foreign
hypothyroidism hypo refers to having too
little and thyroid refers to thyroid
hormones so hypothyroidism refers to a
condition where there's not enough
thyroid hormones
now as treatment for hypothyroidism we
can use thyroid hormone analogues as a
replacement to supply the body with
normal levels of thyroid hormones
there are two different thyroid hormones
triidothyronine or T3 and thyroxine or
T4 there are two tyrosine-based
iodine-containing hormones that are
secreted by the thyroid gland which is
located anteriorly in the neck and
consists of two lobes that look like two
thumbs hooked together in the shape of a
v now if we zoom into the thyroid gland
we'll find thousands of follicles which
are small Hollow spheres whose walls are
lined with follicular cells or
thyrocytes
zooming in these follicular cells have
an apical side that surrounds a central
Lumen filled with a viscous fluid called
the colloid the colloid contains the
precursor hormone thyroglobulin the
basol lateral side of follicular cells
is in contact with blood vessels that
supply these cells
now synthesis of thyroid hormones inside
the follicles involves a few important
steps
first the inorganic iodide ions present
in a low concentration in the blood are
actively taken up by the basol lateral
side of the follicular cells along with
two sodium ions via a sodium iodide
supporter
this step is known as iodide trap the
iodide ion is then pumped into the
colloid via the pendrin protein where it
undergoes oxidation with the enzyme
thyroid peroxidase or TPO which changes
it into an organic iodine atom it's then
attached to tyrosine amino acid residues
which are found throughout thyroglobulin
this step is known as iodination
some tyrosine residues are bound by only
one iodine whereas others are bound by
two iodine atoms yielding mono iodo
tyrosine or MIT and diiodo tyrosine or
dit respectively
these molecules are then coupled
together by the same enzyme thyroid
peroxidase or TPO
this process is known as coupling
coupling one MIT with one dit creates T3
while linking two dit molecules creates
T4
in general T4 is created in Greater
amounts than T3
T3 is the more active form with a
half-life of one to two days while T4 is
the less active form with a longer
half-life of six to eight days
now production and secretion of thyroid
hormones is under the control of the
hypothalamus pituitary axis the
hypothalamus located at the base of the
brain secretes thyrotropin-releasing
hormone or simply trh which stimulates
the anterior pituitary cells called
thyrotroph cells to release the thyroid
stimulating hormone or TSH into the
bloodstream TSH then travels to the
thyroid gland and binds to the TSH
receptors located in the membrane of the
follicular cells of the thyroid gland
when TSH binds to the TSH receptor it
goes on to promote every aspect of T3
and T4 production ranging from the
iodide trapping to the release of
thyroid hormones into the bloodstream
once released from the thyroid gland
most of the T3 and T4 travel via the
blood by binding with the
thyroxine-binding globulin or tbg to
reach the target cells alternatively
small amounts of T3 and T4 stay Unbound
and therefore they are referred to as
free thyroid hormones only free thyroid
hormones are physiologically active
because they are able to enter the cell
now once inside the cell T4 is mostly
converted into T3 by the enzyme
5-diodinase
T3 binds to thyroid hormone receptors
which are within the cell's nucleus and
these receptors regulate gene expression
which ultimately lead to various
metabolic and physiologic effects in the
body
this increase in metabolism uses up
sugars and fats for energy and produces
more body heat thyroid hormones also
help activate the sympathetic nervous
system which is responsible for the
fight-or-flight response this increases
heart rate and cardiac output
respiratory rate and mental alertness
thyroid hormones also increase the
gastrointestinal motility and they are
necessary for normal neuronal
development in growing fetuses and young
children
now there are three types of
hypothyroidism primary secondary and
tertiary in primary hypothyroidism the
thyroid gland is the problem because it
isn't making enough thyroid hormones
iodine deficiency can be a cause of
primary hypothyroidism because the
follicular cells don't have the iodide
ions they need to produce T3 and T4
in countries that do fortify food with
iodide the most common cause of primary
hypothyroidism is Hashimoto thyroiditis
an autoimmune disorder where T cells and
auto antibodies like anti-thyroid
