Ch03-M3427.qxd 3/5/07 12:02 AM Page 31
The thyroid gland 3
By the end of this chapter you should be able to:
• 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
• Envisage how the thyroid and parathyroid glands develop in the embryo.
• List the hormones secreted by the thyroid gland, and describe their actions.
• Describe thyroid hormone synthesis.
• Explain the endocrine control of the thyroid gland.
• State the main causes, symptoms and signs of thyrotoxicosis.
• State the main causes, symptoms and signs of hypothyroidism.
• Describe the treatment of hyperthyroidism and hypothyroidism.
Hormones convey information that maintains • T4—a prohormone that acts as a plasma reservoir.
homeostasis. Levels of thyroid hormone do not • T3—the active hormone.
fluctuate greatly under normal physiological con- Disease of the thyroid gland is the second most com-
ditions, and the hormone therefore acts more like mon endocrine disorder, after diabetes. Thyroid dis-
a substrate that maintains cellular processes than a ease ranges from the production of too much or too
hormone that regulates cellular processes. Nonetheless, little of the thyroid hormones, to the development of
pathological fluctuations in thyroid hormone neoplasia. Excessive release of thyroid hormones in
levels cause significant problems, which makes this the presence of normally functioning downstream
system an important area of study. pathways is referred to as hyperthyroidism. These
The thyroid, from the Greek ‘thyreoeides’, mean- patients tend to be hyperactive, heat sensitive and to
ing shield shaped, is made up of two lobes and a lose weight. Insufficient thyroid hormone is called
bridging ‘isthmus’. The gland consists of spherical hypothyroidism, and is associated with a slow metab-
‘follicles’, which are composed of an outer base- olism, making patients feel lethargic and gain weight.
ment membrane, a peripheral layer of follicular
cells and a core of proteinaceous colloid. The thy-
roid hormones are synthesized and stored in these
follicles and are dependent on an adequate iodine
supply. The thyroid gland acts as a store of iodine
and, in evolutionary terms, has allowed animals to Overview
migrate away from the ocean, the primary source of The thyroid gland is palpable in about 50% of women
iodine. Thyroid hormone levels are regulated by a and 25% of men. It is located in the neck, inferior to the
multiplex negative feedback loop with control from larynx and cricoid cartilage. It has two lobes, each about
the hypothalamic–pituitary axis and autoregulation 5 cm long and joined by a narrow isthmus. The lobes lie
within the thyroid itself. The end product of this either side of the trachea and oesophagus, and the isth-
process is the production of the two thyroid hor- mus crosses the trachea anteriorly, usually over the
mones (Fig. 3.1): second and third tracheal cartilages (Fig. 3.2).
Ch03-M3427.qxd 3/5/07 12:02 AM Page 32
The thyroid gland
cold stress laryngeal cartilage
hypothalamus superior superior
TRH thyroid thyroid
anterior isthmus thyroid
pituitary of thyroid vein
TSH + oestrogen
– + +
feedback recurrent trachea
loop T4 T3 laryngeal nerve
Fig. 3.2 Anterior view of the neck, showing the location and blood
supply of the thyroid gland.
production of CNS
The inferior thyroid artery is a branch of the thyro-
cervical trunk that arises from the subclavian arteries.
increased increased use It ascends behind the carotid sheath to enter the thy-
rate of and availability roid posteriorly. The right recurrent laryngeal nerve is
metabolism of metabolites
intimately related to this artery near the inferior pole
of the thyroid gland. Surgery to the thyroid gland can
Fig. 3.1 Hormonal regulation of the thyroid hormones. (T3, tri- damage this nerve, causing temporary difficulty with
iodothyronine; T4, thyroxine; TRH, thyrotrophin-releasing hormone; speaking. To minimize the risk to this nerve, the artery
TSH, thyroid-stimulating hormone.)
is ligated far away from the thyroid gland during thy-
The superior thyroid artery is usually the first
branch of the external carotid artery. The external
The thyroid gland is surrounded by a fibrous cap-
laryngeal nerve is related to this artery, but it is at less
sule derived from the pretracheal layer of the deep cer-
risk than the recurrent laryngeal during thyroid
vical fascia (Fig. 3.3). Extensions of this capsule into
surgery. The superior thyroid artery is ligated close to
the body of the thyroid create septae, which divide the
the thyroid gland to reduce this risk (Fig. 3.2).
gland into lobules. This connective tissue firmly con-
A third artery, called the thyroid ima artery, is present
nects the thyroid to the larynx and explains why the
in 10% of people. It supplies the isthmus and it arises
thyroid moves on swallowing.
near the aortic arch, although the exact origin varies.
