LO Endocrine 4.

1 Dapots
1. Thyroid gland
 Histology
The thyroid gland is unusual, in that the hormones are stored in cavities, surrounded by secretory cells,
which make up a 'follicle'. The stored hormone is bound to a glycoprotein, and this stored hormone is called
'colloid'. To secrete the hormone, the hormone is re-absorbed from the cavity, and then released into the
surrounding interstitial spaces.
 Exocrine  Asinar
 Endocrine  Islet of langerhans
 Anatomy
 Location  located in the anterior neck, spanning between the C5 and T1 vertebrae, it lies behind the
sternohyoid and sternothyroid muscles, wrapping around the cricoid cartilage and superior tracheal
rings. It is inferior to the thyroid cartilage of the larynx
 Isthmus  Connect the two lobes of the thyroid, have butterfly shape
 The compartment is bound by pretracheal fascia.
 Vascularization
Artery :
 Superior thyroid artery (right and left)  Dipercabangkan dari external carotid artery 
supplies the superior and anterior portions of the gland
 Inferior thyroid artery (right and left)  Arises from the thyrocervical trunk (which in turn
is a branch of the subclavian artery)  Supplies the postero-inferior aspect

Vein :

Venous drainage is carried out by the superior, middle and inferior thyroid veins, which
form a venous plexus. The superior and middle veins drain into the internal jugular veins,
whereas the inferior drains into the brachiocephalic vein.
 Innervation
The thyroid gland is innervated by branches derived from the sympathetic trunk. However, these
nerves do not control endocrine secretion – release of hormones is regulated by pituitary gland.
Sympathetic nerve : Recurrent laryngeal nerve
The are two recurrent laryngeal nerves; one left and one right. They arise from their respective vagus
nerves, and descend into the chest.
 Physiology

 Synthesis and release of thyroid hormone

Hormones are produced in the colloid when atoms of the mineral iodine attach to a glycoprotein, called
thyroglobulin, that is secreted into the colloid by the follicle cells. The following steps outline the hormones’
assembly:

1. Binding of TSH to its receptors in the follicle cells of the thyroid gland causes the cells to actively
transport iodide ions (I–) across their cell membrane, from the bloodstream into the cytosol. As a result,
the concentration of iodide ions “trapped” in the follicular cells is many times higher than the
concentration in the bloodstream.
2. Iodide ions then move to the lumen of the follicle cells that border the colloid. There, the ions undergo
oxidation (their negatively charged electrons are removed). The oxidation of two iodide ions (2 I –)
results in iodine (I2), which passes through the follicle cell membrane into the colloid.
3. In the colloid, peroxidase enzymes link the iodine to the tyrosine amino acids in thyroglobulin to
produce two intermediaries: a tyrosine attached to one iodine and a tyrosine attached to two iodines.
When one of each of these intermediaries is linked by covalent bonds, the resulting compound is
triiodothyronine (T3), a thyroid hormone with three iodines. Much more commonly, two copies of
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the second intermediary bond, forming tetraiodothyronine, also known as thyroxine (T4), a thyroid
hormone with four iodines.

These hormones remain in the colloid center of the thyroid follicles until TSH stimulates endocytosis of colloid
back into the follicle cells. There, lysosomal enzymes break apart the thyroglobulin colloid, releasing free T 3
and T4, which diffuse across the follicle cell membrane and enter the bloodstream.

In the bloodstream, less than one percent of the circulating T3 and T4 remains unbound. This free T3 and T4 can
cross the lipid bilayer of cell membranes and be taken up by cells. The remaining 99 percent of circulating T3
and T4 is bound to specialized transport proteins called thyroxine-binding globulins (TBGs), to albumin, or to
other plasma proteins. This “packaging” prevents their free diffusion into body cells. When blood levels of T3
and T4 begin to decline, bound T3 and T4 are released from these plasma proteins and readily cross the
membrane of target cells. T3 is more potent than T4, and many cells convert T4 to T3 through the removal of an
iodine atom.

