Congenital Hypothyroidism Flashcards
1
Q
Thyroid development
A
- First endocrine gland to develop
- Arises from 2 distinct embryonic lineages:
- Follicular cells: endodermal pharynx
- Produce thyroxine
- Parafollicular C-cells: neural crest
- Produce calcitonin
- Follicular cells: endodermal pharynx
- Gland originates as proliferation of endodermal epithelial cells
- On median surface of pharyngeal floor between 1st and 2nd arches
- Initially hollow - then solidifies and becomes bilobed
2
Q
Thyroid development - descent
A
- Thyroid connected to tongue via thyroglossal duct
- During initial descent
- Completes descent in 7th gestational week
- After migration (10-12 weeks): follicular cells undergo more differentiation
- Characterized by expression of genes essential for TH synthesis
- 10-12 weeks gestation: gland begins to trap iodide & secrete thyroid hormones
3
Q
Thyroid development - late gestation to birth
A
- Hypothalamic-pituitary-thyroid axis functional at midgestation
- TSH detectable in serum at 12 weeks
- Increases from 18th week until term
- HPT feedback control evident by 25 weeks
- Placenta allows passage of small quantities of maternal T4
- Athyrotic neonates: cord blood T4 level is 20% normal
- Fetal brain rich in type II deiodinase
- Converts T4 into active T3
- Within 30 minutes after birth, TSH rises to levels of 60-80 uU/mL
- TSH rise results in increases in T4 and T3 to 15-19 ug/dL by 24 hours
4
Q
Thyroid hormone synthesis
A
- T3 and T4 synthesis: occurs in colloid of thyroid follicule, requires several steps
- Type I and Type II deiodinase:
- Converts T4 to active T3
- Type III deiodinase:
- Converts T4 to inactive T3
5
Q
Congenital hypothyroidism: epidemiology
A
- US prevalence: ~1 in 4000 live births
- Females:males 2:1
- Higher prevalence in Hispanic and less common in Black populations
- Newborn screening routine in most industrialized societies
- Associated congenital heart disease may be as high as 5%
6
Q
Congenital hypothyroidism: etiology
A
- 85% of cases caused by abnormal thyroid gland development (dysgenesis)
- Aplasia
- Hypoplasia
- Ectopy
- 15% of cases due to inborn error of thyroid hormonogenesis
- Inherited AR
- Goiter may be present
*
7
Q
Thyroid dysgenesis: genetic factors
A
- More prominent in girls
- Different incidence in different ethnic groups
- Higher incidence in populations with high blood-related marriages
- 2% of patients have affected relative with dysgenetic gland
- PAX8 gene
- Initiation of thyroid cell differentiation, essential for thyroid cell proliferation
- AD pattern of inheritance
- Varied phenotypes
- TITF2 gene
- Migration of thyroid precursor cells, transcription control of TG and TPO gene promoters
- Homozygous mutations –> Bamforth-Lazarus syndrome
- TITF1 gene
- Development of gland, trancriptional control of TG, TPO, TSH receptor genes
- Heterozygous mutations –> respiratory distress, neurological disorders
- TSHR mutations
- Encodes transmembrane receptor present on surface of follicular cells
- Heterozygous LOF mutations –> partial resistance, normal sized gland, TSH elevation
- Homozygous TSHR mutations –> hypoplastic gland, decreased T4 synthesis
8
Q
Thyroid hormone dysgnesis: genetic factors
A
- NIS gene
- Iodide transport from blood into thyroid cell
- Rate-limiting step in TH synthesis
- Mutations –> hypothyroidism, not always goiter
- SCL26A4 gene
- Encodes pendrin, important for efflux of iodide at apical membrane
- Mutations –> Pendred’s syndrome (AR, associated with sensorineural congenital deafness, goiter)
- Rarely present with CH, most individuals are euthyroid
- Thyroid peroxidase (TPO)
- Responsible for iodide oxidation, organification, iodotyrosine coupling
- Defects –> CH via total iodide organification defect
- Thyroglobulin (TG)
- Key element in TH synthesis and storage
- THOX1, THOX2
- NADPH oxidases involved in H2O2 generation in thyroid
- Essential cofactor for iodination, coupling rxns
9
Q
Central hypothyroidism
A
- Hypothalamic or pituitary deficiency
- Usually occurs in setting of multiple pituitary hormone deficiency
- Evaluate other pituitary hormones, cranial MRI
10
Q
S/S of congenital hypothyroidism
A
- Almost always overlooked - baby appears normal
- Large posterior fontanelle
- Prolonged jaundice
- Macroglossia
- Hoarse cry
- Umbilical hernia
- Hypotonia
11
Q
Newborn screening for congenital hypothyroidism
A
- Best to do at 3-5 days of age
- 2 different screening methods
- Primary T4
- If T4 in lowest 10% of results on a given day, measure TSH
- TSH > 20 uU/mL = abnormal
- TSH < 20 = could be abnormal (central hypothyroidism)
- Primary TSH
- Primary T4
12
Q
Diagnosis of congenital hypothyroidism
A
- If screen abnormal –> draw confirmatory labs
- 75-90% of infants have:
- TSH > 50
- T4 < 6.5
13
Q
Thyroid hormones to measure: binding of thyroid hormones
A
- TBG binds 75% of serum T4
- TBPA binds 20% of T4
- Albumin binds 5% of T4
- Total T4 = bound + free
- Deficiencies/excesses in binding proteins produce changes in total thyroid hormone level
14
Q
Thyroid hormones to measure: free hormones
A
- Free hormone = biologically active component
- Measurement provides most useful assessment of thyroid function
- Most assays correct for moderate variations in binding proteins
- May give inaccurate results in presence of extreme variations of binding protein levels
- Measure FT4 by equilibrium dialysis and/or T3 uptake
- May give inaccurate results in presence of extreme variations of binding protein levels
15
Q
T3 uptake
A
- If T3-uptake and T4 in same direction = thyroid disease
- Low uptake, low T4 = hypothyroid
- If T3-uptake and T4 in opposite directions = TBG abnormality
- High uptake, low T4 = TBG deficient