The thyroid gland is drained by three veins:
Blood supply, nerves, and
lymphatics • Superior thyroid vein.
• Middle thyroid vein.
The thyroid is highly vascular, and a bruit (the sound
• Inferior thyroid vein.
of turbulent blood flow) is sometimes heard in over-
active glands. It is supplied by two arteries that anas- The first two veins drain into the internal jugular,
tomose (join) within the gland: the inferior and whereas the inferior vein drains into the brachio-
superior thyroid arteries. cephalic veins.
Ch03-M3427.qxd 3/5/07 12:02 AM Page 33
Fig. 3.3 Horizontal section of the anterior
isthmus neck at the level of the sixth cervical
cartilage vertebra, showing the location of the
skin anterior thyroid and parathyroid glands and their
carotid sheath contains recurrent laryngeal oesophagus
internal jugular vein nerve
Thyroid lymphatics drain into four groups of DEVELOPMENT
• Prelaryngeal lymph nodes. The thyroid gland develops from an endodermal
• Pretracheal lymph nodes. extension in the floor of the pharynx known as the
• Paratracheal lymph nodes. thyroglossal duct. The thyroglossal duct descends
• Deep cervical lymph nodes.
MICROSTRUCTURE sympathetic and lumen containing large network of
parasympathetic thyroglobin colloid fenestrated capillaries
nerves supply gland supply the gland
The thyroid is composed of about one million spher-
ical follicles or acini. Each follicle is lined by a single
layer of secretory epithelial cells (follicular cells)
around a colloid-filled space. These cells secrete thy-
roglobulin into the lumen of the follicle, and thyroid
hormones are synthesized from thyroglobulin at the
cell–colloid boundary. When the thyroid gland is not
actively secreting hormones, the size of the colloid
store and the follicle itself increase in diameter.
When the follicular cells enter an active secretory
phase, microvilli form on their inner surface and thy-
roglobulin is absorbed. The colloid store shrinks as a lymphatics
result. The absorbed thyroglobulin is broken down to
cuboidal/columnar parafollicular cells thyroid follicle
release thyroid hormone. The histology of the thyroid follicle cells surround (C cells) are outside
gland is shown in Fig. 3.4. each follicle follicles but within
Another type of secretory cell is found between the surrounding follicle
follicles. These parafollicular cells (C cells) synthesize
and secrete calcitonin. Fig. 3.4 Histology of the thyroid gland.
Ch03-M3427.qxd 3/5/07 12:02 AM Page 34
The thyroid gland
through the tongue and usually degenerates when the
thyroid develops. The vestigial marking of the thy-
roglossal duct is the foramen cecum of the tongue. NH2
Remnants of thyroglossal duct anywhere else in its track
HO O CH2 CH
can develop into a thyroglossal cyst. These present as
neck lumps that rise when the tongue is protruded. In COOH
50% of people a remnant of this duct forms a small I I
pyramidal lobe extending superiorly from the isthmus.
The parafollicular (C) cells are derived from the neural Tri-iodothyronine (T3)
crest. I I
HO O CH2 CH
The thyroid gland synthesizes and secretes three hor-
Fig. 3.5 Structures of T3 and T4.
• Thyroxine (T4).
• Tri-iodothyronine (T3). against a steep concentration gradient by the Na/I
• Calcitonin. symporter (NIS). This is a rate-limiting step.
Calcitonin is involved with calcium homeostasis (dis- Iodide oxidation I is rapidly oxidized into iodine (I2)
cussed in Chapter 8). by thyroid peroxidase (TPO) anchored on the
luminal surface of the follicular cell membrane.
