Thyroid Metabolic Hormones

The thyroid gland, located immediately below the larynx on each side of and anterior to the
trachea, 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. Both of these hormones profoundly increase the metabolic rate of
the body. Complete lack of thyroid secretion usually causes the basal metabolic rate to fall 40-
50% below normal, and extreme excesses of thyroid secretion can increase the basal metabolic
rate to 60-100% above normal. Thyroid secretion is controlled primarily by thyroid-stimulating
hormone (TSH) secreted by the anterior pituitary gland. The thyroid gland also secretes
calcitonin, an important hormone for calcium metabolism.

Synthesis and secretion of the thyroid metabolic hormones: About 93% of the metabolically
active hormones secreted by the thyroid gland is thyroxine, and 7% triiodothyronine. However,
almost all the thyroxine is eventually converted to T3 in the tissues, so that both are functionally
important. The functions of these two hormones are qualitatively the same, but they differ in
rapidity and intensity of action. T3 is about four times as potent as thyroxine, but it is present in
the blood in much smaller quantities and persists for a much shorter time than does thyroxine.

Physiologic anatomy of the thyroid gland: The gland is composed of large numbers of closed
follicles (100-300 µm in diameter) filled with a secretory substance called colloid and lined with
cuboidal epithelial cells that secrete into the interior of follicles. The major constituent of colloid
is the large glycoprotein thyroglobulin that contains the thyroid hormones within its molecule.

Iodine is required for the formation of Thyroxine: To form normal quantities of thyroxine,
about 50 mg of ingested iodine in the form of iodides are required each year, or about 1
mg/week. To prevent iodine deficiency, common table salt is iodized with about 1 part sodium
iodide to every 100,000 parts sodium chloride.

Fate of ingested Iodides: Iodides ingested orally are absorbed from the GIT into the blood in
about the same manner as chlorides. Normally, most of the iodides are rapidly excreted by the
kidneys, but only after about one fifth are selectively removed from the circulating blood by the
cells of the thyroid gland and used for synthesis of the thyroid hormones.

Iodide Pump (Iodide Trapping): The first stage in the formation of thyroid hormones is
transport of iodides from the blood into the thyroid glandular cells and follicles. The basal
membrane of the thyroid cell has the specific ability to pump the iodide actively to the interior of
the cell. This is called iodide trapping. In a normal gland, the iodide pump concentrates the
iodide to about 30 times its concentration in the blood. When the thyroid gland becomes
maximally active, this concentration ratio can rise to as high as 250 times. The rate of iodide
trapping by the thyroid is influenced by several factors, the most important being the
concentration of TSH; TSH stimulates and hypophysectomy greatly diminishes the activity of
the iodide pump in thyroid cells.

Thyroglobulin, and Chemistry of Thyroxine and Triiodothyronine Formation

Formation and Secretion of Thyroglobulin by the Thyroid Cells.

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

Each molecule of thyroglobulin contains about 70 tyrosine amino acids, and they are the major
substrates that combine with iodine to form the thyroid hormones. Thus, the thyroid hormones
are formed within the thyroglobulin molecule. That is, the thyroxine and triiodothyronine
hormones formed from the tyrosine, remain part of the thyroglobulin molecule during synthesis
of the thyroid hormones and even afterward as stored hormones in the follicular colloid.

Oxidation of the Iodide Ion. The first essential step in the formation of the thyroid hormones is
conversion of the iodide ions to an oxidized form of iodine, either nascent iodine (I0) or I3, that is
then capable of combining directly with the amino acid tyrosine. This oxidation of iodine is
promoted by the enzyme peroxidase and its accompanying hydrogen peroxide, which provide a
potent system capable of oxidizing iodides.
Iodination of Tyrosine and Formation of Thyroid Hormones—“Organification” of Thyroglobulin
The binding of iodine with the thyroglobulin molecule is called organification of the
thyroglobulin. Oxidized iodine even in the molecular form will bind directly but very slowly
with the amino acid tyrosine. In the thyroid cells, however, the oxidized iodine is associated with
an iodinase enzyme that causes the process to occur within seconds or minutes.

