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The Thyroid Gland

Learning objectives:

To understand the actions of


thyroid hormones and their
regulators

An overview of thyroid disorders


and the drugs used in these
conditions
The Thyroid Gland

The thyroid gland is located


immediately below the larynx, on each
side of, and anterior to the trachea.

The thyroid is one of the largest


endocrine glands and measures about
15-20g in adults.

The thyroid secretes two major


hormones: thyroxine and
triiodothyroxine (T4 and T3
respectively). The release of these
hormones is controlled primarily by the
release of thyroid stimulating
hormone (TSH) from the pituitary.
Regulation of Thyroid Hormones

-
Hypothalamus

Thyrotropin Releasing TRH N




Hormone
+
-
Pituitary

Thyroid Stimulating TSH N




Hormone
+
Thyroid T4 and T3 N


Synthesis and Secretion of Thyroid Hormon

About 93% of the metabolically active hormones secreted by the thyroid gland is
thyroxine (T4) and 7% is triiodothyroxine (T3). However, almost all the T4 is
converted to T3 in the tissues, so both are functionally important. The function of
these two hormones is essentially the same, but they differ in the speed and
intensity of action. T3 is about four times more potent than T4, but is present in
the blood at much lower concentrations and has a much shorter half life than T4.

Anatomy of the Thyroid Gland

The thyroid is composed of large numbers of follicles which contain thyroid


follicular cells and follicular colloid. The thyroid gland has a blood flow about
five times the weight of the gland each minute. This is similar to other parts of the
body.
Synthesis and Secretion of Thyroid Hormon

Iodine Requirement

To form thyroxine about 50 milligrams of ingested iodine is required each year


(about 1mg/week). To prevent iodine deficiency, it is common that iodine is
supplemented in table salt.

Iodine is absorbed in the diet in the same way that other elements are (e.g.
Chloride). Iodides are usually rapidly excreted by the kidneys and only about one
fifth are absorbed by the thyroid gland for hormone synthesis.

The first stage in the formation of thyroid hormones is the transport of iodine
from the blood, into the thyroid follicular cell. The thyroid follicular cell has the
specific ability to actively pump iodine into the cell this is called iodine
trapping.

The rate of iodine trapping is influenced by several factors. The most important
factor is the concentration of TSH. Increased secretion of TSH leads to increased
activity of the iodine pump in thyroid cells.
Synthesis and Secretion of Thyroid Hormon

Thyroglobulin

The thyroid cells are typical protein-secreting glandular cells. The endoplasmic
reticulum synthesise and secrete into the follicles a large glycoprotein molecule
called thyroglobulin which has a molecular weight of about 335,000.

Each molecule of thyroglobulin contains about 70 tyrosine amino acid residues


and these are the major substrates that combine with iodine to form the thyroid
hormones. The thyroid hormones essentially form within the thyroglobulin
molecule and are then broken down and released.

Oxidation of the iodide Ion

The first essential step in synthesis of thyroid hormones is conversion of the


iodide ions to an oxidised formed of iodine, that is capable of combining directly
with the amino acid tyrosine. This oxidation step is promoted by the enzyme
thyroid peroxidase in the presence of hydrogen peroxide.
Synthesis and Secretion of Thyroid Hormon

Iodination of Tyrosine Residues

Oxidised iodine will now bind directly, but very slowly, with the amino acid
tyrosine. In the thyroid cells, the enzyme iodinase is present which causes this
reaction to occur much faster. Iodine binds to about one sixth of the tyrosine
residues available in the thyroglobulin molecule.
Synthesis and Secretion of Thyroid hormon
Synthesis and Secretion of Thyroid Hormon

Storage of Thyroglobulin

The thyroid gland is unusual among the other endocrine glands in its ability to
store large amounts of hormones. After synthesis of thyroid hormones, each
thyroglobulin molecule contains up to 30 thyroxine molecules and a few
triiodothyroxine molecules. In this form, the thyroid hormones are stored in the
follicles in an equal amount sufficient to supply the body with its normal
requirements of thyroid hormones for 2 3 months. Therefore, when synthesis of
thyroid hormones ceases, the physiological effects of deficiency are not seen for
several months.