Synthesis The two components are then combined in the col-
T4 and the less abundant but more potent T3 are syn- loidal lumen:
thesized in a step-by-step process that takes place in Iodination of thyroglobulin Reactive iodine rapidly
both the colloid and the follicular cells. Thyroid hor- attaches to the tyrosine molecules within the
mones are lipophilic, and therefore must be bound extracellular thyroglobulin in a process that is
up as residues of the thyroglobulin molecule during catalysed by TPO. Monoiodotyrosine (MIT or T1)
synthesis in order to restrict their movements. and diiodotyrosine (DIT or T2) are formed.
Thyroglobulin in the colloid acts as a precursor and
Coupling Tyrosine molecules within thyroglobulin
storage form of thyroid hormones. T3 and T4 are syn-
are then coupled together. Combinations of T1 and
thesized by three or four iodination reactions, respec-
T2 can form thyroid hormones:
tively, of tyrosyl residues in thyroglobulin. Their
structures are shown in Fig. 3.5. • T3 is made from T1 + T2.
Thyroid hormones are formed in the lumen of fol- • T4 is made from T2 + T2.
licles, not in the cells. The process of T3 and T4 syn-
Only a small proportion of coupling reactions form
thesis involves the processing of tyrosine and iodine
T3 and T4.
followed by a reaction to bind them together. These
The thyroid hormones can now be released on
steps are also shown in Fig. 3.6.
Tyrosine processing is relatively simple, since tyro-
Secretion Under the direction of thyroid-
sine molecules are already within the cell:
stimulating hormone (TSH or thyrotrophin),
Thyroglobulin synthesis Tyrosine is converted into iodinated thyroglobulin is taken into the follicular
the glycoprotein thyroglobulin, which contains cells by pinocytosis and degraded by lysosomal
approximately 110 tyrosine residues. enzymes. Coupled tyrosine molecules are released,
including some T3 and T4. Some T4 is converted to T3
The processing of iodine involves two stages as
in the follicular cell cytoplasm by the enzyme type
plasma iodine concentrations are very low:
1,5’deiodinase. Whilst the secreted ratio of T4:T3 is
Iodine trapping Plasma iodide ions (I–) are actively usually 20:1 conversion to T3 is promoted by TSH
transported from the plasma into the follicular cells stimulation and can result in the so-called T3
Ch03-M3427.qxd 3/5/07 12:02 AM Page 35
Fig. 3.6 Steps in the synthesis and secretion
I− of T3 and T4. (T3, tri-iodothyronine; T4,
T3 + T 4 T2
T1 + T 2 T1 T4 T2
T3 T4 T
I− T4 T T
thyrotoxicosis. MIT and DIT are also released, but
they are deiodinated by iodotyrosine deholgenase to Thiacarbimide drugs, such as carbimazole, used in the
recycle iodine. treatment of hyperthyroidism, inhibit thyroid
peroxidase. This inhibition results in decreased
oxidation of iodide, decreased iodination of iodides
and ultimately reduced thyroid hormone production.
The majority of plasma T3 is formed by
the deiodination of T4, and not from the
thyroid gland. This is important in the
treatment of hypothyroidism, since only T4 is given 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
Iodine is acquired from the diet mainly from iodized the surface of thyroid follicle cells, activating the G-
salt, meat and vegetables. About 150 mg of iodine is protein–adenyl-cyclase–cAMP and phophatidylinosi-
needed per day, though only a fraction of this is tol (PIP2) pathways. Ultimately, TSH stimulates the
absorbed. The thyroid gland cells are the only cells that following processes in the thyroid gland:
can actively absorb and utilize plasma iodine; a con-
siderable quantity of iodine is stored in the thyroid as • Iodine uptake.
preformed thyroid hormones. Iodine is returned to the • Transcription of thyroglobulin and thyroid
plasma by the breakdown of these thyroid hormones. peroxidase.
Iodine is excreted mainly via the kidneys. • Iodination.
Ch03-M3427.qxd 3/5/07 12:02 AM Page 36
The thyroid gland
Fig. 3.7 Comparison of T3 and T4
• Type 1 5’deiodinase conversion of T4 to T3.
• Pinocytosis and secretion of thyroid hormones. T3 T4
As a result, T3 and T4 are synthesized and secreted Proportion of secreted thyroid hormone 10% 90%
more rapidly (see Fig. 3.1). TSH also has long-term Percentage free in plasma 1% 0.1%
actions on the thyroid gland by increasing its size and Relative activity 10 1
vascularity to improve hormone synthesis.