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

Release of Thyroxine and Triiodothyronine from the Thyroid Gland; Thyroglobulin itself is
not released into the circulating blood in measurable amounts; instead, thyroxine and
triiodothyronine must first be cleaved from the thyroglobulin molecule, and then these free
hormones are released. This process occurs as follows: The apical surface of the thyroid cells
sends out pseudopod extensions that close around small portions of the colloid to
form pinocytic vesicles that enter the apex of the thyroid cell. Then lysosomes in the cell
cytoplasm immediately fuse with these vesicles to form digestive vesicles containing digestive
enzymes from the lysosomes mixed with the colloid. Multiple proteases among the enzymes
digest the thyroglobulin molecules and release thyroxine and triiodothyronine in free form.
These then diffuse through the base of the thyroid cell into the surrounding capillaries. Thus, the
thyroid hormones are released into the blood.

Transport of Thyroxine and Triiodothyronine to Tissues : On entering the blood, over 99 per
cent of the thyroxine and triiodothyronine combines immediately with several of the plasma
proteins, all of which are synthesized by the liver. They combine mainly with thyroxine-binding
globulin and much less so with thyroxine-binding prealbumin and albumin.

Thyroxine and Triiodothyronine are Released Slowly to Tissue Cells. Because of high
affinity of the plasma-binding proteins for the thyroid hormones, these substances— in
particular, thyroxine—are released to the tissue cells slowly. Half the thyroxine in the blood is
released to the tissue cells about every 6 days, whereas half the triiodothyronine—because of its
lower affinity—is released to the cells in about 1 day. On entering the tissue cells, both thyroxine
and triiodothyronine again bind with intracellular proteins, the thyroxine binding more strongly
than the triiodothyronine. Therefore, they are again stored, but this time in the target cells
themselves, and they are used slowly over a period of days or weeks.

Thyroid Hormones Have Slow Onset and Long Duration of Action.: After injection of a
large quantity of thyroxine into a human being, essentially no effect on the metabolic rate can be
discerned for 2 to 3 days, thereby demonstrating that there is a long latent period before
thyroxine activity begins. Once activity does begin, it increases progressively and reaches a
maximum in 10 to 12 days. Thereafter, it decreases with a half-life of about 15 days. Some of the
activity persists for as long as 6 weeks to 2 months. The actions of T3 occur about four times as
rapidly as those of thyroxine, with a latent period as short as 6 to 12 hours and maximal cellular
activity occurring within 2 to 3 days.

Physiologic Functions of the Thyroid Hormones

Thyroid Hormones Increase the Transcription of Large Numbers of Genes

The general effect of thyroid hormone is to activate nuclear transcription of large numbers of
genes. Therefore, in virtually all cells of the body, great numbers of protein enzymes, structural
proteins, transport proteins, and other substances are synthesized. The net result is generalized
increase in functional activity throughout the body.

Most of the Thyroxine Secreted by the Thyroid is Converted to Triiodothyronine: Before acting
on the genes to increase genetic transcription, one iodide is removed from almost all the
thyroxine, thus forming triiodothyronine. Intracellular thyroid hormone receptors have a very
high affinity for triiodothyronine. Consequently, more than 90 per cent of the thyroid hormone
molecules that bind with the receptors is triiodothyronine.

Thyroid Hormones Activate Nuclear Receptors: The thyroid hormone receptors are either
attached to the DNA genetic strands or located in proximity to them. The thyroid hormone
receptor usually forms a heterodimer with retinoid X receptor (RXR) at specific thyroid hormone
response elements on the DNA. On binding with thyroid hormone, the receptors become
activated and initiate the transcription process. Then large numbers of different types of
messenger RNA are formed, followed within another few minutes or hours by RNA translation
on the cytoplasmic ribosomes to form hundreds of new intracellular proteins. However, not all
the proteins are increased by similar percentages—some only slightly, and others at least as
much as six-fold. It is believed that most, if not all, of the actions of thyroid hormone result from
the subsequent enzymatic and other functions of these new proteins.

