Biochemical aspects of
thyroid hormone
metabolism
ng material ; Clinical Chemistry. Principles techniques and correl
Chapter 23
Mahmoud A. Alfaqih BDS
PhD
Jordan University of
Science and Technology
Overview
The thyroid gland, located
immediately below the larynx on
each side of and anterior to the
trachea
Thyroid gland is one of the
largest of the endocrine glands,
normally weighing 15 to 20
grams in adults
The thyroid secretes two major
hormones, thyroxine and
triiodothyronine, commonly
called T4 and T3, respectively
Calcitonin is secreted by parafollicular cells (Involved in
calcium metabolism
Overview
About 93% of the metabolically active
hormones secreted by the thyroid gland is
thyroxine (T4).
7% is triiodothyronine.
Almost all the thyroxine is eventually
converted to triiodothyronine in the
tissues.
Differences between T4
and T3
They differ in rapidity and intensity of
action. How?
Triiodothyronine is about four times
as potent as thyroxine.
Triiodothyronine is present in the
blood in much smaller quantities
T3 has a shorter half life than T4
Note
In tissues, most of the effect of T4 results
from its conversion to T3.
This reaction is catalyzed by seleniumcontaining enzyme iodothyronine
deiodinases.
Deiodination can also produce reverse
triiodothyronine (rT3) (physiologically
inactive)
Congenital
Hypothyroidism
Thyroid hormone is critical to neurologic development of the
fetus.
Congenital hypothyroidism occurs in 1 of 4,000 live births.
If the mother has normal thyroid function, the fetus is protected
during development by maternal thyroid hormone crossing the
placenta.
Postpartum, newborns require initiation of appropriate doses of
thyroid hormone or neurologic development will be impaired
Screening tests are performed on all newborns to diagnose
congenital hypothyroidism and prevent complications
Cretinism
Physiologic anatomy of the thyroid
gland
The thyroid gland is composed of
closed follicles filled with colloid.
Follicles are lined with cuboidal
epithelial cells that secrete colloid
Colloid is mainly made from
thyroglobulin (large glycoprotein)
Thyroid hormones are found
within thyroglobulin.
Major Actions of thyroid
hormones
Thyroid hormones are essential for
normal growth and development and
have many effects on metabolic processes
They stimulate the synthesis of a number
of hormones and enzymes.
One of the key enzymes stimulated is
cytochrome oxidase
Their overall effect on metabolism is to
stimulate the basal metabolic rate,
oxygen consumption and heat
production.
Thyroid hormones increase net catabolism.
Weight loss, muscle wasting and heat
intolerance are features of excessive
secretion of thyroid hormones.
Thyroid hormones increase the
sensitivity of the cardiovascular and
nervous systems to catecholamines.
This leads to an increases in heart
rate, cardiac output, and to increased
arousal.
Synthesis of thyroid
hormones
Thyroid hormone synthesis involves a
number of specific enzyme-catalysed
reactions.
Synthesis begins with the uptake of
iodide by the gland and ends in the
iodination of tyrosine residues in the
protein thyroglobulin.
All of these reactions are stimulated
Synthesis: Detailed reactions
1. Iodide trapping
The first stage in the formation of thyroid hormones, is
transport of iodides from the blood into the thyroid gland.
The basal membrane of the thyroid cell has the specific
ability to pump the iodide actively to the interior of the cell.
The iodide pump concentrates the iodide to about 30 times
its concentration in the blood.
The rate of iodide trapping by the thyroid is influenced by
the concentration of TSH.
Radioactive iodine uptake (RAIU)
can help diagnose thyroid disease
Thiocyanate
Ions Decrease
Iodide Trapping
A note about
thyroglobulin
Each molecule of thyroglobulin contains about 70
tyrosine amino acid residues.
These tyrosine residues are the substrates that bind
with iodine to form the thyroid hormones.
Thyroid hormones form within the thyroglobulin
molecule.
Thyroid hormones remain part of thyroglobulin during
synthesis and later on during storage of the colloid.
Synthesis: Detailed reactions
.2. Oxidation of iodide ion
This is conversion of the iodide ions to an oxidized
form of iodine
Iodide ion is converted to I2 that is capable of
combining directly with tyrosine.
Oxidation of iodine is catalyzed by peroxidase and
its accompanying hydrogen peroxide, which provide
a potent system capable of oxidizing iodides.
When the peroxidase system is blocked rate of
synthesis falls down to zero.
Synthesis; Detailed reactions
3. Organification and coupling
The binding of iodine with the thyroglobulin molecule is called
organification of the thyroglobulin.