Half-life (days) 1 7
A number of factors affect thyroid hormone
release. Three main factors stimulate secretion:
• Long-term exposure to cold temperatures acting
on the anterior pituitary.
• Oestrogens acting on the anterior pituitary. • Type 1—mostly in liver and kidney but also in
other tissues. It supplies plasma with T3 and is
• Adrenaline acting directly on the thyroid gland.
inhibited by the propylthiouracil that is used to
TSH forms part of a negative feedback loop, as its release treat hyperthyroidism.
is inhibited by increased serum T3 and T4 and also by • Type 2—intracellular enzymes that maintain
somatostatin, glucocorticoids and chronic illness. constant T3 in the central nervous system (CNS)
and pituitary gland in the face of rising plasma T4.
Transport of thyroid hormones
A further deiodinase enzyme can remove a different
The thyroid hormones circulate bound to plasma pro-
iodine molecule from T4 to form reverse T3 (rT3). This
teins produced in the liver, which protect the hor-
is an inactive molecule that is rapidly cleared from the
mones from enzymic attack:
circulation by the kidney and liver. Production of rT3
• 70% are bound to thyroid-binding globulin is favoured by low energy stores and illness when
(TBG). energy stores need to be conserved.
• 30% are bound to albumin. Free plasma T3 enters cells and binds to intracellu-
lar T3 receptors, which are capable of binding specific
Only 0.1% of T4 and 1% of T3 are carried unbound—
sequences (or thyroid response elements) of DNA.
it is this free (unbound) fraction that is responsible
Accordingly, after a lag of several hours, the expression
for their hormonal activities.
of various thyroid response genes is up- or downreg-
Both T3 and T4 can cross cell membranes, though a
ulated. The intracellular actions are described in
carrier transport may be involved.
Fig. 3.8 and related to physiological effects.
The concentration of circulating T4 is much higher
In general, T3 promotes energy production in every
than that of T3 (50:1). There are two reasons for this:
cell in the body. This causes heat production and
• The thyroid secretes more T4 than T3. maintains metabolism.
• T4 has a longer half-life (7 days vs 1 day).
Fig. 3.7 describes some of the differences between T4 The thyroid gland is the only endocrine
and T3. T4 is a relatively inactive, stable molecule that gland to store its hormone in an
can be thought of as a prohormone. T3 is the active extracellular compartment. 2–3 months’
hormone, since it is readily available and it has more supply of thyroid hormone are stored within the
effect on receptors. The benefit of producing both follicles, and this delays the onset of symptoms in
hormones is that T4 can maintain a background level deficiency diseases.
of activity, whilst T3 levels can adapt rapidly to chang-
Peripheral tissues can regulate local T3 levels by
increasing or decreasing T3 synthesis. T4 is converted
to T3 by deiodination, i.e. removal of one iodine atom T3 receptors are also found in the pituitary gland and
catalysed by deiodinase enzymes. Two main forms of the hypothalamus, where they inhibit transcription
this enzyme have been found: of the gene for TRH prohormone and the release of
Ch03-M3427.qxd 3/5/07 12:02 AM Page 37
Disorders of the thyroid gland 3
Fig. 3.8 Intracellular and physiological actions of T3
Site of action Intracellular effects Physiological results
Cell membrane Stimulates the Na+/K+ATPase Increased demand for
pump metabolites, e.g. glucose
Mitochondria Stimulates growth, replication Increased heat production,
and activity; basal metabolic oxygen demand, heart rate
rate is raised and stroke volume
Nucleus Increases expression of Lipolysis, glycolysis and
enzymes necessary for energy gluconeogenesis increased to
production raise blood metabolite levels
and cellular metabolite use
Neonatal cells Essential for cell division and Essential for normal
maturation development of CNS
TSH, respectively. Excess T3 inhibits TSH release while (thyrotoxicosis factitia) or ectopic hormone produc-
a deficiency of T3 stimulates TSH release. This feed- tion (ovarian struma or metastatic thyroid cancer) It
back mechanism helps to maintain T3 levels, and is a common disorder affecting 1/50 females and
therefore stabilizes metabolic rate. 1/250 males. The symptoms and signs of thyrotoxi-
cosis are illustrated in Fig. 3.9.