Regulation of TH synthesis

The release of T3 and T4 from the thyroid gland is

regulated by thyroid-stimulating hormone (TSH).
As shown in Figure 2, low blood levels of T3 and T4
stimulate the release of thyrotropin-releasing
hormone (TRH) from the hypothalamus, which
triggers secretion of TSH from the anterior
pituitary. In turn, TSH stimulates the thyroid gland
to secrete T3 and T4. The levels of TRH, TSH, T3, and
T4 are regulated by a negative feedback system in
which increasing levels of T3 and T4 decrease the
production and secretion of TSH.

Functions of Thyroid Hormones

The thyroid hormones, T3 and T4, are often referred

to as metabolic hormones because their levels
influence the body’s basal metabolic rate, the amount of energy used by the body at rest. When T 3 and T4 bind
to intracellular receptors located on the mitochondria, they cause an increase in nutrient breakdown and the
use of oxygen to produce ATP. In addition, T3 and T4 initiate the transcription of genes involved in glucose
oxidation. Although these mechanisms prompt cells to produce more ATP, the process is inefficient, and an
abnormally increased level of heat is released as a byproduct of these reactions. This so-called calorigenic effect
(calor- = “heat”) raises body temperature.

Adequate levels of thyroid hormones are also required for protein synthesis and for fetal and childhood tissue
development and growth. They are especially critical for normal development of the nervous system both in
utero and in early childhood, and they continue to support neurological function in adults. As noted earlier,
these thyroid hormones have a complex interrelationship with reproductive hormones, and deficiencies can
influence libido, fertility, and other aspects of reproductive function. Finally, thyroid hormones increase the
body’s sensitivity to catecholamines (epinephrine and norepinephrine) from the adrenal medulla by
upregulation of receptors in the blood vessels. When levels of T3 and T4 hormones are excessive, this effect
accelerates the heart rate, strengthens the heartbeat, and increases blood pressure. Because thyroid hormones
regulate metabolism, heat production, protein synthesis, and many other body functions, thyroid disorders can
have severe and widespread consequences.

Disorders of the…
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Endocrine System: Iodine Deficiency, Hypothyroidism, and Hyperthyroidism
As discussed above, dietary iodine is required for the synthesis of T 3 and T4. But for much of the world’s
population, foods do not provide adequate levels of this mineral, because the amount varies according to the
level in the soil in which the food was grown, as well as the irrigation and fertilizers used. Marine fish and
shrimp tend to have high levels because they concentrate iodine from seawater, but many people in landlocked
regions lack access to seafood. Thus, the primary source of dietary iodine in many countries is iodized salt.
Fortification of salt with iodine began in the United States in 1924, and international efforts to iodize salt in the
world’s poorest nations continue today.

Dietary iodine deficiency can result in the impaired ability to synthesize T3 and T4, leading to a variety of severe
disorders. When T3 and T4 cannot be produced, TSH is secreted in increasing amounts. As a result of this
hyperstimulation, thyroglobulin accumulates in the thyroid gland follicles, increasing their deposits of colloid.
The accumulation of colloid increases the overall size of the thyroid gland, a condition called a goiter (Figure
3). A goiter is only a visible indication of the deficiency. Other iodine deficiency disorders include impaired
growth and development, decreased fertility, and prenatal and infant death. Moreover, iodine deficiency is the
primary cause of preventable mental retardation worldwide. Neonatal hypothyroidism (cretinism) is
characterized by cognitive deficits, short stature, and sometimes deafness and muteness in children and adults
born to mothers who were iodine-deficient during pregnancy.

In areas of the world with access to iodized salt, dietary deficiency is rare. Instead, inflammation of the thyroid
gland is the more common cause of low blood levels of thyroid hormones. Called hypothyroidism, the
condition is characterized by a low metabolic rate, weight gain, cold extremities, constipation, reduced libido,
menstrual irregularities, and reduced mental activity. In contrast, hyperthyroidism—an abnormally elevated
blood level of thyroid hormones—is often caused by a pituitary or thyroid tumor. In Graves’ disease, the
hyperthyroid state results from an autoimmune reaction in which antibodies overstimulate the follicle cells of
the thyroid gland. Hyperthyroidism can lead to an increased metabolic rate, excessive body heat and sweating,
diarrhea, weight loss, tremors, and increased heart rate. The person’s eyes may bulge (called exophthalmos) as
antibodies produce inflammation in the soft tissues of the orbits. The person may also develop a goiter.