Thyroid Hormones Increase Cellular Metabolic Activity: The thyroid hormones increase the
metabolic activities of almost all the tissues of the body. The basal metabolic rate can increase to
60 to 100 per cent above normal when large quantities of the hormones are secreted. The rate of
utilization of foods for energy is greatly accelerated. Although the rate of protein synthesis is
increased, at the same time the rate of protein catabolism is also increased. The growth rate of
young people is greatly accelerated. The mental processes are excited, and the activities of most
of the other endocrine glands are increased.

Thyroid Hormones Increase the Number and Activity of Mitochondria. When thyroxine or T3
is given to an animal, the mitochondria in most cells of the animal’s body increase in size as well
as number. Furthermore, the total membrane surface area of the mitochondria increases almost
directly in proportion to the increased metabolic rate of the whole animal. Therefore, one of the
principal functions of thyroxine might be simply to increase the number and activity of
mitochondria, which in turn increases the rate of formation of ATP to energize cellular function.
However, the increase in the number and activity of mitochondria could be the result of
increased activity of the cells as well as the cause of the increase.

Thyroid Hormones increase Active Transport of Ions Through Cell Membranes: One of the
enzymes that increases its activity in response to thyroid hormone is Na+-K+- ATPase. This in
turn increases the rate of transport of both sodium and potassium ions through the cell
membranes of some tissues. Because this process uses energy and increases the amount of heat
produced in the body, it has been suggested that this might be one of the mechanisms by which
thyroid hormone increases the body’s metabolic rate. In fact, thyroid hormone also causes the
cell membranes of most cells to become leaky to sodium ions, which further activates the sodium
pump and further increases heat production.

Regulation of Thyroid Hormone Secretion

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

TSH (from the Anterior Pituitary Gland) increases Thyroid Secretion. TSH, also known as
thyrotropin, is an anterior pituitary hormone, a glycoprotein with a molecular weight of about
28,000. This hormone increases the secretion of thyroxine and T3 by the thyroid gland. Its
specific effects on the thyroid gland are as follows:

1. Increased proteolysis of the thyroglobulin that has already been stored in the follicles, with
resultant release of the thyroid hormones into the circulating blood and diminishment of the
follicular substance itself.

2. Increased activity of the iodide pump, which increases the rate of ―iodide trapping‖ in the
glandular cells, sometimes increasing the ratio of intracellular to extracellular iodide
concentration in the glandular substance to as much as eight times normal.

3. Increased iodination of tyrosine to form the thyroid hormones.

4. Increased size and increased secretory activity of the thyroid cells.

5. Increased number of thyroid cells plus a change from cuboidal to columnar cells and much
infolding of the thyroid epithelium into the follicles
In summary, TSH increases all the known secretory activities of the thyroid glandular cells. The
most important early effect after administration of TSH is to initiate proteolysis of the
thyroglobulin, which causes release of thyroxine and T3 into the blood within 30 minutes. The
other effects require hours or even days and weeks to develop fully.

cAMP Mediates the Stimulatory Effect of TSH. In the past, it was difficult to explain the
many and varied effects of TSH on the thyroid cell. It is now clear that most, if not all, of these
effects result from activation of the ―second messenger‖ cAMP system of the cell. The first event
in this activation is binding of TSH with specific TSH receptors on the basal membrane surfaces
of the thyroid cell. This then activates adenylyl cyclase in the membrane, which increases the
formation of cAMP inside the cell. Finally, the cAMP acts as a second messenger to activate
protein kinase, which causes multiple phosphorylations throughout the cell. The result is both an
immediate increase in secretion of thyroid hormones and prolonged growth of the thyroid
glandular tissue itself. This method for control of thyroid cell activity is similar to the function of
cAMP as a ―second messenger‖ in many other target tissues of the body.

Anterior Pituitary Secretion of TSH is Regulated by Thyrotropin-Releasing Hormone from the

Hypothalamus: Anterior pituitary secretion of TSH is controlled by a hypothalamic hormone,
thyrotropin-releasing hormone (TRH), which is secreted by nerve endings in the median
eminence of the hypothalamus. From the median eminence, the TRH is then transported to the
anterior pituitary by way of the hypothalamic hypophysial portal blood. TRH has been obtained
in pure form. It is a simple substance, a tripeptide amide—pyroglutamyl-histidylproline-amide.
TRH directly affects the anterior pituitary gland cells to increase their output of TSH. When the
blood portal system from the hypothalamus to the anterior pituitary gland becomes blocked, the
rate of secretion of TSH by the anterior pituitary decreases greatly but is not reduced to zero. The
molecular mechanism by which TRH causes the TSH-secreting cells of the anterior pituitary to
produce TSH is first to bind with TRH receptors in the pituitary cell membrane. This in turn
activates the phospholipase second messenger system inside the pituitary cells to produce large
amounts of phospholipase C, followed by a cascade of other second messengers, including
calcium ions and diacyl glycerol, which eventually leads to TSH release.

