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7
Case
7.1
Weight loss: 2
Case note: Why knowledge of anatomy is
essential in his management
The fact that a neck mass is of thyroid origin can be shown
by clinical examination and a knowledge of the anatomy
and relations of the thyroid. The thyroid gland is wrapped
in a layer of tissue called the pretracheal fascia, which is
inserted into the trachea (Fig. 7.1). Thus, thyroid masses
grow around the trachea and move with the trachea when
the patient is asked to swallow. The trachea may become
narrowed and even occluded by a thyroid mass, a potential medical and surgical emergency. The surgical anatomy
of the thyroid gland is important in operations to remove
the thyroid and in counselling patients about the risks of
such procedures. The surgeon may have to contend with
retrosternal extension and recurrent laryngeal nerve and
parathyroid injury. The trachea often descends behind the
sternum in older patients owing to a kyphosis of the neck;
this is easily appreciated if the cricoid cartilage is found to
be at the sternal notch.
Mr Smith’s chest radiograph (Fig. 7.5) confirms that the
thyroid is exerting pressure on the trachea and indicates a
role for surgical removal once the overactive thyroid state
has been fully controlled by medication.
(T4) (Figs 7.6 and 7.7). When iodine is in short supply,
however, it is common for the reaction to favour the formation of mono- iodotyrosine. Therefore, when there is a
shortage of iodine, thyroid hormone synthesis favours T3
production over T4. These two hormones are the thyroid
hormones. This iodinated colloid acts as a reserve of thyroid hormone for the body. Normally, the thyroid contains 5–6 weeks’ supply of hormone. When the follicular
cells are stimulated to produce thyroid hormones, the
droplets of colloid are taken up by endocytosis into the
cell to form vesicles. These vesicles fuse with lysosomes,
which contain enzymes that cut the thyroglobulin to
release the pairs of iodinated tyrosine residues. While the
iodothyronines are released into the blood, the remainder of the thyroglobulin is recycled in the follicular cell
and used to make further colloid.
Iodine
Iodine is a monovalent anion, belonging to the same
chemical group as chlorine: the halogens. It is a trace element in the diet and is essential for normal thyroid function. The UK Department of Health recommends a daily
iodine intake of 140 µg for most people and the World
Health Organization suggests that pregnant and lactating women need 200 µg/day. In the diet, sea fish, shellfish, and sea salt are particularly rich in iodine, reflecting
the high iodine content of sea water. More surprisingly,
perhaps, cow’s milk is also a good source of iodine.
Maybe this is not so surprising to people who are aware
that iodine is used as a cattle feed supplement and as a
sterilising agent applied to cows’ teats in milking parlours. Iodine is also present in a wide range of multivitamin and mineral supplements. Dietary iodine deficiency
is a serious public health problem (see below), and therefore, in the USA and many other countries, iodine is
added as a supplement to table salt.
THE THYROID GLAND
Fig. 7.5 Chest radiograph of Mr Smith showing tracheal
deviation. The increased size of his thyroid has exerted pressure
on the trachea, causing it to shift to one side. (From Chew S,
Leslie D (eds). Clinical endocrinology and diabetes: an illustrated
colour text. Churchill Livingstone, 2006. With permission.)
secreted into a pool of colloid, which is surrounded by
follicular cells. The iodide is also secreted into the lumen
of the follicle by the action of a sodium- independent
iodide transporter, called ‘pendrin’. On the luminal (next
to the colloid) surface of these cells, there is an enzyme
called thyroperoxidase, which catalyses the reaction
between tyrosine residues in the thyroglobulin and the
iodide, forming mono- iodotyrosine and di- iodotyrosine.
These iodinated tyrosine residues combine in pairs to
form either tri- iodothyronine (T3) or tetra- iodothyronine
Interesting fact
While daily microgram quantities of iodide are essential for the thyroid to work properly, taking an excess of
iodide (0.5–1.5 mg/day) paradoxically suppresses thyroid
function and causes hypothyroidism. This is only a shortterm effect, however. In the longer term, the thyroid gland
adapts to the increased supply of iodide, and the person
normally returns to the euthyroid state.