Calcitonin

The thyroid gland also secretes a hormone called calcitonin that is produced by the parafollicular cells (also
called C cells) that stud the tissue between distinct follicles. Calcitonin is released in response to a rise in blood
calcium levels. It appears to have a function in decreasing blood calcium concentrations by:

 Inhibiting the activity of osteoclasts, bone cells that release calcium into the circulation by degrading
bone matrix
 Increasing osteoblastic activity
 Decreasing calcium absorption in the intestines
 Increasing calcium loss in the urine

However, these functions are usually not significant in maintaining calcium homeostasis, so the importance of
calcitonin is not entirely understood. Pharmaceutical preparations of calcitonin are sometimes prescribed to
reduce osteoclast activity in people with osteoporosis and to reduce the degradation of cartilage in people with
osteoarthritis. The hormones secreted by thyroid are summarized in Table 4.
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Hyperthyroidism

Hyperthyroidism is a condition in which the thyroid gland is overactive and makes excessive amounts of
thyroid hormone. It's about 10 times more common in women than men and it typically starts between 20 and
40 years of age.

 Primary hyperthyroidism
Means that the cause of hyperthyroidism is due to the malfunctioning of the thyroid gland. The gland
produces excess thyroid hormones and causes hypermetabolism. Causes of primary hyperthyroidism
include Graves’ disease, thyroiditis, multinodular goiter, or a single hyperfunctioning “hot” nodules.
Common diseases that cause primary hyperthyroidism include Graves disease, toxic multinodular
goiter, a solitary toxic adenoma and follicular thyroid carcinoma. Primary thyroid disorders result in
alterations of thyroid hormone (TH) levels with secondary feedback effects on pituitary TSH levels. For
example, when there are primary elevations in TH level, TSH level will secondarily decrease because of
negative feedback. When TH level is decreased because of a condition affecting the thyroid gland, TSH
level will be elevated.
 Secondary (central) hyperthyroidism
Caused by dysfunctions outside the thyroid gland. The main cause of secondary hyperthyroidism is a
thyroid stimulating hormone (TSH) secreting pituitary adenoma or benign tumor found on the pituitary
gland. Other causes include gestational thyrotoxicosis (hyperthyroidism during pregnancy), and a
human chorionic gonadotropin-producing tumor.
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Other signs :

- Exophthalmos  Protrusion of the eyeballs. The condition sometimes becoming 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. The cause of the protruding eyes is edematous swelling of the retro-orbital tissues and
degenerative changes in the extraocular muscles.
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Differential Diagnosis
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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.

 An antithyroid antibody test to see if you have the kind of antibodies that attack thyroid tissue. This test
can help diagnose Graves' disease and autoimmune thyroiditis.
 A radioactive thyroid scan and radioactive iodine uptake tests, which use radiation and a special camera
to find out the cause of your hyperthyroidism. If you have Graves' ophthalmopathy, your doctor may
also do an ultrasound, an MRI, or a CT scan to look more closely at your eyes.
 TSH (Thyroid-Stimulating Hormone or Thyrotropin) Test - A low TSH level in the blood is the most
accurate indicator of hyperthyroidism. The body shuts off production of this pituitary hormone when
the thyroid gland even slightly overproduces thyroid hormone. If the TSH level is low, it is very
important to also check thyroid hormone levels to confirm the diagnosis of hyperthyroidism.
 Estimates of free thyroxine and free triiodothyronine – the active thyroid hormones in the blood. When
hyperthyroidism develops, free thyroxine and free triiodothyronine levels rise above previous values in
that specific patient (although they may still fall within the normal range for the general population)
and are often considerably elevated.
 TSI (thyroid-stimulating immunoglobulin) - a substance often found in the blood when Graves’ disease
is the cause of hyperthyroidism.
 Radioactive iodine uptake (RAIU) - a measurement of how much iodine the thyroid gland can collect,
and thyroid scan, which shows how the iodine is distributed throughout the thyroid gland. This
information can be useful in determining the cause of hyperthyroidism and, ultimately, its treatment.
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Hyperthyroidism complications :