Presentation is usually slow with a history lasting
DISORDERS OF THE THYROID over 6 months.
An acute exacerbation of symptoms is called a thy-
GLAND rotoxic crisis; it is usually brought on by infection in pre-
viously undiagnosed patients. Surgery or radioactive
The thyroid gland is prone to a number of diseases that ablation of the thyroid gland can also be responsible as
can alter its function and structure. These diseases fre- the damaged thyroid follicles release their contents.
quently have wide-ranging systemic effects because thy- The main causes of hyperthyroidism are:
roid hormones regulate the metabolism of almost every
cell in the body. The main categories of disease are: • Diffuse toxic goitre: Graves’ disease—an
autoimmune disease involving autoantibody
• Hyperthyroidism—excess of thyroid hormone stimulation of TSH receptors.
production. • Toxic multinodular goitre—nodular enlargement
• Hypothyroidism—deficiency of thyroid of the thyroid in the elderly.
hormone production. • Toxic nodule—autonomously functioning
• Goitre formation. thyroid nodule; most are adenomas (benign
• Adenoma (benign growths) of the thyroid. thyroid hormone producing tumours).
• Carcinoma of the thyroid. • Lymphocytic thyroiditis—inflammation causes
release of stored hormones (followed by
Hyperthyroidism hypothyroid phase).
Hyperthyroidism is defined as an overactive thyroid • Subacute thyroiditis—thyroiditis associated with
gland, leading to excess thyroid hormones (T4 and a painful goitre.
T3). When this becomes symptomatic it is called thy-
rotoxicosis. Thyrotoxicosis can occur in the absence Diagnosis
of true hyperthyroidism. This phenomenon is seen Thyroid function tests are the main component of
during inflammation of the thyroid (thyroiditis), diagnosis. Serum TSH, free T3, and free T4 are mea-
which stimulates the release of stored hormone or can sured by radioimmunoassay (RIA). Raised T3 and T4
be the result of excess exogenous thyroid hormone indicate that hyperthyroidism is present. Raised TSH
Ch03-M3427.qxd 3/5/07 12:02 AM Page 38
The thyroid gland
Fig. 3.9 Symptoms and signs of
thyrotoxicosis (hyperthyroidism). The brain
features in italic are only found in Graves’ - emotional lability
disease. - fatigue
eyes - anxiety
- exophthalmos (protruding eyes) - restlessness
- lid retraction
- lid lag neck
- predisposes to keratitis - goitre
- palpitations - proximal myopathy
- tachycardia (rapid pulse) (in upper arms and legs)
- atrial fibrillation
- increased appetite
hands - menorrhagia
- tremor - infertility
- warmth - reduced libido
skin and adipose tissue
- increased sweating
- heat intolerance
- weight loss
- pretibial myxoedema
suggests the fault lies in or above the pituitary gland, the patient becomes euthyroid. The alternative is
whereas low TSH points to a thyroid organ lesion. the ‘block and replace’, which involves full-dose
Other tests include: carbimazole and thyroxine replacement.
• Radioactive iodine therapy—131I is only taken up
• Autoantibody detection, e.g. Graves’ disease.
by thyroid tissue; it kills the cells leading to
• Radioisotope scanning to show the size of the
reduced T3 and T4 synthesis. The response is slow
thyroid gland and any abnormal ‘hot’ areas such
and carbimazole may be required. The benefits
as a toxic adenoma.
include a reduced chance of relapse and taking
• ECG for sinus tachycardia or atrial fibrillation.
away the need to take carbimazole, which carries
Treatment risk of agranulocytosis, in the long term.
• Partial thyroidectomy—the thyroid gland is
There are three methods of treatment:
surgically removed leaving some tissue and the
• Carbimazole—this drug inhibits the peroxidase parathyroid glands. Used in patients with
reactions of T3 and T4 synthesis. It takes 3–4 weeks relapsing disease or allergy to medical treatment.
to have an effect. Two principal regimes exist for Carries risk of recurrent laryngeal nerve palsy and
antithyroid therapy. The titration regime involves hypocalcaemia due to the removal of parathyroid
giving increasing doses of anti-thyroid drug until glands.