Thyroxine and T3: the thyroid hormones in blood
The active thyroid hormone is T3, but thyroxine can be
converted to T3 in many tissues of the body by a process called ‘peripheral de- iodination’. The thyroid gland
and the mechanism of peripheral de- iodination can
79THE ENDOCRINE SYSTEM
7
Exocytosis
Thyroxine (T4)
TX3
(3, 5,
COOH
(3, 5′, 3′ triiodothyronine)
THE THYROID GLAND
(secretion of
thyroid hormones)
T3/T4
Proteolysis
and liberation
of T3 and T4
2Na
+Ι−
cAMP
TSH
G-
protein
Nucleus
Adenylyl
cyclase
ATP
Lysosomes
Phagocytosis
of colloid
Iodinated tyrosine
residues
ΙΙ
ΙΙ
Fig. 7.6 Synthesis of thyroid hormones. Iodine is actively concentrated by the thyroid cells. An enzyme called thyroperoxidase catalyses the
addition of iodine to the tyrosine residues in thyroglobulin, a large protein rich in tyrosine residues, which is synthesised in the thyroid cells. The
iodinated thyroglobulin is stored in the thyroid in the form of ‘colloid’. In response to TSH stimulation, portions of the colloid are taken back into
the thyroid cell by phagocytosis, and pairs of iodinated tyrosine residues (thyroxine) are released into the circulation. Antithyroid drugs, such as
carbimazole, act by inhibiting thyroperoxidase activity. AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate.
Thyroid
peroxidase
−
Ι
Synthesis of
thyroglobulin
Endoplasmic
reticulum
Colloid
(pool of thyroglobulin)
Tyrosine
residues
(3, 5, 3′, 5′ tetraiodothyronine)
I
HO
II
HO
Fig. 7.7 Structure of thyroxine and T3. These small lipophilic hormones act
by binding to the intracellular receptors. Thyroxine (T4) is converted to T3 or
reverse T3 by de- iodination in peripheral tissues. Reverse T3 is inactive.
O
I
3′ triiodothyronine)
O
I
CH
2
NH
80 SYSTEMS OF THE BODY
I
CH
CH COOH
2
I
CH COOH
2
HO
Reverse T3
NH
2
II
O
I
CH
2
NH
CH
also produce an inactive form of T3, called ‘reverse T3’
(see Fig. 7.7). The thyroid hormones are poorly soluble in blood plasma and must therefore circulate in the
blood attached to a binding protein. In fact, 99.9% of
thyroid hormone in blood is protein- bound. There are
two plasma binding proteins for thyroid hormones.
Thyroxine binding globulin (TBG) is the most important
of these, binding approximately 70% of the circulating
thyroid hormones. The other is called transthyretin and
binds only around 10% of thyroid hormones, less than
the 15%–20% that is loosely bound to serum albumin.
Thyroxine binding globulin circulates in far lower concentrations than does either transthyretin or albumin,
but it has a much higher affinity for thyroid hormones
than do the other proteins. It also has a long half- life of
2
around 5 days, compared with 2 days for transthyretin.
Like the other binding globulins, TBG is produced by the
liver and is actively regulated, principally by oestrogens.
This means that levels of TBG increase in pregnancy
and in women taking the combined oral contraceptive
pill; however, thyroid hormone secretion also increases,
7
Hypothalamus
Cold stress, exercise,
Glucocorticoids
and these women remain euthyroid. TBG levels are also
raised in people taking methadone or heroin, and major
tranquillisers and are decreased in people taking glucocorticoids or androgen therapy.
Case
7.1
Weight loss: 3
Case note: Investigations
Mr Smith’s doctor requested a thyroid function test, estimation of sex hormone binding globulin (SHBG) level, thyroid
auto- antibodies, and an ECG.
