Congenital Hypothyroidism Flashcards Preview

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Flashcards in Congenital Hypothyroidism Deck (31):
1

Thyroid Development

a. First endocrine gland to develop

b. Arises from 2 distinct embryonic lineages:
1) follicular cells (endodermal pharynx) - produce
thyroxine
2) parafollicular C-cells (neural crest) – produce
calcitonin

c. Gland originates as proliferation of
endodermal epithelial cells on median surface
of pharyngeal floor between 1st and 2nd arches

d. Initially hollow, then solidifies and becomes
bilobed

e. Thyroid connected to tongue via thyroglossal
duct as it begins initial descent
i. Completes its descent in 7th gestational week

2

Thyroid Development- Thyroid Gland Develops

a. Arises from 2 distinct embryonic lineages:

b. follicular cells (endodermal pharynx) - produce
thyroxine

c. parafollicular C-cells (neural crest) – produce
calcitonin

3

Thyroid Development

a. Gland originates as proliferation of
endodermal epithelial cells on median surface
of pharyngeal floor between 1st and 2nd arches

b. Initially hollow, then solidifies and becomes
bilobed

c. Thyroid connected to tongue via thyroglossal
duct as it begins initial descent
i. Completes its descent in 7th gestational week

4

Arrested Migration of
Thyroid

a. Thyroid gland should move down duct from behind the tongue

b. Can arrest at many different points of the thyroglossal duct

c. Will still produce thyroid hormone, but cannot form enough follicular cells, will not have thyroid hormone
i. due to thyroid gland not moving down enough

5

Thyroid Development

a. Following migration (10-12 weeks), thyroid follicular cells undergo further differentiation characterized by the expression of genes that are essential for thyroid hormone synthesis

b. Thyroid gland begins to trap iodide and secrete thyroid hormones at 10-12 weeks

6

Maternal iodine crosses placenta

a. Iodine from mother will cross into the placenta (for the baby)

b. Iodine will cross basolateral side of follicular cell

c. Fetus will still have organification of Iodide and have it attach to thyroglobulin's Tyrosine residues

d. T3 will have 3 Iodide residues, while T4 will have 4 Iodide residues

e. Thyroid Gland makes predominantly T4 hormone
i. Rest of cells in body will turn T4 into T3

7

T4, T3, and rT3

a. Active--> both of these Deiodinase will turn T4---->T3 (active form)
Type 1 Deiodinase
Type II Deiodinase

b. Inactive
Type III Deiodinase
i. Create rT3 (reverse T3)
ii. is being inactivated

8

Thyroid Development

a. Maturation of thyroid function in the fetus reflects changes at the level of the thyroid as well as hypothalamus and pituitary

b. TSH detectable in serum at 12 weeks gestation

c. Hypothalamic-pituitary-thyroid axis functional at midgestation and feedback control evident by 25 weeks

9

Thyroid Development

a. Both TSH and T4 gradually increase to term

b. Within 30 minutes after birth, TSH rises to levels of 60-80 uU/ml
i. TSH rise results in increases in T4 and T3
levels by 24 hours
ii. TSH will drop drastically 40 hours after birth, due to T3 and T4 getting TSH to lower by negative feedback

10

What if the fetus doesn’t make
thyroid hormone?

a. Placenta allows passage of small quantities of maternal T4 (in athyrotic neonates, cord blood T4 level is about 25-30% normal)
i. some of maternal T4 enters the placenta--> critical for fxn
ii. not good if mother is Hypothyroidism

b. Fetal brain rich in type II deiodinase which converts T4 into active hormone T3
i. uses the T4 that passes into placenta

c. Both of these play critical roles in minimizing
adverse effects of fetal hypothyroidism

