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Describe the anatomical shape and location of the thyroid and parathyroid glands, and
explain why the thyroid gland moves during swallowing.
Describe the blood supply to the thyroid gland, and describe the nerves that are related
to these vessels.
Describe how the cells of the thyroid gland are arranged, and how this relates to
hormone synthesis.
Envisage how the thyroid and parathyroid glands develop in the embryo.
List the hormones secreted by the thyroid gland, and describe their actions.
T
4
a prohormone that acts as a plasma reservoir.
T
3
the active hormone.
Disease of the thyroid gland is the second most com-
mon endocrine disorder, after diabetes. Thyroid dis-
ease ranges from the production of too much or too
little of the thyroid hormones, to the development of
neoplasia. Excessive release of thyroid hormones in
the presence of normally functioning downstream
pathways is referred to as hyperthyroidism. These
patients tend to be hyperactive, heat sensitive and to
lose weight. Insufficient thyroid hormone is called
hypothyroidism, and is associated with a slow metab-
olism, making patients feel lethargic and gain weight.
ANATOMY
Overview
The thyroid gland is palpable in about 50% of women
and 25% of men. It is located in the neck, inferior to the
larynx and cricoid cartilage. It has two lobes, each about
5 cm long and joined by a narrow isthmus. The lobes lie
either side of the trachea and oesophagus, and the isth-
mus crosses the trachea anteriorly, usually over the
second and third tracheal cartilages (Fig. 3.2).
31
Ch03-M3427.qxd 3/5/07 12:02 AM Page 31
The thyroid gland
The thyroid gland is surrounded by a fibrous cap-
sule derived from the pretracheal layer of the deep cer-
vical fascia (Fig. 3.3). Extensions of this capsule into
the body of the thyroid create septae, which divide the
gland into lobules. This connective tissue firmly con-
nects the thyroid to the larynx and explains why the
thyroid moves on swallowing.
Blood supply, nerves, and
lymphatics
The thyroid is highly vascular, and a bruit (the sound
of turbulent blood flow) is sometimes heard in over-
active glands. It is supplied by two arteries that anas-
tomose (join) within the gland: the inferior and
superior thyroid arteries.
The inferior thyroid artery is a branch of the thyro-
cervical trunk that arises from the subclavian arteries.
It ascends behind the carotid sheath to enter the thy-
roid posteriorly. The right recurrent laryngeal nerve is
intimately related to this artery near the inferior pole
of the thyroid gland. Surgery to the thyroid gland can
damage this nerve, causing temporary difficulty with
speaking. To minimize the risk to this nerve, the artery
is ligated far away from the thyroid gland during thy-
roidectomy.
The superior thyroid artery is usually the first
branch of the external carotid artery. The external
laryngeal nerve is related to this artery, but it is at less
risk than the recurrent laryngeal during thyroid
surgery. The superior thyroid artery is ligated close to
the thyroid gland to reduce this risk (Fig. 3.2).
A third artery, called the thyroid ima artery, is present
in 10% of people. It supplies the isthmus and it arises
near the aortic arch, although the exact origin varies.
The thyroid gland is drained by three veins:
Thyroxine (T
4
).
Tri-iodothyronine (T
3
).
Calcitonin.
Calcitonin is involved with calcium homeostasis (dis-
cussed in Chapter 8).
Synthesis
T
4
and the less abundant but more potent T
3
are syn-
thesized in a step-by-step process that takes place in
both the colloid and the follicular cells. Thyroid hor-
mones are lipophilic, and therefore must be bound
up as residues of the thyroglobulin molecule during
synthesis in order to restrict their movements.
Thyroglobulin in the colloid acts as a precursor and
storage form of thyroid hormones. T
3
and T
4
are syn-
thesized by three or four iodination reactions, respec-
tively, of tyrosyl residues in thyroglobulin. Their
structures are shown in Fig. 3.5.
Thyroid hormones are formed in the lumen of fol-
licles, not in the cells. The process of T
3
and T
4
syn-
thesis involves the processing of tyrosine and iodine
followed by a reaction to bind them together. These
steps are also shown in Fig. 3.6.
Tyrosine processing is relatively simple, since tyro-
sine molecules are already within the cell:
Thyroglobulin synthesis Tyrosine is converted into
the glycoprotein thyroglobulin, which contains
approximately 110 tyrosine residues.
The processing of iodine involves two stages as
plasma iodine concentrations are very low:
Iodine trapping Plasma iodide ions (I
) are actively
transported from the plasma into the follicular cells
against a steep concentration gradient by the Na/I
symporter (NIS). This is a rate-limiting step.
Iodide oxidation I
T
3
is made from T
1
+ T
2
.