Ch03-M3427.qxd 3/5/07 12:02 AM Page 39
Disorders of the thyroid gland 3
Both radioactive iodine and partial thyroidectomy Thyroid hormone resistance
carry a high risk of long-term hypothyroidism. The
remaining thyroid tissue may be insufficient to meet
the body’s needs, especially as the patient ages. Their This is a rare condition that occurs due to a mutation
treatment is described under hypothyroidism. in one of the thyroid receptor genes. In most cases the
raised levels of T3 and T4 compensate for the resis-
Graves’ disease tance, but ‘generalized resistance’ can present with
Graves’ disease, the most common form of thyrotox-
icosis, is an autoimmune disease in which autoanti-
bodies against the TSH receptors stimulate the
receptors so that thyroid hormones are produced in Hypothyroidism is defined as an underactive thyroid
excess. Graves’ disease is the most common cause of gland leading to deficient thyroid hormones (T4 and
hyperthyroidism; it is especially common in middle- T3). When this becomes symptomatic, it is called
aged women (B:D, 8:1) and it has a genetic com- myxoedema. It is slightly less common than hyper-
ponent with some human leucocyte antigen (HLA) thyroidism, affecting 1/100 females and 1/500 males.
association. The symptoms and signs of myxoedema are illustrat-
The disease follows either a relapsing-remitting ed in Fig. 3.10. Presentation is even more gradual than
course or one with fluctuating severity. Rarely in hyperthyroidism, with many symptoms frequent-
Graves’ disease can progress to hypothyroidism with ly being ignored.
time. Thyroid hormones are essential between birth and
Graves’ disease can cause the classical picture of puberty for the normal development of the CNS.
hyperthyroidism with bulging eyes (exophthalmos), Deficiency can cause irreversible mental retardation
goitre (with bruit) and swollen legs (pretibial called cretinism. TSH levels are checked in all new-
myxedema). It is diagnosed by detection of autoan- borns for this relatively common abnormality; the
tibodies along with low TSH and raised T3. The thy- levels will be raised if the thyroid gland is not func-
roid autoantibodies, thyroglobulin antibody (Tg Ab) tioning correctly.
and thyroid peroxidase (TPO) antibody, are present
in both Graves’ disease and Hashimoto’s thyroiditis.
However, stimulating thyroid-stimulating hormone Hypothyroidism is not investigated as thoroughly as
receptor (TSH-R) antibodies are specific to Graves’ hyperthyroidism, since treatment does not vary. Free
disease. The treatment is consistent with other caus- T3 and T4 levels are low, whereas TSH levels are usual-
es of hyperthyroidism, but radioactive iodine and ly raised. If TSH is low then a lesion of the hypothal-
surgery are especially likely to cause hypothy- amus or pituitary is likely. Autoantibodies can be
roidism. detected in Hashimoto’s thyroiditis.
Eye disease is an important symptom of Graves’ dis-
ease as it can lead to compromised vision due to optic Treatment
nerve compression and corneal ulcers. Inflammation All hypothyroidism is treated with thyroxine (T4)
of the orbit causes the eye to protrude, which can lead administered as an oral tablet in varying doses. The
to discomfort and double vision. This symptom may dose is increased over several months, with regular
occur before thyroid hormone levels rise. monitoring of TSH levels until they are within the
normal boundaries. This process is slow, since it takes
4 weeks for TSH levels to reflect an increased dose due
to the long half-life of thyroxine. Thyroxine therapy is
usually maintained for life.
The major symptoms of hyperthyroidism
can be remembered as: ‘Don’t Evade Overtreatment of hyperthyroidism
Feeling Hot And Sweaty Patients’ i.e. Radioactive ablation and surgical removal of the thy-
Diarrhoea, Emotional lability, Fatigued, Heat roid gland initially cure hyperthyroidism, but with
intolerance, increased Appetite, Sweating, and time, the remaining thyroid tissue is often insufficient.
Palpitations. Hypothyroidism can develop and life-long thyroxine
treatment is required.