The following test results were obtained:
Free T4 28 (normal, 9–25) pmol/L
TSH 0.01 (normal, 0.4–4) mU/L
Free T3 10.8 (normal, 3.1–6.6) pmol/L)
SHBG 135 (normal male, 25–55) nmol/L
Thyroid microsome
auto- antibodies
ECG Atrial fibrillation, rate 140 bpm
Negative
Interpretation of thyroid function test results
Mr Smith has abnormally high serum thyroxine (T4) and
tri- iodothyronine (T3) levels. The normal thyroid produces
mostly (80%) T4, and this is converted by the loss of one
iodine molecule (called de- iodination) to the active T3 by
the tissues. The production of T4 is normally under the control of the pituitary hormone TSH. However, in Mr Smith’s
case, the thyroid nodules are autonomously making large
amounts of T3 and some T4. The TSH is therefore inhibited
by the negative feedback effects of the thyroid hormones.
The thyroid hormones stimulate the liver to produce
SHBG, which is a marker of the thyroid state and which
binds and inactivates testosterone. The reduction in testosterone action allows an increased effect of oestrogen
on the breast tissue, causing hyperplasia. The latter fact
explains the swollen breast tissue (called gynaecomastia).
An alternative diagnosis may have been autoimmune thyroid disease, in which thyroid auto- antibodies
are usually present. Thus, the negative thyroid autoantibodies result supports a diagnosis of toxic nodular
goitre, as opposed to Graves disease.
The ECG confirms atrial fibrillation, which is a dangerous cardiac complication of thyrotoxicosis. Atrial fibrillation is a classical complication and carries a risk of stroke.
Clots can form in the fibrillating atria and may move into
the arterial system (a process called embolisation).
Thyroxine has an unusually long plasma half- life for
a hormone, of around 6–7 days, while T3 has a shorter
half- life of around 10 hours. The long half- life of thyroxine means that it does not have a significant diurnal
rhythm and also that any drug treatment to reduce thyroid hormone secretion takes at least a week to have any
significant effect on the plasma hormone levels.
pregnancy
TRH
Somatostatin
(cortisol)
Fig. 7.8 The hypothalamo–pituitary–thyroid axis.
TSH
T
3
Thyroid
T
4
Interesting fact
The swelling of the neck that we know as goitre is a very
obvious change in a person’s appearance; therefore, it
should not come as a surprise to learn that it was a condition known to ancient medicine. The earliest descriptions
we know of come from Chinese medical texts from nearly
four thousand years ago. What is particularly astonishing is
that ancient Chinese medicine also came up with an effective cure for goitre due to low iodine intake: patients were
told to ingest a dose of seaweed or burnt sponge, each
of which is now known to contain significant amounts of
iodine, at least twice a year.
The recognition and effective treatment of goitre are
also described in the ancient Greek writings of Hippocrates
(active in the 5th century BCE) and the Roman physician
Galen (active in the 2nd century CE). However, it was not
until 1820 that the Swiss physician Coindet demonstrated
that the active ingredient in burnt sea sponge was the
recently discovered element iodine and that tincture of
iodine was effective in treating goitre.
Control of thyroid function
The thyroid gland is regulated by a peptide hormone
secreted from the anterior pituitary, quite sensibly called
thyroid stimulating hormone (TSH). The control of thyroid hormone secretion is shown in Fig. 7.8. This is a
classical hypothalamic–pituitary axis, with thyroid hormones exerting negative feedback control of the axis.
There is also inhibitory input from other hormones,
including somatostatin and glucocorticoids. Examples
of stimuli that increase the activity of the hypothalamo–
pituitary–thyroid axis include cold exposure, exercise,
and pregnancy. TSH acts on specific receptors on the
apical surface of the thyroid follicular cell (Fig. 7.6).
THE THYROID GLAND
81THE ENDOCRINE SYSTEM
7
Thyroid hormone
The TSH receptor is a classical seven- transmembrane
domain, G- protein coupled receptor linked to adenylyl
cyclase. Activation of the receptor causes an increase in
cAMP, which then brings about a range of intracellular
responses to TSH stimulation over different periods.
The most immediate effect of TSH is to increase cellular
uptake and processing of the colloid to bring about the
release of thyroid hormones. There is also an increase
in iodide uptake and synthesis of thyroglobulin. In the
THE THYROID GLAND
longer term, TSH stimulates thyroid growth with both
hyperplasia (increased size) and hypertrophy (increased
number) of follicular cells. When there is excess TSH, this
leads to the development of a goitre (see above).
