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DEMS Unit 4 > Congenital Hypothyroidism > Flashcards

Congenital Hypothyroidism Flashcards

1
Q

First endocrine gland to develop

A

thyroid

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2
Q

from what do the follicular cells arise

A

endodermal pharynx– produce thyroxine

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3
Q

embryonic lineage of parafollicular C cells

A

neural crest cells – produce calcitonin

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4
Q

Embyology of thyroid gland

A

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
  • connected to tongue via thyroglossal duct as it begins initial descent
  • completes descent in 7th gestational week
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5
Q

when does thyroid complete its descent

A

7th gestational week

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6
Q

arrested migration of thyroid

A

when thyroid doesn’t make it all the way down to where it should be– leads to hypothyroidism– typically hypoplastic and won’t work
- can present as congenital hypothyroidism or make some then halt later in life

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7
Q

what happens in thyroid development after migration

A

at about 10-12 weeks, thyroid follicular cells undergo further differentiation – express genes that are essential for thyroid hormone synthesis
- gland begins to trap iodide and secrete thyroid hormones at 10-12 weeks

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8
Q

when does thyroid gland start making thyroid hormones

A

about 10-12 weeks gestation

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9
Q

how is iodide taken up

A

via sodium iodide symporter–oxidized to iodine on apical side of membrane then bound to tyrosyl residues in TG – forms MIT and DIT – coupling occurs and TG stored in colloid. When thyroid secretion needed (gets stimulated by TSH), TG taken up by endocytosis and digested by lysosomes to release T3, T4 into circulation

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10
Q

ratio of secretion of T4:T3 by thyroid

A

10:1

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11
Q

T3 vs rT3

A
  • T3= active; made by thyroid or converted from T4 via Type 1/II Deiodinase that takes off iodine from outer ring
  • rT3= inactive; made by deiodination of inner ring of T4
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12
Q

where do you find the different deiodinases

A

Type 1- liver/kidney
Type 2- brain, sk muscle, pit, adipose
Type 3- placenta and brain

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13
Q

when is TSH first detected

A

12 weeks and increases from 18th week until birth

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14
Q

when is H-P-T axis functional

A

midgestation

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15
Q

HPT feedback control present at ? weeks

A

25 weeks

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16
Q

in what nuclei of hypothalamus is TRH produced

A

supraoptic and supraventricular

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17
Q

Does T3 or T4 feed back to hypothalamic and pituitary to control secretion

A

both can but mostly T3

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18
Q

will fetuses with agenesis of thyroid have T4

A

yes; some maternal passes through placenta, so have T4 level of about 20% nl levels, and brain with type II deiodinase converts T4 to active T3

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19
Q

what protects hypothyroid babies from significant neuro sequellae

A

placental passage of maternal T4 and fetal brain rich in type II deiodinase

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20
Q

what happen to thyroid hormones immediately after birth

A

TSH rises to 60-80 microunits/ml within 30 min of birth; this causes increased T3 and T4 to 1519 micrograms/dl by 24 hours
- comes down after several days

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21
Q

congenital hypothyroidism

A

absent or decreased action of thyroid hormone

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22
Q

Prevalence of congenital hypothyroidism

A

1 in 4000; more common in Hispanic, less common in black

- Females:males = 2:1

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23
Q

how is congenital hypothyroidism detected

A

newborn screening in most industrialized countries– important since few to no sxs at birth and can cause permanent developmental delays when delaying treatment

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24
Q

other conditions associated with congenital hypothroidism

A

congenital heart disease (may be as high as 5%)–usually ASD or PDA

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25
Q

Causes of dysgeneisis of thyroid

A

aplasia (no thyroid tissue), hypoplasia (poorly developed/small), ectopy (arrested migration)

26
Q

2 main causes of congenital hypothyroidism

A

85% due to abnormal thyroid development (dysgenesis)

  • also can be problem with enzymes for thyroid hormone synthesis
27
Q

PAX8

A
  • transcription factor
  • important in initiation of thyroid cell differentiation, maintenance of differentiated state, and essential for thyroid cell proliferation
  • AD inheritance
  • variable phenotypes–severe hypoplasia associated with compensaged or overt hypothyroidism, ectopy, normal glands at birth
  • few cases associated w/renal agenesis (also in nephrogenic mesenchyme)
28
Q

TITF2

A

transcription factor important in migration of thyroid precursor cells and transcriptional control of TG and TPO gene promoters in thyroid development
- homozygous mutations result in Bamforth-Lazarus syndrome (CH, cleft palate, spiky hair, and variably bifid epiglottis and choanal atreasia)

29
Q

TITF1

A
  • homeobox domain transcription factor
  • important in development of gland and trasncriptional control of TG, TPO, and TSH receptor genes
  • also expressed in lung, forebrain, and pituitary gland
  • humans with heterozygous mutations associated with various combinations of CH, respiratory distress and neurological disorders
30
Q

Bamforth-Lazarus

A
  • associated with mutation in TITF2 transcription factor

- have congenital hypothyroidism (CH), cleft palate, spiky hair, and variably bifid epiglottis and choanal atresia