Release of T4 and T3 from the Thyroid

T4 and T3 must be cleaved from thyroglobulin in order to be released from the


cell in a free hormone form. Proteases break down the thyroglobulin molecule
and release T4 and T3 which can then be released into the blood. Some of the
iodinated tyrosine residues in thyroglobulin will never become thyroid hormones.
Instead the iodine in these residues is recycled within the gland via a deiodinase
Synthesis and Secretion of Thyroid Hormon

Daily Rate of Excretion of T4 and T3

Although much more T4 than T3 is released from the thyroid gland, during the
previous few days about half of the T4 has been converted to T3, therefore the
hormone that is used by the tissues is T3. a total of about 35 micrograms of T3 is
used by the tissues each day.

Transport of T4 and T3 to Tissues

On entering the blood over 99% of T4 and T3 are bound to plasma proteins such
as thyroxine binding globuin, thyroxine binding prealbumin and albumin.
T4 and T3 are released slowly to the tissues due to the high affinity they have for
their binding proteins. Once released to the cells, the thyroid hormones bind to
proteins within the cell which allows them to be stored until required.

Thyroid hormones have a slow onset and a long duration of action. The
actions of T3 are about four times as rapid as T4
Synthesis and Secretion of Thyroid Hormon
Endothelium
Follicle Colloid Thyroid Follicular Cell
Blood
Thyroglobulin Endoplasmic Reticulum
Exocytosis

I-
[O]
I0
I0-
Pendrin
Proteolysis Na/I Symporter
Iodination Na+
Conjugation

T3

T4

Endocytosis
Physiological Functions of Thyroid Hormon

Thyroid hormones increase the transcription of large numbers of genes. The


general effect of thyroid hormones is to activate nuclear transcription of genes. In
all cells of the body, thyroid hormones cause greater numbers of transport
proteins, structural proteins, enzymes and other substances. The net
result is generalised increase in functional activity throughout the body.

Before acting on the genes, T4 is converted to T3 by removal of one iodide.


Intracellular thyroid hormone receptors have a very high affinity for T3 and
consequently more than 90% of the hormone-receptor complexes contain T3.

The thyroid hormone receptors are either attached to the DNA genetic
strands, or located in proximity to them. On binding with the hormone, the
receptor becomes activated and initiates the transcription process producing
messenger RNA and synthesis of proteins.
Physiological Functions of Thyroid Hormon

Thyroid Hormones Increase Cellular Metabolic Activity

The thyroid hormones increase the metabolic activity in almost all of the
tissues of the body. The basal metabolic rate can increase 60 100 % above
normal when large numbers of these hormones are secreted. The rate of
utilisation of foods for energy is increased. Protein synthesis and catabolism is
increased. The rate of growth is increased in young people and the mental
processes are excited. The activity of most other endocrine glands is also
increased.

The number of mitochondria in the cells is increased which generates more


energy for the cell.

Thyroid hormones increase active transport of ions through membranes.

Thyroid Hormones and Growth

Thyroid hormones have both general and specific effects on growth. Thyroid
Physiological Functions of Thyroid Hormon
Increased thyroid hormones results in
Stimulation of fat metabolism
decreased concentration of
Stimulation of carbohydrate cholesterol, phospholipids and
metabolism
Increased blood flow and cardiac triglycerides. Free fatty acids are
output increased.
Increased heart rate and strength Increased requirement for vitamins as
Normal arterial pressure, but raised they are required as cofactors for
pulse enzymes.
Increased respiration as the utilisation Effects on other endocrine glands
of oxygen and formation of carbon Effects of Thyroid
dioxide is increased Hormones Increased basal metabolic rate due to
Increased gastrointestinal motility the increase in metabolism in all cells
(increased GI secretions and of the body
Decreased body weight (not always
movements)
Excitatory effects on the CNS seen as thyroid hormones also

Effects on muscle function (tremor) increase appetite and may


counterbalance
Effects this)
on sexual function
Effects on sleep requirement for
more sleep due to the exhausting
effects of the hormones on the
muscles and CNS, but difficulty
sleeping due to the effects on nerve
Regulation of Thyroid Hormone Secretion

To maintain normal levels of metabolic activity in the body, precisely the right
about of thyroid hormone must be secreted at all times. To achieve this, there are
specific feedback mechanisms that operate through the hypothalamus and
anterior pituitary gland to control the rate of hormone secretion.