Effects of Cold and Other Neurogenic Stimuli on TRH and TSH Secretion. One of the best
known stimuli for increasing the rate of TRH secretion by the hypothalamus, and therefore TSH
secretion by the anterior pituitary gland, is exposure of an animal to cold. This effect almost
certainly results from excitation of the hypothalamic centers for body temperature control.
Various emotional reactions can also affect the output of TRH and TSH and therefore indirectly
affect the secretion of thyroid hormones. Excitement and anxiety—conditions that greatly
stimulate the sympathetic nervous system—cause an acute decrease in secretion of TSH, perhaps
because these states increase the metabolic rate and body heat and therefore exert an inverse
effect on the heat control center.
Feedback Effect of Thyroid Hormone to Decrease Anterior Pituitary Secretion of TSH
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. Almost all this feedback depressant effect occurs even
when the anterior pituitary has been separated from the hypothalamus. So, it is probable that
increased thyroid hormone inhibits anterior pituitary secretion of TSH mainly by a direct effect
on the anterior pituitary gland itself. Regardless of the feedback mechanism, its effect is to
maintain 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 substances are thiocyanate, propylthiouracil, and high concentrations of
inorganic iodides. The mechanism by which each of these blocks thyroid secretion is different
from the others, and they can be explained as follows.

Thiocyanate Ions Decrease Iodide Trapping: The same active pump that transports iodide ions
into the thyroid cells can also pump thiocyanate ions, perchlorate ions, and nitrate ions.
Therefore, the administration of thiocyanate (or one of the other ions as well) in high enough
concentration can cause competitive inhibition of iodide transport into the cell— that is,
inhibition of the iodide-trapping mechanism. The decreased availability of iodide in the
glandular cells does not stop the formation of thyroglobulin; it merely prevents the thyroglobulin
from becoming iodinated and therefore from forming the thyroid hormones. This deficiency of
the thyroid hormones in turn leads to increased secretion of TSH by the anterior pituitary gland,
which causes overgrowth of the thyroid gland even though the gland still does not form adequate
quantities of thyroid hormones. Therefore, the use of thiocyanates and some other ions to block
thyroid secretion can lead to development of an enlarged thyroid gland, which is called a goiter.

Propylthiouracil decreases Thyroid Hormone Formation. Propylthiouracil (and other, similar

compounds, such as methimazole and carbimazole) prevents formation of thyroid hormone from
iodides and tyrosine. The mechanism of this is partly to block the peroxidase enzyme that is
required for iodination of tyrosine and partly to block the coupling of two iodinated tyrosines to
form thyroxine or triiodothyronine. Propylthiouracil, like thiocyanate, does not prevent
formation of thyroglobulin. The absence of thyroxine and T3 in the thyroglobulin can lead to
tremendous feedback enhancement of TSH secretion by the anterior pituitary gland, thus
promoting growth of the glandular tissue and forming a goiter.

Iodides in High Concentrations Decrease Thyroid Activity and Thyroid Gland Size: When
iodides are present in the blood in high concentration (100 times the normal plasma level), most
activities of the thyroid gland are decreased, but often they remain decreased for only a few
weeks. The effect is to reduce the rate of iodide trapping, so that the rate of iodination of tyrosine
to form thyroid hormones is also decreased.
Because iodides in high concentrations decrease all phases of thyroid activity, they slightly
decrease the size of the thyroid gland and especially decrease its blood supply, in
contradistinction to the opposite effects caused by most of the other antithyroid agents. For this
reason, iodides are frequently administered to patients for 2 to 3 weeks before surgical removal
of the thyroid gland to decrease the necessary amount of surgery, especially to decrease the
amount of bleeding.

