/day.Infants with severe hypothyroidism (very low T4, very high TSH and absence of distal femoral and proximal tibial epiphyses on radiograph of knee) should be started with the highest dose of 15g/Kg/day.

Preferred preparation is Sodium Levothyroxine. It has uniform potency, reliable absorption and good bioavailability.Daily dose should be crushed and placed directly on the tongue in the morning.Iron and Calcium preparations interfere with its absorption.If a dose is missed, then double dose should be given on the next day.

Monitoring:

T4 andTSH should be monitored according to following schedule.0 to 6 months Every month6 months to 2 yearsEvery 2- 3 monthsBeyond 2 years Every 6 months6 to 8 weeks after any dose change. It takes less than a week for T4to raise and 4-5 weeks for TSH to normalize.Overtreatment-craniosynotosis & temprament problem

Prognosis:Final outcome in CH is closely related to the :- nature & severity of underlying thyroid abnormality.- age at diagnosis & onset of treatment- adequacy & regularity of treamentWorldwide neonatal screening programs for CH have a significant impact on reducing intellectual deficits in hypothyroid infants diagnosed & treated early Early diagnosis & adequate treatment from 1st week of life leads to normal linear growth & intelligence

In severe affected infant with lowest T4 level have reduce IQ level & neuropsychological sequelae.Without treatment child have mental deficient & growth retarted.Delay in diagnosis & failure to correct initial hypothyroxinemia rapidly, inadequate treatment & poor compliance in first 2-3 yrs of life result in variable degree of brain damage. When onset of hypothyroidism occur after 2yr of age, outlook for normal development is much better even if diagnosis & treatment have been delayed.

Thank you..