Anatomical
considerations:
- Origination:
- embryologically
from pharyngeal epithelial
evagination with additional
contributions from lateral
pharyngeal pouches
- Some properties of the fetal
thyroid:
- concentration and
organification of iodine begins
at 10 weeks gestation.
- T4
and TSH (thyrotropin) are
detectable (blood)
shortly thereafter.
- Increasing
serum T4
due to:
- increased
secretion
- appearance
of thyroxine-binding
globulin (TBG)
- increasing
TSH concentration
(following maturation of
fetal hypothalamus which
results in enhanced TRH
(thyrotropic-releasing
hormone) secretion.
- Adult thyroid: (anatomical
aspects)
- Two lobes-- joined
by an isthmus
- Found just anterior
and caudal to the larynx
cartilages
- Glands divided into
pseudolobules by fibrous septa
- Pseudolobules:
composed of follicles or acini
(surrounded by capillaries)
- Follicles: composed
of cuboidal epithelium
- Luminal
component --
proteinaceous colloid
containing:
- thyroglobulin
(peptide sequence -- T4 and T3
)
- Thyroid also
contains C cells:
- source of
calcitonin
- malignant
transformation of the
cells result in medullary
thyroid carcinoma
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- Iodide:
- Metabolism:
- Iodide intake:
gastrointestinal tract
absorption from food,
water, or medication.
- Iodide:
- rapid
absorption
- enters
extracellular pool
- thyroid
removes amount required
for hormone secretion
- excess
iodide: urinary excretion
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- Thyroid hormone synthesis: Steps
--
- Iodide transport into
the gland: iodide trapping
- may be
inhibited by thiocyanate, perchlorate, etc.
- iodide
removed from plasma by:
- thyroid
- kidneys
- salivary
and gastrointestinal
glands (GI iodide
reabsorbed)
- Thyroid and
kidney compete for plasma
iodide:
- Renal
clearance --dependent on
GFR (glomerular
filtration rate), not
affected by humoral
factors or plasma iodide
concentration
- thyroid
iodide uptake regulated
by thyroid (not affected
by renal factors)
- Active Thyroid
Transport involves:
- Na+/I+
symporter
- thyroid
oxidative metabolism
supplies energy
cotransport
- thyroid/plasma
gradient equals 25: 1 to
500: 1
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- Iodide then oxidized
by thyroidal peroxidase
(inhibited
by thioamides) to iodine; (thyroidal peroxidase
uses hydrogen peroxide generated
by thyroid oxidative metabolism)
- associated with
iodination of newly
synthesized thyroglobulin
tyrosine residues
forming:
- monoiodotyrosine
(MIT): iodide
organification at
cell-colloid interface
- diiodotyrosine
(DAT): iiodide
organification at
cell-colloid interface
- Thyroglobulin:
glycoprotein synthesized
in thyroid follicular
cells.
- Two molecules of
diiodotyrosine (DIT) combine
within thyroglobulin to form L-thyroxine (T4).
(oxidative
condensation; peroxidase
mediated)
- One molecule of
monoiodotyrosine (MIT) and one
molecule of diiodotyrosine (DIT)
combines to form T3. (oxidative
condensation)
- Thyroid hormone release:
- exocytosis
- proteolysis
of thyroglobulin
- Location:
apical colloid border
- Mechanism: Thyroglobulin
(as colloid droplets{formed by
pinocytosis of follicular
colloid had apical cell
margin}) in lysosomes
is subject to action of
proteolytic enzymes
(inhibited by
intrathyroidal iodide):
- Thyroglobulin
hydrolysis products:
- T4
-- released
- T3
-- released
- MIT}deiodinated
within the gland, iodine
reutilized
- DIT}deiodinated
within the gland, iodine
reutilized
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- Thyroglobulin T4
/T3 ratio = 5:1 --therefore T4
(thyroxine) is primarily
released; Circulating T3
levels mainly result from
thyroxine peripheral metabolism.
- Above reactions may be
inhibited by agents, collectively termed
goitrogens which indirectly
stimulate TSH secretion --
inducing goiter. Examples:
- perchlorate --
inhibit iodide transport
- thiocyanate --
inhibit iodide transport
- thiourea
derivatives: inhibit
iodide oxidation;
decrease DIT/MIT ratios;
block coupling of
iodotyrosines to active
iodothyronines
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- Hormonal
transport:
- T4
and T3 : protein bound
-- primarily to thyroxine-binding
globulin (TBG)
- Others:
- T4 --
binding prealbumin
- albumin
- high-density
lipoproteins
- TBG (thyroxine-binding
globulin): major determinant
of normal binding
 Changes in TBG
concentration influence T4
and T3 levels:
- increased TBG:
 serum
T4 and T3
levels; percent
FT4, FT3,
RT3U
- decreased TBG:serum
T4 and T3
levels; percent
FT4, FT3,
RT3U
- Two types of
thyroid hormone-plasma protein
anomalies:
- Thyroid-pituitary
axis: normal with intact
homeostatic thyroid
hormone secretion control
- Changes
in TBG concentration is
compensated for by
mechanisms that insure
return of free hormone
concentration to normal
- Altered
thyroid hormone buying
interaction is due to
primary change in thyroid
hormone blood
concentration, e.g.
hypothyroidism or
thyrotoxicosis-normal
homeostatic control of
hormone secretion is lost
- TBG
concentration changes
little but free-hormone
varies directly with
total hormone
concentration
- homeostatic
mechanisms do not
function to restore
hormone level and
persistent abnormal
levels result in altered
metabolic state
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- Thyroid Hormone Peripheral
Metabolism:
- Primary pathway for thyroxine peripheral
metabolism:
- monodeiodination
of T4 (outer
ring)
 T3
(3,5,3'-triiodothyronine,
3 to 4 times more potent
T4);
- since about 30%
of T4 is
converted toT3
and given the relative
potency of T3
and T4: nearly
all of the metabolic
effects of T4
is due to T3
derived from T4.
- deiodination
of T4 (inner
ring, 40%) reverse
T3, RT3
(3,3',5'-triiodothyronine,
metabolically inactive)
- 5'-deiodinase,
required for T4
T3
conversion may be
inhibited.
- Second major pathway for
T4 and T3 (and
their metabolites) metabolism:
- Hepatic
metabolism:
- conjugation (glucuronate, sulfate)
- conjugates:
either deiodinated
locally or biliary
excreted
- probably
limited reabsorption
- Agents
that increase metabolic
clearance of thyroid
hormone:
- phenobarbital (Luminal)
- phenytoin
(Dilantin)-- total and
free T4
reduced; normal metabolic
state retained, possibly
due to increasing T3
formation.
- Causes of decreased T4
T3
conversion
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