Diseases of the Thyroid

Hyperthyroidism: Causes (Toxic Goiter, Thyrotoxicosis, Graves’ Disease). In most patients
with hyperthyroidism, the thyroid gland is increased to two to three times normal size, with
tremendous hyperplasia and infolding of the follicular cell lining into the follicles, so that the
number of cells is increased greatly. Also, each cell increases its rate of secretion severalfold;
radioactive iodine uptake studies indicate that some of these hyperplastic glands secrete thyroid
hormone at rates 5 to 15 times normal. The changes in the thyroid gland in most instances are
similar to those caused by excessive TSH. However, plasma TSH concentrations are less than
normal rather than enhanced in almost all patients and often are essentially zero. However, other
substances that have actions similar to those of TSH are found in the blood of almost all these
patients. These substances are immunoglobulin antibodies that bind with the same membrane
receptors that bind TSH. They induce continual activation of the cAMP system of the cells, with
resultant development of hyperthyroidism. These antibodies are called thyroid-stimulating
immunoglobulin and are designated TSI. They have a prolonged stimulating effect on the thyroid
gland, lasting for as long as 12 hours, in contrast to a little over 1 hour for TSH. The high level of
thyroid hormone secretion caused by TSI in turn suppresses anterior pituitary formation of TSH.
The antibodies that cause hyperthyroidism almost certainly occur as the result of autoimmunity
that has developed against thyroid tissue. Presumably, at some time in the history of the person,
an excess of thyroid cell antigens was released from the thyroid cells, and this has resulted in the
formation of antibodies against the thyroid gland itself.

Thyroid Adenoma. Hyperthyroidism occasionally results from a localized adenoma (a tumor)

that develops in the thyroid tissue and secretes large quantities of thyroid hormone. This is
different from the more usual type of hyperthyroidism, in that it usually is not associated with
evidence of any autoimmune disease. An interesting effect of the adenoma is that as long as it
continues to secrete large quantities of thyroid hormone, secretory function in the remainder of
the thyroid gland is almost totally inhibited because the thyroid hormone from the adenoma
depresses the production of TSH by the pituitary gland.

Symptoms of Hyperthyroidism: (1) a high state of excitability, (2) intolerance to heat,

(3) increased sweating, (4) mild to extreme weight loss (sometimes as much as 100 pounds),
(5) varying degrees of diarrhea, (6) muscle weakness, (7) nervousness or other psychic disorders,
(8) extreme fatigue but inability to sleep, and (9) tremor of the hands.
Exophthalmos: Most people with hyperthyroidism develop some degree of protrusion of the
eyeball. This condition is called exophthalmos. A major degree of exophthalmos occurs in about
one third of hyperthyroid patients, and the condition sometimes becomes so severe that the
eyeball protrusion stretches the optic nerve enough to damage vision. Much more often, the eyes
are damaged because the eyelids do not close completely when the person blinks or is asleep. As
a result, the epithelial surfaces of the eyes become dry and irritated and often infected, resulting
in ulceration of the cornea.

Diagnostic Tests for Hyperthyroidism. For the usual case of hyperthyroidism, the most
accurate diagnostic test is direct measurement of the concentration of ―free‖ thyroxine (and
sometimes triiodothyronine) in the plasma, using appropriate radioimmunoassay procedures.
Other tests that are sometimes used are as follows:
1. The basal metabolic rate is usually increased to +30 to +60 in severe hyperthyroidism.
2. The concentration of TSH in the plasma is measured by radioimmunoassay. In the usual type
of thyrotoxicosis, anterior pituitary secretion of TSH is so completely suppressed by the large
amounts of circulating thyroxine and triiodothyronine that there is almost no plasma TSH.
3. The concentration of TSI is measured by radioimmunoassay. This is usually high in
thyrotoxicosis but low in thyroid adenoma.
Physiology of Treatment in Hyperthyroidism. The most direct treatment for hyperthyroidism
is surgical removal of most of the thyroid gland. In general, it is desirable to prepare the patient
for surgical removal of the gland before the operation. This is done by administering
propylthiouracil, usually for several weeks, until the basal metabolic rate of the patient has
returned to normal. Then, administration of high concentrations of iodides for 1 to 2 weeks
immediately before operation causes the gland itself to recede in size and its blood supply to
diminish.