11

Congenital Hypothyroidism

a. Lack of thyroid hormones present from birth - if not detected and treated early, it is associated with irreversible neurological problems and poor growth

b. Prevalence in US historically ~1:4000 live births but over last 2 decades decreased to 1:2000

c. Prevalence higher in Hispanic and Asian Americans and less common in black Americans

d. As many as 5-10% may have other congenital
anomalies (cardiac, nervous system, eye)
i. nervous and cardiac deffects can be irreversible

e. Newborn screening allows for early detection and treatment

12

Causes of Congenital
Hypothyroidism

*know these for test

1. Defect in thyroid gland development – thyroid
dysgenesis
i. mutations in genes for thyroid descent
ii. mutations in transcription factors for thyroid devlopment

2. Defects in thyroid hormone synthesis – thyroid
dyshormonogenesis
i. unable to synthesize thyroid hormone

3. TSH resistance

4. Transient forms

5. Central (Hypothalamic/ Pituitary deficiencies)

13

Thyroid Dysgenesis

a. Accounts for 85% of congenital hypothyroidism

b. Aplasia , hypoplasia, or ectopy

c. Female to male predominance 2:1

d. Cause unknown in most cases but evidence
supports some underlying genetic component

e. ~2% are caused by a mutation in one of the
transcription factors important for thyroid
development

14

Thyroid dysgenesis

1. Transcription factor defect PAX8 (paired box gene 8)
i. Autosomal dominant pattern of inheritance
ii. Phenotypes vary from mild to severe hypoplasia
iii. Can have compensated or overt hypothyroidism
iv. Few cases assoc w/ renal agenesis

2. Transcription factor defect TITF1(thyroid transcription factor 1)
i. Also expressed in the lung, forebrain, and pituitary
gland
ii. Humans with heterozygous mutations associated
with various combinations of CH, respiratory distress and neurological disorders

3. Transcription factor defect TITF2
i. Homozygous mutations result in Bamforth-Lazarus
syndrome: CH, cleft palate, spiky hair, and variably bifid epiglottis and choanal atresia

15

Patients with TITF-2 mutations

(Picture of patient on slide)

a. Patients with TITF-2 mutations, showing
spiky hair, micrognathia, and hypertelorism (A), and cleft palate

b. Transcription factor defect TITF2
i. Homozygous mutations result in Bamforth-Lazarus
syndrome: CH, cleft palate, spiky hair, and variably bifid epiglottis and choanal atresia

16

Thyroid Dyshormonogenesis

a. Accounts for 10-15% of congenital hypothyroidism

b. Generally inherited in autosomal recessive pattern

c. Goiter may be present

d. Mutations in several genes coding for proteins
important in thyroid hormone synthesis have been found

17

Mutations in Iodine

(Thyroid Dyshormonogenesis)

a. Abnormal iodide uptake via NaI transporter (NIS)

b. Defective iodide transport from follicular cell into colloid (SLC26A4 – pendrin transport protein)

c. Thyroid organification, or
coupling defect (TPO)

d. Defects in H2O2 generation (DUOX2, DUOXA2)

e. Thyroglobulin synthesis defect (Tg gene)

f. Deiodination defect (DEHAL1)

18

Pendred Syndrome

a. Caused by mutation in gene SLC26A4 which
encodes pendrin, a protein that mediates iodide
efflux from follicular cell to colloid

b. Autosomal recessive disorder associated with
goiter and sensorineural congenital deafness
i. - dilated semicircular canals on CT (Mondini’s
cochlea)

c. Thyroid phenotype mild, appears to depend on
nutritional iodine intake, and seldom presents
in newborn period

19

TSH Resistance

a. Mutation in TSH receptor
1) TSHR encodes a transmembrane receptor present on the surface of follicular cells which mediates the effects of TSH and is critical for the development and function of the thyroid gland
2) Heterozygous loss-of-function mutations – partial
resistance with normal size gland and TSH elevation
3) Homozygous TSHR mutations usually cause CH with hypoplastic gland and decreased T4 synthesis

b. Defective TSH signaling

20

Transient Forms of Hypothyroidism

a. Maternal TSH receptor-blocking antibodies
(TRBAb)