peroxidase and antithyroglobulin
infiltrate the thyroid and cause
follicular cell damage and inhibit
normal thyroid function
primary hypothyroidism can also happen
after treatment for hyperthyroidism
which usually involves surgically
removing the thyroid gland or destroying
it with radioiodine therapy
now in secondary hypothyroidism also
called Central hypothyroidism the issue
is that the body doesn't produce enough
TSH
is a really important hormone which
stimulates the thyroid gland to uptake
iodide from the circulation and produce
T3 and T4 when needed it typically
happens because there's a tumor in the
anterior pituitary which compresses the
gland and prevents TSH production which
leads to decreased level of T3 and T4
finally in tertiary hypothyroidism the
hypothalamus doesn't produce enough
thyrotropin releasing hormone or trh as
a result these individuals have
decreased levels of TSH and subsequently
decreased production of T3 and T4
another form of hypothyroidism is
congenital hypothyroidism which is
defined as thyroid hormone deficiency
present at birth it can occur due to an
absent or underdeveloped thyroid gland
which is known as thyroid discgenesis or
due to an ineffective production of
thyroid hormones also known as thyroid
dis-harmonogenesis
a person with low thyroid hormone levels
typically has cold dry skin cold
intolerance hair loss
weight gain and constipation they might
also suffer mental symptoms like
lethargy and fatigue in infants and
children hypothyroidism could delay
physical and mental development
now in some elderly individuals with low
levels of thyroid hormones any stressful
event like an infection or a heart
attack can lead to an acute decrease in
T3 and T4
this leads to a medical emergency known
as myxedema coma a rare condition
associated with clinical features such
as sudden drop in body temperature low
heart rate low blood pressure
hypoventilation confusion and coma
okay now in a person with hypothyroidism
we want to increase the T3 and T4 to
normal levels and if the hypothyroidism
is due to iodine deficiency the
treatment is to give foods rich in
iodine like fish eggs meat and iodized
salt on the other hand in individuals
with primary secondary tertiary or
congenital hypothyroidism the treatment
of choice is to give synthetic thyroid
hormone Replacements or thyroid
replacement therapy now the synthetic
hormone that's similar to T3 is called
lyothyranine and the one that's similar
to T4 is called levothyroxine both
lyothyronine and levothyroxine are
usually given pororal but can also be
given via the intravenous route
of the two synthetic thyroid hormones
lyothyronine is shorter acting but much
more potent meaning it's able to treat
the symptoms of hypothyroidism at a
lower dose since it's a T3 analog it
could directly enter the target cell and
take effect very rapidly
this is why intravenous lyothyronine is
the drug of choice in emergencies like
myxedema coma its high potency also
leads to more severe side effects which
are the same as hyperthyroidism this
includes heat intolerance anxiety
diarrhea Tremors and tachycardia which
may lead to cardiac arrhythmias
that's why lyothyronine is
contraindicated in individuals with
heart conditions
on the other hand levothyroxine is much
less potent but longer acting just like
natural T4 when it reaches the target
cells it first needs to be converted to
T3 by the enzyme 5diodinase due to this
levothyroxine takes effect much slower
than lyothyronine and individuals may
require six to eight weeks of therapy to
achieve a normal T3 and T4 level
levothyroxine is the medication of
choice in the long-term treatment of
hypothyroidism but also in the treatment
of hypothyroid individuals during
pregnancy it's important to note that
the dose of Levothyroxine should be
increased once the pregnancy is detected
because during pregnancy there are high
levels of circulating estrogen which
increases the concentration of
thyroxine-binding globulins and more
thyroxine-binding globulins means less
free T4 don't forget that the thyroid
hormones are also important for normal
fetal development
after delivery the levothyroxine dose
should be reduced to the dose that was
taken before the pregnancy
in contrast to lyothyronine the
hyperthyroidism side effects associated
with levothyroxine are less severe but
the elderly individuals with
cardiovascular problems and individuals
with long-standing hypothyroidism are at
risk for developing cardiovascular side
effects these individuals have an
increased sensitivity to stimulatory
effects of T4 on the heart thus they