T
4
is made from T
2
+ T
2
.
Only a small proportion of coupling reactions form
T
3
and T
4
.
The thyroid hormones can now be released on
demand:
Secretion Under the direction of thyroid-
stimulating hormone (TSH or thyrotrophin),
iodinated thyroglobulin is taken into the follicular
cells by pinocytosis and degraded by lysosomal
enzymes. Coupled tyrosine molecules are released,
including some T
3
and T
4
. Some T
4
is converted to T
3
in the follicular cell cytoplasm by the enzyme type
1,5deiodinase. Whilst the secreted ratio of T
4
:T
3
is
usually 20:1 conversion to T
3
is promoted by TSH
stimulation and can result in the so-called T
3
34
The thyroid gland
HO O
I
I
I
I
CH
2
CH
NH
2
COOH
Thyroxine (T
4
)
HO O
I I
I
CH
2
CH
NH
2
COOH
Tri-iodothyronine (T
3
)
Fig. 3.5 Structures of T
3
and T
4
.
Ch03-M3427.qxd 3/5/07 12:02 AM Page 34
Running head
thyrotoxicosis. MIT and DIT are also released, but
they are deiodinated by iodotyrosine deholgenase to
recycle iodine.
Iodine metabolism
Iodine is acquired from the diet mainly from iodized
salt, meat and vegetables. About 150 mg of iodine is
needed per day, though only a fraction of this is
absorbed. The thyroid gland cells are the only cells that
can actively absorb and utilize plasma iodine; a con-
siderable quantity of iodine is stored in the thyroid as
preformed thyroid hormones. Iodine is returned to the
plasma by the breakdown of these thyroid hormones.
Iodine is excreted mainly via the kidneys.
Regulation
Hypothalamic thyrotrophin-releasing hormone (TRH)
stimulates the release of thyroid-stimulating hormone
(TSH) from thyrotrophs in the anterior pituitary gland
and also causes upregulation of TSH gene transcrip-
tion. TSH acts on extracellular receptors (TSH-R) on
the surface of thyroid follicle cells, activating the G-
proteinadenyl-cyclasecAMP and phophatidylinosi-
tol (PIP
2
) pathways. Ultimately, TSH stimulates the
following processes in the thyroid gland:
Iodine uptake.
Iodination.
35
3 Hormones
T
4
T
2
T
4
T
4
T
4
T
3
T
1
T
3
T
1
,T
4
I
ATPase
iodine
trapping
thyroglobulin
synthesis
peroxidase
I
2
T
1
+ T
2
T
3
+ T
4
T
4
T
T
T
T
T
tyrosine
T
T
T
T
2
T
1
T
2
T
2
T
1
T
T
2
coupling
secretion
thyroglobulin
colloid
i
o
d
i
n
a
t
i
o
n
follicular cells
iodine
oxidation
The majority of plasma T
3
is formed by
the deiodination of T
4
, and not from the
thyroid gland. This is important in the
treatment of hypothyroidism, since only T
4
is given
Thiacarbimide drugs, such as carbimazole, used in the
treatment of hyperthyroidism, inhibit thyroid
peroxidase. This inhibition results in decreased
oxidation of iodide, decreased iodination of iodides
and ultimately reduced thyroid hormone production.
Fig. 3.6 Steps in the synthesis and secretion
of T
3
and T
4
. (T
3
, tri-iodothyronine; T
4
,
thyroxine.)
Ch03-M3427.qxd 3/5/07 12:02 AM Page 35
The thyroid gland
Coupling.
T
4
has a longer half-life (7 days vs 1 day).
Actions
Fig. 3.7 describes some of the differences between T
4
and T
3
. T
4
is a relatively inactive, stable molecule that
can be thought of as a prohormone. T
3
is the active
hormone, since it is readily available and it has more
effect on receptors. The benefit of producing both
hormones is that T
4
can maintain a background level
of activity, whilst T
3
levels can adapt rapidly to chang-
ing environments.
Peripheral tissues can regulate local T
3
levels by
increasing or decreasing T
3
synthesis. T
4
is converted
to T
3
by deiodination, i.e. removal of one iodine atom
catalysed by deiodinase enzymes. Two main forms of
this enzyme have been found:
Hypothyroidismdeficiency of thyroid
hormone production.
Goitre formation.
Thyroid cysts.
Follicular adenoma.
Malignancy.
Five separate forms of cancer can arise in the thyroid
gland, but three of these are derived from the follicle
cells. These tumours are summarized in Fig. 3.11.
Medullary carcinomas of the parafollicular cells
often secrete ectopic hormones, including:
Calcitoninusually asymptomatic.