Case
7.1
Weight loss: 4
Case note: Establishing the diagnosis
Mr Smith exhibits the effects of an excess of thyroid hormone (thyrotoxicosis), caused by a toxic nodular goitre. A
goitre is an enlarged thyroid gland (see above). Most people over 40 years have small thyroid nodules detectable by
high- resolution ultrasonography. Some of these nodules in a
minority of patients will grow sufficiently to be seen or felt.
Thyroid nodules may grow beyond the normal control mechanisms and become autonomous. Autonomy means that
the nodules produce thyroid hormones independently of
control by the pituitary gland. Thus, the TSH level may fall,
while the nodule continues to produce thyroid hormones.
Autonomous thyroid hormone production from the nodule
then insidiously increases until finally an excess of circulating
thyroid hormones produces symptoms of thyrotoxicosis. Such
thyroid glands are called ‘toxic’ for this reason.
Cellular action of thyroid hormones
Thyroid hormones are able to exert both genomic and nongenomic effects on virtually all cells. In the classical model
of thyroid hormone action, thyroid hormone T3 diffuses
across the plasma membrane into the cell and binds to specific thyroid hormone receptors (TR) in the nucleus. There
is a family of thyroid hormone receptors encoded by two
TR genes, alpha and beta. Alternative splicing of the gene
products means that there are four distinct thyroid hormone receptor proteins, with different tissue distributions
and binding characteristics. These are TR alpha 1 and 2 and
TR beta 1 and 2. All the thyroid hormone receptors apart
from TR alpha 2 have a much higher affinity for T3 than
for T4, and therefore, T4 is usually considered to be a prohormone. The TR beta 2 receptor is only found in the brain,
but the other receptors are found throughout the body.
Thyroid hormone receptors form dimers in order
to interact with the hormone response elements. Most
commonly, these are heterodimers with the retinoic acid
X receptor (RXR), but occasionally they form homodimers with another TR. Unusually for nuclear receptors,
Nucleus
Co-repressor
RXRTR
HRE
Fig. 7.9 Cellular action of thyroid hormones. The thyroid hormone
receptors (TR) are located in the nucleus of the target cell. They form
dimers, either between two thyroid hormone receptors (homodimers)
or with the retinoic acid receptor (RXR) and one thyroid hormone
receptor (heterodimers). In the absence of thyroid hormone, the
thyroid hormone receptors bind to a hormone response element
in DNA and attract co- repressors which block gene transcription.
Conversely, in the presence of thyroid hormone the co- repressors are
replaced by co- activators, forming an initiation complex which allows
gene transcription to proceed.
Nuclear pore
Co-repressor
Co-activator
RXRTR
Initiation
complex
mRNA
the thyroid hormone receptors bind to the hormone
response element on DNA even in the absence of thyroid
hormones. The unoccupied receptor dimers recruit corepressor proteins and repress gene transcription. This is
reversed when the hormone binds, allowing the recruitment of co- activator proteins and allowing transcription
to take place (Fig. 7.9). A key molecular target of thyroid
hormone action is increased transcription of the genes
encoding mitochondrial uncoupling proteins.
The non- genomic actions of thyroid hormones are
less well understood but appear to be mostly the result
of direct T4 action on membrane receptors. The T4 receptors may be linked to MAP kinase or to the generation
of second messengers, producing rapid effects which are
seen in cardiac cells, among others.
Effects of thyroid hormones
Thyroid hormones (Table 7.1) have a range of subtle
effects in the body. Although the direct effects of these hormones on particular tissues or cells may be subtle, both
thyroid hormone insufficiency and excess result in significant disease. Like glucocorticoids, thyroid hormones do
not have a single specific target tissue, but their receptors
are found in most cells and tissues of the body. Although
it is possible to state that cells need thyroid hormones to
maintain their appropriate function, it has been difficult to
identify the hormones’ precise physiological effects.
82 SYSTEMS OF THE BODY
7
Table 7.1 Actions of thyroid hormones.