should start the treatment with lower
Doses and gradually increase it to
prevent cardiovascular side effects
now moving on to Major interactions of
Levothyroxine with other medications
which can be subdivided into several
groups the first group includes
medications that decrease levothyroxine
absorption such as iron calcium aluminum
hydroxide proton pump inhibitors or ppis
sucralfate and bile acid binding agents
like cholesteramine since they are
associated with decreased absorption
individuals treated with these
medications require higher doses of
Levothyroxine to achieve therapeutic
effects the next group covers
medications that increase thyroid
hormone metabolism such as Rifampin
phenytoin and carbamazepine just like
with the first group these individuals
require higher doses of Levothyroxine
next we have medications that increase
the concentration of thyroxine-binding
globulins in the blood such as estrogen
reloxaphene tamoxifen heroin and
methadone more thyroxine binding
globulins in the blood means less free
T4 therefore these individuals also
require more levothyroxine to achieve
therapeutic effects on the flip side the
last group covers medications that
decrease the concentration of thyroxine
binding globulins in the blood such as
androgens glucocorticoids anabolic
steroids and slow release nicotinic acid
in other words less thyroxine binding
globulins in the blood means more free
T4 so these individuals require lower
doses of Levothyroxine
finally it's important to note that
Propranolol inhibits the enzyme
5-de-iodinase and reduces the conversion
of T4 to T3 as a result Propranolol
favors the less active form of thyroid
hormones T4 therefore individuals on
Propranolol also require higher doses of
Levothyroxine
another indication of synthetic thyroid
hormones is TSH suppressive therapy
let's put it this way some conditions
such as thyroid cancer or thyroid
nodules are TSH sensitive meaning they
grow when there are high levels of
thyroid stimulating hormone in the blood
in TSH suppressive therapy synthetic
thyroid hormones inhibit the secretion
of thyrotropin-releasing hormone thereby
reducing the secretion of thyroid
stimulating hormone
now more specifically lyothyronine can
be used to prevent the growth of thyroid
nodules while levothyroxine can be used
to prevent the recurrence of thyroid
cancer
since thyroid hormones stimulate bone
resorption and bone remodeling long-term
treatment with thyroid hormones can
cause osteoporosis
but they can also worsen glycemic
control in individuals with diabetes
finally thyroid replacement therapy
should not be used to treat obesity or
cause weight loss
now as far as the contraindications go
thyroid replacement therapy is
contraindicated in individuals with
uncorrected adrenal insufficiency this
is because thyroid hormones increase the
hepatic metabolism of glucocorticoids
which are hormones produced by the
adrenal glands
now in adrenal insufficiency adrenal
glands are unable to increase
glucocorticoid production and compensate
for increased turnover ultimately this
can precipitate adrenal crisis
so it's important to note that
individuals with hypothyroidism should
treat adrenal insufficiency before
hypothyroidism
other preparations of thyroid hormones
used to treat hypothyroidism include
liatrix and desiccated thyroid layatrix
is a synthetically made mixture of T4
and T3 in a four to one weight-based
ratio on the other hand porcine-derived
desiccated thyroid also known as thyroid
extract contains a mix of natural T3 and
T4 hormones derived from pigs however
it's not as reliable as the synthetic
hormones since the amount of T3 and T4
in each dose could vary which leads to
unpredictability in its potency and
duration
both liatrix and desiccated thyroid are
given orally
alright as a quick recap when treating
hypothyroidism iodine deficiency can be
treated by giving foods rich in iodine
if the cause is thyroid or pituitary
damage synthetic or non-synthetic
thyroid hormone replacement therapy
could be used
lyothyronine and levothyroxine are
synthetic forms of T3 and T4
levothyroxine is the drug of choice for
treating chronic hypothyroidism while
lyothyronine is used for myxedema coma
liatrix is a synthetically made mixture
of T4 and T3 in a four to one
weight-based ratio
non-synthetic thyroid hormone
replacement uses porcine-derived
desiccated thyroid which is a mix of
natural T3 and T4 derived from pigs but
its effects are much less reliable when
compared to synthetic thyroid hormones
helping current and future clinicians
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