This process is catalyzed by the enzyme iodinase
Tyrosine is first iodized to monoiodotyrosine (MIT) and then to
diiodotyrosine (DIT)
Iodotyrosine residues become coupled with one another and the
coupling reactions result in the formation of thyroid hormones T4 and
T3
Under normal condition 70% of tyrosine residues of thyreoglobulin are
in the form MIT and DIT and 30% as thyroxine (with minor part of T 3)
Organification and coupling
Organification and coupling
Propylthiouracil inhibit
peroxidase enzyme as
well as coupling of
iodinated tyrosine
residues
Storage of thyroglobulin
Thyroid gland can store large amounts of hormone (unlike
other endocrine glands).
Each thyroglobulin molecule contains up to 30 thyroxine
molecules and a few triiodothyronine molecules.
The thyroid hormones stored in the follicles are sufficient
to supply the body with thyroid hormones for 2 to 3
months.
When synthesis of thyroid hormone ceases, the
physiologic effects of deficiency are not observed for
several months.
Release and Secretion of
thyroid hormones
Thyroglobulin itself is not released
into the circulating blood.
Thyroxine and Triiodothyronine are
cleaved from the thyroglobulin and
then released.
Release and secretion of thyroid
hormones
1. Thyroid cells sends out pseudopod extensions that
close around portions of the colloid to form pinocytic
vesicles.
2. Lysosomes in the cell cytoplasm immediately fuse with
these vesicles.
3. Multiple proteases digest the thyroglobulin molecules
and release thyroxine and triiodothyronine in free form.
4. T4 and T3 then diffuse through the base of the thyroid
cell into the surrounding capillaries.
.Figure 22.14 Cellular mechanisms for T3 and T4 release into bloodstream
.Redrawn from Berne, R. M., and Levy, M. L.(Eds.). Physiology, 2d ed. New York: Mosby, 1990, 938
. Textbook of Biochemistry with Clinical Correlations, 7e edited by Thomas M. Devlin 2011 John Wiley & Sons, Inc
Recycling of iodine
During the digestion of the thyroglobulin
molecule to release thyroxine and
triiodothyronine, MIT and DIT released from
thyroglobulin
MIT and DIT are not secreted into the blood in
large amounts.
Instead, their iodine is cleaved by deiodinase
enzyme that makes iodine available for making
thyroid hormones.
Regulation of thyroid hormone
secretion:
1. TSH
TSH (thyrotropin) an anterior pituitary hormone is chemically a
glycoprotein.
This hormone, increases the secretion of thyroxine and
triiodothyronine by the thyroid gland.
Specific effects on thyroid gland:
1. Increased proteolysis of the stored thyroglobulin.
2. Increased activity of the iodide pump.
3. Increased iodination of tyrosine to form the
thyroid hormones.
4. Increased size and increased secretory activity of
the thyroid cells (hypertrophy).
5. Increased number of thyroid cell (hyperplasia).
Note
The most important early effect after
administration of TSH is to initiate
proteolysis of thyroglobulin.
Thyroxine and triiodothyronine will get
released into the blood within 30 minutes.
Most of the effects of TSH are mediated by
cAMP second messenger system.
Regulation of thyroid hormone
secretion
2. Thyrotropin-Releasing Hormone (TRH)
Anterior pituitary secretion of TSH is controlled by a
hypothalamic hormone, thyrotropin-releasing
hormone (TRH).
TRH is secreted by nerve endings in the median
eminence of hypothalamus.
TRH is transported to the anterior pituitary by
hypothalamic hypophysial portal blood.
TRH causes an increase in the output of TSH by
anterior pituitary.
Regulation of thyroid hormone secretion
3. Cold and Anxiety
Cold is a stimuli for increasing the
rate of TRH secretion by the
hypothalamus and therefore TSH
secretion by the anterior pituitary
gland.
Excitement and anxiety cause an
acute decrease in the rate of
secretion of TSH.
Feedback Effect of Thyroid Hormone
to Decrease Anterior Pituitary
Secretion of TSH
Transport of thyroid
hormones
When released into the circulation, only 0.04% of T4 and 0.4% of T3
are unbound by proteins (physiologically active)
The three major binding proteins, in order of significance, are
thyroxine-binding globulin (TBG), thyroxine-binding
prealbumin, and albumin
The quantity of T4 and T3 in the circulation can be affected by the
amount of binding protein available for carrying these hormones
High TBG levels result in higher levels of bound thyroid hormones,
leading to high levels of total T3 and total T4
Measurement of free T4 and free T3 may be necessary to
eliminate any confusion caused by abnormal binding protein levels
Mechanism of action of thyroid
hormones
Mechanism of action of thyroid
hormones
Free thyroid hormone receptor (TR) without bound
hormone is bound to hormone response element
of DNA (HRE) and corepressor (CoR)
Binding T3 to its receptor liberates co-repressor
and recruits coactivator and RNA polymerase
which drives mRNA transcription
Thyroid autoantibodies