Cardiovascular effects
Increased cardiac output
Increased heart rate and stroke volume
Decreased systemic vascular resistance
Increased systolic pressure
Metabolic effects
Increased basal metabolic rate
Increased oxygen consumption
Increased thermogenesis (increased expression of
mitochondrial uncoupling proteins)
Increased protein turnover (as a result of enhancing the
actions of growth hormone, glucocorticoids, adrenaline,
noradrenaline, and glucagon)
Neurological effects
Enhances
Wakefulness
Memory
Reflexes
Essential for maintenance of normal emotional tone
Growth and development
Essential for normal foetal neural development
Essential for normal bone growth after birth
Required for normal tooth development
Reproduction
Has a permissive role in both male and female
reproduction: essential for normal reproductive function
Metabolic and respiratory effects
decreased peripheral resistance and increased stroke volume. Thyroid hormones act to alter the responsiveness
of cells to other hormones, especially to catecholamines,
and together they have a synergistic effect on the heart
rate.
Developmental effects
During foetal development and early childhood, thyroid
hormones have an important role in both neural and
skeletal development. Up to 11 weeks of foetal life, the
developing foetus depends on the small amount of thyroxine that passes across the placenta from the maternal
circulation. During the second trimester of pregnancy,
the foetal thyroid becomes active. Although there is a
significant increase in circulating maternal thyroid hormones (see Ch. 9), this is accompanied by an increase in
plasma binding globulin; therefore, the concentration of
free thyroxine is unchanged.
Other effects of thyroid hormones
At least partly by enhancing responsiveness to catecholamines, thyroid hormones affect the central nervous system. They are important in maintaining normal mood,
memory formation, and attention, as well as in peripheral neural reflexes. Thyroid hormones have a role in
maintaining healthy bones, skin, teeth, and reproductive
systems. They are required for the normal functioning of
much of the endocrine system, and have a role in regulating growth hormone secretion and in levels of expression of CYP19, the aromatase enzyme which converts
androgens to oestrogens. It is difficult to overstate the
importance of a properly functioning thyroid gland.
THE THYROID GLAND
One of the main actions of thyroid hormones is to
increase the basal metabolic rate and in cells’ oxygen
consumption and heat production. Thyroid hormones
achieve this by increasing expression of the genes
which encode mitochondrial uncoupling proteins.
Alongside this effect, thyroid hormones increase the
resting respiratory rate and cause an increase in erythrocyte numbers by stimulating renal erythropoietin
production. These effects work together over a period
of weeks to maintain the blood oxygen levels when
demand for oxygen is increased. Thyroid hormones
also increase sweating, probably in response to the
increased thermogenesis.
Cardiovascular effects
Thyroid hormones increase the cardiac output both
directly and indirectly (as a result of increased oxygen
utilisation and CO2 production in the body). The direct
cardiovascular effects of thyroid hormones include
Interesting fact
Across the animal world, all chordates, from amphioxus
to great apes, produce thyroid hormones. In higher vertebrates, they function very similarly to the human system; however, in animals that metamorphose (like some
fish and amphibians), they have a very different role. It is
thyroid hormones that initiate and control the process of
metamorphosis. So, for example, in the absence of thyroid
hormone, tadpoles cannot become frogs.
Disorders of thyroid hormone secretion
As we have seen, thyroid hormones have significant
effects on virtually every system of the body. They affect
the metabolism, cardiovascular system, nervous system,
bone, mood, endocrine system, and almost everything
else. It is, therefore, not surprising that the effects of
thyroid hormone excess or insufficiency are global and
severe.
83THE ENDOCRINE SYSTEM
7
Agitated, anxious,
Case
7.1
Weight loss: 5
Case note: Explanation of symptoms
Mr Smith’s symptoms are due to an excess of thyroid hormones (thyrotoxicosis):
• Increasedmetabolicratecausessweating,heat
intolerance, and weight loss despite good appetite
THE THYROID GLAND
• Effectsonskeletalmusclemaycauseproximalmyopathy
• Effectsoncardiacsmoothmusclemaycauseatrial
fibrillation (causing palpitations)
• Effectsonbraincauseagitationandlabilemood
• Effectsonbetaadrenoceptorscauseincreasedheartrate
and peripheral tremor
poor sleep
Exophthalmos
(Graves)
Possible goitre
Heat intolerance
Tachycardia
Swollen breast tissue
Weight loss
Sweating
Thyroid acropachy
(Graves)
Diarrhoea
Fine tremor
Pretibial myxoedema
(Graves)
Muscle weakness
Fig. 7.11 Graves exophthalmia (proptosis). In this case, only one
eye is affected. A combination of fat deposition behind the eyes and
retraction of the eyelids causes this effect, which is characteristic of
Graves disease and is probably an effect of the antibodies, rather than
the increased levels of thyroid hormones.