Treatment of the Hyperplastic Thyroid Gland with Radioactive Iodine: Eighty to 90 per cent
of an injected dose of iodide is absorbed by the hyperplastic, toxic thyroid gland within 1 day
after injection. If this injected iodine is radioactive, it can destroy most of the secretory cells of
the thyroid gland. Usually 5 millicuries of radioactive iodine is given to the patient, whose
condition is reassessed several weeks later. If the patient is still hyperthyroid, additional doses
are administered until normal thyroid status is reached.

Hypothyroidism
The effects of hypothyroidism, in general, are opposite to those of hyperthyroidism, but there are
a few physiologic mechanisms peculiar to hypothyroidism. Hypothyroidism, like
hyperthyroidism, probably is initiated by autoimmunity against the thyroid gland, but immunity
that destroys the gland rather than stimulates it. The thyroid glands of most of these patients first
have autoimmune ―thyroiditis,‖ which means thyroid inflammation.This causes progressive
deterioration and finally fibrosis of the gland, with resultant diminished or absent secretion of
thyroid hormone. Several other types of hypothyroidism also occur, often associated with
development of enlarged thyroid glands, called thyroid goiter, as follows.
Endemic Colloid Goiter Caused by Dietary Iodide Deficiency. The term ―goiter‖ means a
greatly enlarged thyroid gland. As pointed out in the discussion of iodine metabolism, about 50
milligrams of iodine are required each year for the formation of adequate quantities of thyroid
hormone. In certain areas of the world, notably in the Swiss Alps, the Andes, and the Great
Lakes region of the United States, insufficient iodine is present in the soil for the foodstuffs to
contain even this minute quantity. Therefore, in the days before iodized table salt, many people
who lived in these areas developed extremely large thyroid glands, called endemic goiters. The
mechanism for development of large endemic goiters is the following: Lack of iodine prevents
production of both thyroxine and triiodothyronine. As a result, no hormone is available to inhibit
production of TSH by the anterior pituitary; this causes the pituitary to secrete excessively large
quantities of TSH. The TSH then stimulates the thyroid cells to secrete tremendous amounts of
thyroglobulin colloid into the follicles, and the gland grows larger and larger. But because of
lack of iodine, thyroxine and triiodothyronine production does not occur in the Thyroglobulin
molecule and therefore does not cause the normal suppression of TSH production by the anterior
pituitary. The follicles become tremendous in size, and the thyroid gland may increase to 10 to
20 times normal size.

Idiopathic Nontoxic Colloid Goiter. Enlarged thyroid glands similar to those of endemic
colloid goiter can also occur in people who do not have iodine deficiency. These goitrous glands
may secrete normal quantities of thyroid hormones, but more frequently, the secretion of
hormone is depressed, as in endemic colloid goiter. The exact cause of the enlarged thyroid
gland in patients with idiopathic colloid goiter is not known, but most of these patients show
signs of mild thyroiditis; therefore, it has been suggested that the thyroiditis causes slight
hypothyroidism, which then leads to increased TSH secretion and progressive growth of the
noninflamed portions of the gland. This could explain why these glands usually are nodular, with
some portions of the gland growing while other portions are being destroyed by thyroiditis. In
some persons with colloid goiter, the thyroid gland has an abnormality of the enzyme system
required for formation of the thyroid hormones. Among the abnormalities often encountered are
the following:

1. Deficient iodide-trapping mechanism, in which iodine is not pumped adequately into the
thyroid cells

2. Deficient peroxidase system, in which the iodides are not oxidized to the iodine state

3. Deficient coupling of iodinated tyrosines in the thyroglobulin molecule, so that the final
thyroid hormones cannot be formed

4. Deficiency of the deiodinase enzyme, which prevents recovery of iodine from the iodinated
tyrosines that are not coupled to form the thyroid hormones (this is about two thirds of the
iodine), thus leading to iodine deficiency. Finally, some foods contain goitrogenic substances
that have a propylthiouracil-type of antithyroid activity, thus also leading to TSH-stimulated
enlargement of the thyroid gland. Such goitrogenic substances are found especially in some
varieties of turnips and cabbages.