TSH (an anterior pituitary hormone) increases the secretion of thyroxine and
triiodothyroxine by the thyroid gland. It has specific effects on the thyroid:

Increased breakdown of thyroglobulin that has already been stored in the


follicles, therefore releasing hormones

Increased activity of the iodine pump which increases the rate of iodine
trapping in the follicular cells

Increased iodination of tyrosine

Increased size and activity of the thyroid cells

Increased number of thyroid cells


Regulation of Thyroid Hormones

Secretion of TSH from the anterior pituitary is controlled by the hypothalamic


hormones thyrotrophin releasing hormone (TRH).

One of the best known stimuli for increasing the rate of TRH secretion from the
hypothalamus and therefore the rate of TSH secretion is exposure of an animal to
cold. This results from excitation of the hypothalamic centres for body
temperature control.

Various emotional reactions can also affect the output of TRH and TSH
excitement and anxiety greatly stimulate the nervous system and cause a
decrease in TSH secretion.

Increased thyroid hormone in the body fluids decreases secretion of TSH by the
anterior pituitary. When the rate of thyroid hormone secretion rises to about 1.75
times normal, the rate of TSH secretion falls essentially to zero. This negative
feedback mechanisms maintains an almost constant concentration of free
thyroid hormones in the circulating body fluids.
Antithyroid Substances

Drugs that suppress thyroid secretion are called antithyroid substances.


The best known of these are thiocyanate, propylthioracil and high
concentrations of inorganic iodides.

Thiocyanate ions decrease iodide trapping. The same pump that transports
iodide ions into the thyroid cells can also pump thiocyanate ions, perchlorate ions
and nitrate ions. Therefore, the administration of thiocyanate in high enough
concentration can cause complete inhibition of iodide transport into the
cells inhibiting the iodide trapping mechanism. The decreased availability
of iodide in the glandular cell does not stop the formation of thyroglobulin, it just
prevents iodination of tyrosine residues and therefore blocks thyroid
hormone synthesis. Deficiency of thyroid hormones leads to increased secretion
of TSH which causes overgrowth of the thyroid gland even though the gland still
doesnt form adequate quantities of thyroid hormones. The use of thiocyanates can
lead to the development of a greatly enlarged thyroid gland, which is called a
goiter.
Antithyroid Substances

Propylthiouracil decreases thyroid hormone formation. Propylthiouracil (and


other related compounds such as methimazole and carbimazole) prevent the
formation of thyroid hormones from iodides and tyrosine. The mechanism of
this is to partly block the peroxidase enzyme that is required for iodination of
tyrosine, and partly to block the coupling of two iodinated tyrosine residues
to form T4 and T3. Treatment with these drugs does not prevent formation of
thyroglobuin. The absence of thyroid hormone feeds back to the pituitary and
results in increased TSH secretion and can lead to a goiter.

Iodides in high concentration decrease thyroid activity and thyroid gland


size. At high concentrations of iodides, most activities of the thyroid gland are
decreased. There is a decreased rate of trapping so that the rate of
iodination of tyrosine is also decreased. There is almost immediate
shutdown of thyroid hormone secretion into the blood. Because iodides in
high concentrations decrease all phases of thyroid activity, they slightly
decrease the size of the gland. This treatment is often used to shrink the
Diseases of the Thyroid

Non-thyroidal illness
Subclinical hyperthyroidism Hyperthy Central hypothyroidism
Recent treatment for hyperthyroidism roid Isolated TSH deficiency
Drugs (e.g. Steroids)
Non-thyroidal illness FT4/FT3
FT4/FT3 N TSH FT4/FT3
TSH TSH N or
Euthyroid
FT4/FT3 N
TSH N FT4/FT3
FT4/FT3 N
TSH N or
TSH Hypothyr

oid
Subclinical hyperthyroidism FT4/FT3 Assay interference
Poor compliance with thyroxine Thyroxine replacement therapy
TSH
Malabsorption of thyroxine Poor compliance
Drugs (e.g. Amiodarone) Drugs (e.g. Amiodarone)
Assay interference Non-thyroidal illness
Non-thyroidal illness Neonatal period
TSH resistance TSH-secretion pituitary adenoma
Resistance to thyroid hormone
Disorders of thyroid hormone transpo
or metabolism
Diseases of the Thyroid

Hyperthyroidism

Most of the effects are obvious from what we have discussed already, however
some specific effects should be mentioned.