31
Q

TSH receptor mutations

A
  • TSH receptor gene encodes transmembrane receptor on surface of follicular cells; mediate effects of TSH and is critical for development/function of thyroid gland
  • can be heterozygous or homozygous
  • Heterozygous loss of funciton mutations- partial resistance with nl size gland and TSH elevation
  • Homozygous TSHR mutations usually cause CH with hypoplastic gland and decreased T4 synthesis
32
Q

thyroid dyshormonogenesis

A

causes 15% of congenital hypothyroidism

  • generally autosomal recessive
  • goiter may be present
  • mutations in several genes coding proteins important in thyroid hormone synthesis
33
Q

NIS

A
  • sodium/iodide symporter - important for iodide transport from blood into thyroid cell (basal membrane)
  • mutations cause hypothyroidism of variable severity; goiter not always present (ppl with more iodide intake less likely to have severe hypothyroidism compared to those with iodide deficient diets)
34
Q

rate-limiting step in thyroid hormone synthesis

A

iodide transport into cell via Na/I symporter

35
Q

SCL26A4

A

encodes pendrin- important for efflux of iodide at apical membrane of thyroid follicular cells

  • mutations = Pendred’s syndrome (associated with sensorineural congenital deafness adn goiter)
  • rarely present with CH; majority of individuals are euthyroid, at least under conditions of nl thyroid intake
36
Q

TPO

A
  • mutations here one of most common
37
Q

TG

A

glycoprotein which is a key element

38
Q

THOX1 and THOX2

A

?

39
Q

Central hypothyroidism

A

hypothalamic or pituitary deficiency (TRH or TSH)

  • usually occurs in setting of multiple pituitary hormone deficiency (i.e. septo-optic dysplasia–affects pituitary, optic nerves, brain develops; developmental delays and blindness)
  • need to eval other pit hormones and obtain cranial MRI
40
Q

Signs/sxs of congenital hypothyroidism

A
  • not many so important to have newborn screen!!
  • large posterior fontanel
  • prolonged jaundice
  • macroglossia
  • hoarse cry
  • umbilical hernia
  • myotonia
41
Q

Newborn screening

A

do at 3-5 days of age (not first day when elevated TSH–usually do last thing before babies go home)
- 2 ways to do screening—

1) Primary T4– if T4 in lowest 10% of results on a given day, TSH will be measured. Abnormal if TSH >20 and will call PCP.
If TSH

42
Q

labs on primary congenital hypothyroidism

A

no/little T4/T3 – lack of inhibition – elevated TSH

43
Q

why is thyroid hormone measurement complicated

A
  • complicated due to binding to protein in blood
  • deficiencies and excess of thyroid binding proteins changes values of total thyroid hormones (deficient in TBG– will have low total T4)
44
Q

how much of T4 bound to TBG

A

75%

45
Q

how much of T4 bound to TBPA

A

20%

46
Q

how much T4 bound to albumin

A

4%

47
Q

if you suspect issues with binding proteins what do you do

A

check free T4 and T3 uptake

48
Q

T3 Uptake test

A

take pt sample and - used to look at binding proteins
-add radiolabeled T3 tracer that will bind to available binding sites in pts serum – add resin that will take up whatever T3 not bound to sites is taken up by resin. Result given by percent of initial radiolabeled T3
- nl is 25-35% taken up by resin
-

49
Q

T3 uptake test in hypothyroid

A
50
Q

T3 uptake test in hyperthyroid

A

> 35%

  • have more sites bound already in pts serum, so less binds and more available to be taken up by resin
51
Q

If T3 uptake and T4 in same direction

A

thyroid disease

i.e. low uptake and low T4 –hypothyroid

52
Q

If T3 uptake and T4 in opposite directions

A

TBG abnormality

(i. e. high uptake and low T4 – TBG deficient)
- low TBG means less sites available for T3 to bind, so more will be taken up by resin

53
Q

T3 uptake result in pregnancy

A

more TBG, so more binding sites for radioactive tracer to bind, meaning less can be bound by resin

54
Q

why nl TSH but high total T4 common in adolescent girls

A

Estrogen and OCP–

55
Q

what would you do if newborn screening showed low T4 and high TSH?

A
  • confirmatory labs; if the same –primary hypothyroidism– start baby on thyroid
56
Q

what would you do if low T4 and low TSH?

A
  • confirmatory labs with uptake and free T4
57
Q

if low T4/TSH and nl FT4 with higher T3 uptake

A

TBG deficiency

58
Q

what should neonatal T4 be on screening?

A

8-9

59
Q

low T4, low TSH with low FT4 and lower T3 uptake

A

central hypothyroidism

60
Q

Treatment for hypothyroidism

A

levothyroxine as early as possible

  • have to crush up–suspension not reliable
  • monitor levels every 3 months first 3 years in addition to 4 weeks after dose change
61
Q

Pendred’s syndrome

A

due to mutation in SCL26A4 –

  • Autosomal recessive disorder associated with sensorineural congenital deafness and goiter
    • rarely present with CH; majority are euthyroid, at least when adequate iodide intake

DEMS Unit 4 (16 decks)

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