Ch03-M3427.qxd 3/5/07 12:02 AM Page 40
The thyroid gland
Fig. 3.10 Symptoms and signs of
myxoedema (hypothyroidism). The main hair brain
features are shown in bold. - coarse and thin hair - mental slowing
- loss of outer third of eyebrows - apathy
face - psychosis
- myxoedemic features, i.e. hoarse voice
pale puffy face, coarse
- deafness - goitre
- bradycardia muscles
(slow pulse) - slowing of activity
- muscle weakness in
upper arms and legs
- cold hands
- carpal tunnel syndrome
- slow relaxing
skin and adipose tissue
- weight gain/obesity
- intolerance to cold
- decreased sweating
- chronic oedema (caused by
increased capillary escape
- cold, dry skin
Many drugs can also cause reversible hypothy- The initial destruction of the thyroid gland can
roidism including lithium amiodarone and excess release the thyroglobulin colloid causing temporary
iodine. hyperthyroidism. The patients usually progress to a
euthyroid (normal) state and finally develop pro-
Hashimoto’s thyroiditis gressive hypothyroidism.
When the thyroid gland is inflamed, the disease is
called thyroiditis. This can be caused by autoimmune Subacute (de Quervain’s) thyroiditis
or viral processes. Hashimoto’s thyroiditis is a destruc- De Quervain’s thyroiditis is inflammation of the thy-
tive autoimmune disease that is especially common roid gland caused by a virus. It is common in young
in middle-aged women. It is mediated by autoanti- or middle-aged women, in whom it causes a tender
bodies against rough endoplasmic reticulum (micro- swollen gland along with a febrile illness. The inflam-
somal antibodies) or thyroglobulin. The presence of mation causes an initial increase in thyroid hormone
these antibodies can be tested to confirm the diagno- release followed by destroying the follicles, which
sis. The thyroid gland is infiltrated by lymphocytes causes hypothyroidism and leakage of the thyroglob-
that cause the gland to enlarge, forming a goitre. ulin colloid. An immune reaction against this colloid
Ch03-M3427.qxd 3/5/07 12:02 AM Page 41
Thyroid gland neoplasia 3
causes the formation of granulomas, so this disease is becomes very vascular, to the extent that a bruit can be
also called granulomatous thyroiditis. heard using a stethoscope.
Primary atrophic hypothyroidism
Spontaneous or primary atrophic hypothyroidism is Graves’ ophthalmopathy is caused by lymphocytic
a disease resulting in hypothyroidism in the elderly. infiltration of the periorbital tissues and activation of
The biochemical profile may include the presence of fibroblasts to secrete osmotically active hyaluronic
TSH-R blocking autoantibodies, but in this condition acid. This increases the pressure and pushes the eye
the thyroid fibroses and shrinks so that there is no forward, resulting in proptosis. This pressure change
goitre. It is suspected that this disease is the end-stage also causes muscle fibrosis and diplopia due to
of many thyroid diseases, including Hashimoto’s and weakening of the extraocular muscles. The eye
de Quervain’s thyroiditis. disease may precede the onset of thyroid dysfunction,
and does not respond to correction of thyroid status.
Dyshormonogenesis Treatment involves radiotherapy and surgery.
This is an inherited defect in the synthesis of thyroid
hormones, and can present with hypothyroidism and
Puberty and pregnancy
Iodine deficiency Higher levels of thyroid hormones are required in
Iodine deficiency was once a common cause of goitre puberty and pregnancy so the thyroid gland often
in regions where the soil lacked iodine (e.g. Derby, enlarges to meet the increased demand. This enlarge-
England), but nowadays iodine is added to salt to ment is a physiological response, not a pathological
prevent this. Deficient iodine means that thyroid hor- process. The goitre regresses once the demand lessens.
mones cannot be synthesized with a resultant rise in
TSH levels. TSH causes thyroid enlargement by stim- Multinodular goitre
ulating follicle growth and the development of new Many elderly people have an enlarged thyroid that con-
blood vessels, so the thyroid gland enlarges. tains many nodules of varying sizes. These nodules are
formed from hyperplasia (increased number) of thy-
Goitres roid cells. The excess cells sometimes cause excess
A goitre is a swelling in the neck caused by an thyroid hormone production, i.e. hyperthyroidism. The
enlarged thyroid gland. It is a common finding, and disease is then called toxic multinodular goitre.