The two most common causes of thyrotoxicosis are
toxic nodular goitre and Graves disease. In both of these
diseases, thyroid function is increased in the absence of
stimulation from the pituitary gland. In toxic nodular
disease, there is an autonomous nodule in the thyroid
gland that slowly increases thyroid hormone production.
Graves disease is an autoimmune condition in which
auto- antibodies stimulate the TSH receptor. These antibodies were first recognised to be the cause of Graves
disease in the late 1950s, although the clinical condition
of Graves disease itself was described in 1835. The autoantibodies take over control of the thyroid from TSH,
and therefore, the usual negative feedback control does
not work to limit thyroid hormone secretion. Graves disease is part of a spectrum of organ- specific autoimmune
disease, including conditions such as pernicious anaemia. Both toxic nodular goitre and Graves disease cause
the symptoms of excess thyroid hormone secretion (see
below), but additional signs and symptoms are seen in
Graves disease. In particular, effects on the eye are seen,
with upper lid retraction and exophthalmos being most
noticeable (Fig. 7.11). Graves disease is also associated
with vitiligo (patchy skin depigmentation), myxoedema
(thickening of the skin on the lower legs), and finger
clubbing.
Interesting fact
Fig. 7.10 Signs and symptoms of hyperthyroidism (thyrotoxicosis).
Disorders of the thyroid: hyperthyroidism
The diagnosis of an ‘overactive thyroid’ is relatively
common. It has been estimated that up to 5% of British
women have hyperthyroidism at some time in their lives,
with half of these women having thyroid stimulating
antibodies in their blood. Thyroid disorders are much
less common in men. Hyperthyroidism results in a clinical condition called thyrotoxicosis, in which the levels of
circulating thyroid hormones are so high that they cause
symptoms (Fig. 7.10).
84 SYSTEMS OF THE BODY
Thyroxine is available over the internet as an ‘aid to
weight loss’. A quick glance at the effects of excess thyroid hormones should be enough to convince you of the
foolishness of this course of action. Thyroxine supplements should be taken only on the advice of a qualified
doctor.
Effects of excess thyroid hormone secretion: thyrotoxicosis
Thyroid hormones have effects on most tissues of the
body, and the effects of excess thyroxine are exaggerations of the normal physiological actions (see Fig. 7.10).
The increased basal metabolic rate makes a person feel
7
hot and sweaty. This is often noticed by the individual as
heat intolerance, feeling hot even in cool temperatures.
As glycolysis increases, there is increased demand for
glucose; therefore, weight loss and increased appetite are
often seen together. The general catabolic state leads to a
loss of muscle mass, with consequent muscle weakness.
This is most noticeable in the large muscles around the
hip and shoulder.
Thyroid hormones alter the actions of other hormones,
especially the catecholamines; therefore, tachycardia
(increased heart rate) is seen. Tachycardia is a very serious problem which may be associated with atrial fibrillation, heart failure, and death. Thyrotoxicosis is therefore
a significant illness and should be treated promptly.
The enhanced adrenergic effect also causes a peripheral
tremor, typically a fine tremor of the hands. There are
effects on mood, and excess thyroid hormones can cause
elation, restlessness, anxiety, or irritability. Excess thyroid
hormones can also cause diarrhoea by directly stimulating gut motility and menstrual irregularities. The menstrual irregularities arise from a combination of weight
loss and the direct effects of the thyroid hormones on
hypothalamic and pituitary hormones.