Physiologic Characteristics of Hypothyroidism. Whether hypothyroidism is due to thyroiditis,

endemic colloid goiter, idiopathic colloid goiter, destruction of the thyroid gland by irradiation,
or surgical removal of the thyroid gland, the physiologic effects are the same. They include
fatigue and extreme somnolence with sleeping up to 12 to 14 hours a day, extreme muscular
sluggishness, slowed heart rate, decreased cardiac output, decreased blood volume, sometimes
increased body weight, constipation, mental sluggishness, failure of many trophic functions in
the body evidenced by depressed growth of hair and scaliness of the skin, development of a
froglike husky voice, and, in severe cases, development of an edematous appearance throughout
the body called myxedema.

Myxedema: Myxedema develops in the patient with almost total lack of thyroid hormone
function. In this condition, for reasons not explained, greatly increased quantities of hyaluronic
acid and chondroitin sulfate bound with protein to form excessive tissue gel in the interstitial
spaces, and this causes the total quantity of interstitial fluid to increase. Because of the gel nature
of the excess fluid, it is mainly immobile, and the edema is the nonpitting type.

Atherosclerosis in Hypothyroidism. As pointed out earlier, lack of thyroid hormone increases

the quantity of blood cholesterol because of altered fat and cholesterol metabolism and
diminished liver excretion of cholesterol in the bile. The increase in blood cholesterol is usually
associated with increased atherosclerosis. Therefore, many hypothyroid patients, particularly
those with myxedema, develop atherosclerosis, which in turn results in peripheral vascular
disease, deafness, and coronary artery disease with consequent early death.

Diagnostic Tests in Hypothyroidism: The tests already described for diagnosis of

hyperthyroidism give opposite results in hypothyroidism. The free thyroxine in the blood is low.
The basal metabolic rate in myxedema ranges between -30 and -50. And the secretion of TSH by
the anterior pituitary when a test dose of TRH is administered is usually greatly increased
(except in those rare instances of hypothyroidism caused by depressed response of the pituitary
gland to TRH).

Treatment of Hypothyroidism. Figure 76–4 shows the effect of thyroxine on the basal
metabolic rate, demonstrating that the hormone normally has a duration of action of more than 1
month. Consequently, it is easy to maintain a steady level of thyroid hormone activity in the
body by daily oral ingestion of a tablet or more containing thyroxine. Furthermore, proper
treatment of the hypothyroid patient results in such complete normality that formerly
myxedematous patients have lived into their 90s after treatment for more than 50 years.
Cretinism

Cretinism is caused by extreme hypothyroidism during fetal life, infancy, or childhood. This
condition is characterized especially by failure of body growth and by mental retardation. It
results from congenital lack of a thyroid gland (congenital cretinism), from failure of the thyroid
gland to produce thyroid hormone because of a genetic defect of the gland, or from iodine lack in
the diet (endemic cretinism). The severity of endemic cretinism varies greatly, depending on the
amount of iodine in the diet, and whole populaces of an endemic geographic iodine-deficient soil
area have been known to have cretinoid tendencies. A neonate without a thyroid gland may have
normal appearance and function because it was supplied with some (but usually not enough)
thyroid hormone by the mother while in utero, but a few weeks after birth, the neonate’s
movements become sluggish and both physical and mental growth begin to be greatly retarded.
Treatment of the neonate with cretinism at any time with adequate iodine or thyroxine usually
causes normal return of physical growth, but unless the cretinism is treated within a few weeks
after birth, mental growth remains permanently retarded.This results from retardation of the
growth, branching, and myelination of the neuronal cells of the central nervous system at this
critical time in the normal development of the mental powers. Skeletal growth in the child with
cretinism is characteristically more inhibited than is soft tissue growth. As a result of this
disproportionate rate of growth, the soft tissues are likely to enlarge excessively, giving the child
with cretinism an obese, stocky, and short appearance. Occasionally the tongue becomes so large
in relation to the skeletal growth that it obstructs swallowing and breathing, inducing a
characteristic guttural breathing that sometimes chokes the child.