 Heart problems  Some of the most serious complications of hyperthyroidism involve the heart. These
include a rapid heart rate, a heart rhythm disorder called atrial fibrillation and congestive heart failure
— a condition in which your heart can't circulate enough blood to meet your body's needs.
 Osteoporosis  Uncontrolled hyperthyroidism can cause your body to pull calcium and phosphate out
of the bones and to excrete too much calcium and phosphorous (through the urine and stool).
 Eye problems  People with Graves' ophthalmopathy develop eye problems, including bulging, red or
swollen eyes, sensitivity to light, and blurring or double vision. Untreated, severe eye problems can lead
to vision loss.
 Thyrotoxic crisis  Hyperthyroidism also places you at risk of thyrotoxic crisis — a sudden
intensification of your symptoms, leading to a fever, a rapid pulse and even delirium. If this occurs, seek
immediate medical care.

Hyperthyroidism prognosis :

The prognosis for a patient with hyperthyroidism is good with appropriate treatment. Even with aggressive
treatment, some manifestations of the disease may be irreversible, including ocular, cardiac, and psychologic
complications. Patients treated for hyperthyroidism have an increased all-cause mortality risk, as well as
increased risk of mortality from thyroid, cardiovascular and cerebrovascular diseases, and hip fractures.
Morbidity can be attributed to the same causes, and patients should be screened and treated for osteoporosis
and atherosclerotic risk factors. Patients who have been treated previously for hyperthyroidism have an
increased incidence of obesity and insulin resistance. The effect of hyperthyroidism on endothelial function
may be an independent risk factor for thromboembolism.

Thyroxine

Thyroxine is a hormone the thyroid gland secretes into the bloodstream. Once in the bloodstream, thyroxine
travels to the organs, like the liver and kidneys, where it is converted to its active form of triiodothyronine.
Thyroxine plays a crucial role in heart and digestive function, metabolism, brain development, bone health,
and muscle control. It affects almost all of the body's systems, which means proper thyroxine levels are vital for
health. This is why many doctors will test T4 levels along with the more common T3 levels when testing for
thyroid disorders.

Triiodothyronine

Receptors for thyroid hormones are intracellular DNA-binding proteins that function as hormone-responsive
transcription factors, very similar conceptually to thereceptors for steroid hormones.Thyroid hormones enter
cells through membrane transporter proteins. A number of plasma membrane transporters have been
identified, some of which require ATP hydrolysis; the relative importance of different carrier systems isnot yet
clear and may differ among tissues. Once inside the nucleus, the hormone binds its receptor, and the hormone-
receptor complex interacts with specific sequences of DNA in the promoters of responsive genes.The effect of
the hormone-receptor complex binding to DNA is to modulate gene expression, either by stimulating or
inhibiting transcription of specific genes.Thyroid hormones stimulate diversemetabolic activities most tissues,
leading to an increase in basal metabolic rate. One consequence of this activity is to increase body heat
production, which seems to result, at least inpart, from increased oxygen consumption and rates of ATP
hydrolysis. By way of analogy, the action of thyroid hormones is akin to blowing on a smouldering fire. A few
examples of specific metabolic effects of thyroid hormones include:
*.Lipid metabolism: Increased thyroid hormone levels stimulate fat mobilization, leading to increased
concentrations of fatty acids in plasma. They also enhance oxidation of fatty acids in many tissues. Finally,
plasma concentrations of cholesterol and triglycerides are inversely correlated with thyroid hormone levels -
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one diagnostic indiction of hypothyroidism is increased blood cholesterol concentration.
*.Carbohydrate metabolism: Thyroid hormones stimulate almost all aspects of carbohydrate metabolism,
including enhancement of insulin-dependent entry of glucose into cells and increased gluconeogenesis and
glycogenolysis to generate free glucose.

Calcitonin

Calcitonin is a hormone formed by parafollicular cells (so-called C-cells) of the thyroid gland. From the
chemical point of view it is a 32 amino acid long peptide and the whole molecule determines its biological
activity. By an alternative splicing of its gene another peptide is formed – termed CGRP (calcitonin gene
related peptide). The half-life of calcitonin is about 10 minutes.

Calcitonin decreases the plasma level of calcium through 3 main mechanisms:

1) Inhibition of ionized calcium absorption from intestines

2) Inhibition of calcium reabsorption in renal tubuli

3) Inhibition of osteoclasts activity