Treatment of thyrotoxicosis
The aim of the treatment of thyrotoxicosis is to reduce
the rate of secretion of thyroid hormones and to bring
the circulating levels of thyroid hormones and TSH
within the normal range. There are several different
ways in which this can be achieved. The first- line treatment is therapy with antithyroid drugs such as carbimazole (methimazole). In some cases, this is used as a
long- term treatment and in others it is used to reduce the
size of a goitre prior to surgical treatment of the hyperthyroidism. Antithyroid drugs act by inhibiting the synthesis of thyroid hormones. Carbimazole (methimazole)
is the most commonly used antithyroid drug in the UK.
It acts by inhibiting the iodination of tyrosine residues
on thyroglobulin. It is thought to do this by competing
with tyrosine for binding to the thyroperoxidase enzyme.
Propylthiouracil, another antithyroid drug, has a similar
mechanism of action in the thyroid, but it additionally
inhibits the conversion of T4 to T3 in the peripheral tissues, and therefore, its effects may be seen more rapidly.
Typically, the effects of antithyroid drugs take 4–6 weeks
to become apparent. This is due to both the long half- life
of thyroxine in the circulation and the large reserve of
iodinated thyroglobulin stored in the thyroid gland.
An alternative treatment for thyrotoxicosis is radioactively labelled iodine. The thyroid gland is the only
organ in the body that traps iodine with great efficiency,
and thus, radioiodine will localise nearly exclusively to
the thyroid and will painlessly and safely destroy the
thyroid tissue over several weeks to months. With all
antithyroid treatments, it is easy to go too far, resulting in hypothyroidism. Because of this, it is common to
use a ‘blocking- replacement’ treatment where the aim
is to block endogenous thyroid hormone secretion completely and to administer a replacement dose of thyroxine. Beta- blockers such as propranolol are often used for
immediate relief of the symptoms caused by enhanced
adrenergic activity, such as tremor and arrhythmias.
Case
7.1
Weight loss: 6
Case note: Treatment
There are several aims in treating Mr Smith:
1. Control of thyroid hormone levels.
2. Treatment of atrial fibrillation and its complications.
3. Long- term treatment of the nodular goitre.
Mr Smith was started on the antithyroid drug carbimazole. However, it usually takes several weeks for the drug
to be fully effective, and the tissue effects of thyrotoxicosis may take weeks to resolve after the introduction of
antithyroid drugs. Thus, the beta adrenoceptor blocking
drug, propranolol, was also started. High thyroid hormone
levels act together with catecholamines to stimulate the
heart and tissues. Blocking the beta adrenoceptor may
improve some symptoms in many patients.
The treatment of Mr Smith’s atrial fibrillation is essential,
as there is a risk of clot formation in the heart with embolisation to the brain and other parts of the vascular tree. Mr
Smith was therefore administered warfarin (an anticoagulant) to reduce the risk of clots.
Nodular goitres may be treated by surgery or radioactive iodine. A treatment plan for Mr Smith was made which
included the use of radioactive iodine several weeks after
he had been rendered clinically and biochemically euthyroid by drug treatment.
Causes of thyroid hyposecretion
Hypothyroidism as a whole is far more common than is
hyperthyroidism and has many causes. Globally, hypothyroidism is most commonly caused by dietary iodine
deficiency, although this is not usually seen in Western
societies. There are also autoimmune causes, and hypothyroidism may result from insufficient pituitary secretion of TSH, although this is uncommon.
Iodine deficiency hypothyroidism
The thyroid gland has an absolute requirement for a supply of iodine in the diet. The World Health Organization
recently reported that 30% of the world’s population is
at risk of iodine deficiency disorders. Children born to
severely iodine- deficient mothers have a condition of
severe intellectual impairment termed cretinism, which
is the result of a lack of thyroid hormones. At the start
THE THYROID GLAND
85THE ENDOCRINE SYSTEM
7
of the 21st century, 750 million people were reported to
have iodine deficiency goitre. Some 43 million people
have brain damage resulting from a deficiency of iodine
and therefore of thyroid hormones. This is the commonest preventable cause of brain damage in the world
today.