b. Maternal iodine deficiency or excess

c. Maternal radiodine administration

d. Maternal medicaions
i. Amiodorone
ii. Propylthiouracil, Methimazole

21

Central Hypothyroidism

a. Hypothalamic or pituitary deficiency
i. secondary deficiency

b. Usually occurs in setting of multiple pituitary
hormone deficiency
i. 97% of time have growth hormone deficiency as well
ii. may have cortiosl deficiency as well (not as often)

c. Need to evaluate other pituitary hormones and
obtain cranial MRI

22

Signs/Symptoms of Congenital
Hypothyroidism

1. Baby usually appears entirely normal as sign/symptoms may not develop for a few weeks

2. Large posterior fontanel

3. Prolonged jaundice

4. Macroglossia

5. Umbilical hernia

6. Hypotonia

7. Feeding difficulties

8. Hoarse cry

23

Newborn Screening

a. Best to do after 2-3 days of age

b. Two different screening methods:
1.Primary T4 – if T4 is in the lowest 10% of results
on a given day, TSH will also be measured
i. If TSH >20, Health department will consider abnormal and call PCP
ii. If TSH <20, Health department will not call PCP but still could be abnormal (ie central hypothyroidism)

2. Primary TSH screen

24

Diagnosis

a. If abnormal screen, draw confirmatory labs

b. In infants with proven CH, 90% have TSH greater
than 50 and 75% have T4 less than 6.5

25

Thyroid Hormones – What to
Measure?

a. The measurement of thyroid hormones is
complicated by the high degree of protein binding
of T4 and T3
i. TBG - thyroid-binding globulin binds 75% of serum T4
ii. TBPA - thyroxine-binding prealbumin binds 20% of T4
iii. Albumin – binds 5% of T4

b. Deficiencies and excesses of thyroid binding proteins produce changes in values of total thyroid hormones (total T4 = bound + free)

26

Thyroid Hormones – What to
measure?

a. Free hormone is the biologically active component so its measurement theoretically provides the most useful assessment of thyroid function

b. Most of the free hormone assays correct for moderate variations in thyroid-binding proteins but may give inaccurate results in the presence of extreme variations in the concentrations of these
proteins ( in this setting measure FT4 by equilibrium dialysis and/or T3-uptake)

27

T3-Uptake

Why is this test important?
T3 uptake is an indirect measure of the quantity of thyroxine binding proteins (thyroid binding prealbumin, albumin, and TBG) in plasma.

It is directly proportional to the degree of saturation of the binding proteins by thyroxine.
i. T3U is decreased during pregnancy, with supra-normal doses of estrogen, early in acute hepatitis, and with genetic TBG excess.
ii. It is increased by anabolic hormones and glucocorticoids, the nephrotic syndrome, and genetic TBG deficiency. T3U is not useful alone but should be combined with T4 to calculate the FTI

28

T3-Uptake Diagnosis

*important slide

a. If T3-Uptake and T4 are in same direction – thyroid disease
i. Low T3 uptake and Low T4 – Hypothyroid

b. If T3-Uptake and T4 are in opposites directions
– TBG abnormality
i. High T3 uptake and Low T4 – TBG deficient

29

Treatment

a. Start treatment with levothyroxine as early as
possible!!

b. Initial dose is 10 - 15 ug/ kg/day (usually comes
out to 37.5 or 50 ug)

c. Have parents crush tablet (do not have pharmacy make suspension)

d. Levels monitored every 3 months in the first 3 years of life in addition to 4 weeks after dose change

30

Outcome

a. Before screening programs, IQ of CH children
was 76 with 40% requiring special education

b. Now with early (<3 weeks) and high-dose treatment, developmental outcomes are
excellent

31

T3 uptake review

a. Used when someone has a normal TSH, but a low T4
i. Differential diagnosis is either central hypothyroidism or a TBG deficiency

b. If T3-Uptake and T4 are in same direction – thyroid disease
i. Low T3 uptake and Low T4 – Hypothyroid

c. If T3-Uptake and T4 are in opposites directions
– TBG abnormality
i. High T3 uptake and Low T4 – TBG deficient