Causes of Hyperthyroidism

In most patients with hyperthyroidism, the thyroid gland is increased to two or


three times normal size, usually due to thyroid stimulating immunoglobulins which
promote the simulating effect on the thyroid, despite the TSH level being below
normal levels. These antibodies that cause hyperthyroidism almost certainly occur
as the result of an autoimmune process. The body has produced antibodies
against the thyroid gland itself. This results in the pattern of thyroid hormones
associated with hyperthyroidism TSH below normal and T4 above normal.

Occasionally hyperthyroidism results from a tumour that develops thyroid tissue


and secretes large amounts of thyroid hormones.
Diseases of the Thyroid

Symptoms of Hyperthyroidism

The symptoms are a direct result of excess secretion of thyroid hormones and
include:

High state of excitability, intolerance to heat, increased sweating, weight


loss, diarrhoea, muscle weakness, nervousness, anxiety, tremor of the
hands, extreme fatigue but inability to sleep, goiter.
Diseases of the Thyroid

Exopthalmos

Most people with hyperthyroidism develop some degree of protrusion of the


eyeballs. This is caused by swelling of the tissues surrounding the eyes and
degeneration of the muscles involved. It is thought that this is probably an
autoimmune process with antibodies to eye muscle being produced.
Diseases of the Thyroid

Diagnosis

Hyperthyroidism can be strongly suspected clinically, but the most accurate


diagnostic test is measurement of the concentration of thyroid hormones and
TSH in the patients blood. The pattern usually associated with hyperthyroidism
is an elevation of thyroid hormones (T4/T3) and a suppressed TSH concentration.

Treatment of Hyperthyroidism

The most direct treatment is surgical removal of the thyroid gland followed by
pharmacological replacement of thyroxine.

Patients may also be treated with radioactive iodine which destroys the thyroid
gland tissue. The patients then take thyroxine.

It is also possible to treat via a block and replace method. The patient takes a
drug that blocks thyroid hormone secretion (such as carbimazole) and then
replace the thyroid hormone using synthetic thyroxine.
Diseases of the Thyroid

Hypothyroidism

The symptoms of hypothyroidism are almost the opposite of hyperthyroidism.

Causes of Hypothyroidism

Dietary iodine deficiency results in formation of a goiter as there is not sufficient


iodine in the body to make thyroid hormones, so the negative feedback
mechanism stimulates the production of TSH which causes enlargement of the
thyroid gland.

The most common cause of hypothyroidism is autoimmune destruction of the


thyroid gland. This causes thyroiditis (inflammation of the thyroid gland) and
results in fibrosis of the gland and diminished production of thyroid hormones.

Hypothyroidism can be caused by abnormalities in the many enzyme systems


involved in production of thyroid hormones deficient iodine trapping mechanism,
deficient peroxidase system, deficient coupling of tyrosine residues in the
Diseases of the Thyroid

Symptoms of Hypothyroidism

Whatever the cause of hypothyroidism, the symptoms tend to be the same.

Symptoms include: fatigue, excessive amounts of sleeping, extreme


muscular sluggishness. Slowed heart rate, decreased cardiac output,
decreased blood volume, weight gain, constipation, mental sluggishness,
slow hair growth, scaliness of the skin, deepening of the voice,
myxedema.
Diseases of the Thyroid

Myxedema

This develops in patients with almost total lack of thyroid hormone function.
The patient develops bagginess under the eyes and general swelling of the face.
These patients have an odematous appearance throughout the body.
Diseases of the Thyroid

Due to the lack of thyroid hormones the concentration of cholesterol increases


in the blood because of altered fat and cholesterol metabolism and diminished
excretion in the liver. The increase in blood cholesterol is usually associated with
increased atherosclerosis. In patients with hypothyroidism that develop
atherosclerosis, the complications of the disease can include peripheral vascular
resistance, deafness and coronary artery disease. This may lead to early
death.

Diagnosis of Hypothyroidism

As with hyperthyroidism, this condition can be strongly suspected clinically, but


is confirmed by a biochemical test. The concentration of TSH and thyroid
hormones can be measured in the patients blood and the pattern associated with
hypothyroidism is a level of TSH above normal and the level of thyroid
hormones (T4/T3) below normal.
Diseases of the Thyroid

Treatment of Hypothyroidism

It is easy to maintain a steady level of thyroid hormone activity in these patients


by daily oral ingestion of a tablet containing thyroxine. Monitoring of blood
levels in these patients is necessary to ensure the correct levels of hormone
activity are being reached.

Treatment of both hypo and hyperthyroidism removes all the symptoms the
patient experienced before treatment and they can live a long healthy life.