it is usually asymptomatic; however, large goitres can
compress the oesophagus and trachea. If a goitre is Thyroiditis
associated with hyperthyroidism it is described as Inflammation of the thyroid gland can cause swelling,
‘toxic’. Non-toxic goitres secrete normal or reduced and infiltration by lymphocytes can also cause enlarge-
levels of thyroid hormones. Non-toxic goitres are usu- ment. The goitre formed is usually slightly nodular, but
ally the result of excessive TSH stimulation in the it may be tender if the inflammation is acute.
presence of hypothyroidism. Goitres are treated by
correcting the underlying pathology or by surgical
removal for cosmetic reasons or to prevent compres-
sion of surrounding structures. Thyroid gland neoplasia
Thyroid lumps are common and usually benign;
Iodine deficiency however, they must be investigated. Solitary thyroid
The goitre formed by this process is diffusely enlarged lumps are found in 5% of women and it is very diffi-
and smooth. It is sometimes called an endemic goitre cult to distinguish between benign (80%) and malig-
because it occurred in certain regions. nant (20%) on clinical grounds. A fine-needle
aspiration should be performed along with thyroid
Graves’ disease function tests. Aspiration alone will not distinguish a
The constant stimulation of TSH receptors in Graves’ follicular adenoma from a follicular carcinoma but
disease causes a goitre in a similar manner to iodine low TSH suggests the former as malignant nodules are
deficiency with similar characteristics. The gland not usually hyperfunctioning.
Ch03-M3427.qxd 3/5/07 12:02 AM Page 42
The thyroid gland
Causes of solitary thyroid lumps include: an abnormal ‘fusion protein’ (PAX-8/PPARγ), which
is the result of two gene fragments coming together by
• Thyroid cysts.
translocation and producing a single gene product.
• Nodule of multinodular goitre.
Medullary thyroid cancer often occurs as part of the
• Follicular adenoma.
multiple endocrine neoplasia syndrome and as such
is often associated with RET mutations. The more
Five separate forms of cancer can arise in the thyroid aggressive form, anaplastic thyroid cancer, is often
gland, but three of these are derived from the follicle associated with a p53 mutation. This new knowledge
cells. These tumours are summarized in Fig. 3.11. of the events driving thyroid neoplastic transforma-
Medullary carcinomas of the parafollicular cells tion has opened up novel avenues for therapy.
often secrete ectopic hormones, including:
• Calcitonin—usually asymptomatic.
• Adrenocorticotrophic hormone (ACTH)—
• 5-hydroxytryptamine (5-HT; serotonin)— Occasionally thyroid disorders can present as
carcinoid syndrome. emergencies. A thyrotoxic crisis (thyroid storm) is an
acute episode of hyperthyroidism with pyrexia, and
The molecular biology of thyroid can cause life-threatening arrhythmias. Thyroid storms
cancer can be precipitated by radioactive iodine treatment,
A great deal has been learnt about the molecular biol- thyroid surgery or by severe illness. Treatment is
ogy of thyroid cancer. 50% of papillary thyroid cancers aimed at preventing cardiovascular complications, and
have a translocation that causes constitutive activation the mainstays are antithyroid therapy and beta-
of the RET proto-oncogene. RET is a transmembrane blockers. Undertreated hypothyroidism can progress
receptor with tyrosine kinase activity, which when to a life-threatening myxoedema coma. This rare
active can drive oncogenesis (the development of neo- condition is characterized by bradycardia and
plasia). In follicular thyroid cancer (FTC), 40% of hypotension. Plasma levels of glucose and sodium can
cases have an activating point mutation of the RAS also drop, and type II respiratory failure may develop.
proto-oncogene. 60% of FTCs were shown to produce
Fig. 3.11 Characteristics of the five primary thyroid gland malignancies
Type Cell type Age group Route of metastasis Prognosis
Papillary Follicle cells All Cervical lymphatics Excellent
Follicular Follicle cells Middle-aged Blood to bone, Good
lung and brain
Medullary Parafollicular Middle-aged Cervical lymphatics Variable but
cells and elderly usually good
Malignant Lymphatics Elderly Local invasion Poor
Anaplastic Follicle cells Elderly Local invasion Very poor