Autoimmune thyroid disease
THE THYROID GLAND
Several autoimmune disorders such as Hashimoto thyroiditis cause impaired thyroid hormone secretion. These
disorders are caused by auto- antibodies directed against
thyroglobulin or thyroid peroxidase. These antibodies
cause progressive destruction of the thyroid gland that is
often associated with local inflammation and pain. Like
Graves disease, autoimmune thyroiditis is 10–20 times
more common in women than in men and has a peak
occurrence between the ages of 45 and 65.
Congenital hypothyroidism
Congenital hypothyroidism may be due to abnormal
development of the thyroid gland, a genetic defect affecting thyroid hormone production, or a lack of iodine in
the mother’s diet during pregnancy. In children, hypothyroidism is very serious and can result in severe brain
damage. Congenital hypothyroidism occurs in about
1 in 4000 children born in the UK. This relatively high
incidence, combined with the seriousness of the condition and its simple treatment once detected, mean that
a national screening programme has been introduced
in the UK. All babies born in the UK have a heel- prick
blood test when they are about 7 days old. The blood
spot is tested for thyroid hormones, and thyroxine treatment is started if there is evidence of hypothyroidism.
There is good evidence that thyroid hormone replacement prevents the consequences of hypothyroidism in
these children, although it does not correct any damage
that occurred before birth.
Effects of thyroid hormone insufficiency in adults
The symptoms of hypothyroidism in adults develop only
slowly, over a long period. The symptoms are often of
general tiredness and lethargy. There may be weight gain
despite poor appetite. Hypothyroidism causes depression in about 50% of cases, as well as cognitive impairment and a general sluggishness of intellectual process.
There is reduced cardiac output, and the pulse rate is
slow (Fig. 7.12). In some cases, where thyroid hormone
insufficiency has remained undetected for a significant
period, a condition called myxoedema may develop.
In the context of thyroid hormone insufficiency, myxoedema means any severe, advanced hypothyroidism that
may even result in emergency admission with myxoedema coma. Confusingly, the term myxoedema is also
used (more correctly) to describe the non- pitting oedema
in the shins seen with hyperthyroidism.
Case
7.2
Depression: 1
Case history
Ms Cooper, a 54- year- old bank executive, was referred to the
psychiatry outpatients for assessment of her depression, which
was resistant to treatment. She had felt increasingly depressed
over the past 6 months and had presented to her GP 6 weeks
earlier, whereupon treatment with an antidepressant had
been started. This had had no effect on her mood and other
symptoms to the point where Ms Cooper was becoming suicidal. She described low mood, lack of energy, and lack of
enjoyment – the three core features of depression.
Ms Cooper had been unable to work for the past month
and had considerable difficulty concentrating. She was very
pessimistic about the future and felt guilty that she was unable to ‘snap out of it’. Her appetite was decreased, but she
had not lost weight, despite eating much less than usual. She
reported increased sleep at night and daytime sleepiness.
Ms Cooper had no history of psychiatric disorders or
other significant illness. There was no family history of
depression or other psychiatric disorders, but Ms Cooper’s
mother had a history of hypothyroidism.
On direct questioning, Ms Cooper described how she had
been feeling tired and run down for over a year and that she
had become intolerant of cold, wearing thick winter clothing on a warm August day. Normally she was very energetic,
with a busy lifestyle, and was particularly distressed that she
had had to gradually give up more and more of her activities
due to her tiredness and lack of concentration.
A thyroid function test was requested. The results were:
Free T4 6.7 (normal, 9–25) pmol/L
TSH 112 (normal, 0.4–4) mU/L
Ms Cooper was started on 50 µg thyroxine/day and was stabilised on 125 µg/day.
Within 3 weeks of starting thyroxine treatment her mood
had lifted, her tiredness had decreased, she felt less sleepy, and
her appetite had increased. Some 3 weeks later, she had made
a full recovery, returned to work, and started some other activities. At this point, the antidepressant medication was stopped.
This case raises the question: Why was a thyroid function
test requested, rather than alternative forms of antidepressant treatment?
Treatment of hypothyroidism
Thyroxine replacement is given to treat hypothyroidism. It is active orally, and therefore, can be taken in tablet form. The long half- life of thyroxine in blood means
that it can be taken once daily. The aim of treatment is
to bring the patient into a ‘euthyroid’ state. This is best
86 SYSTEMS OF THE BODY
7
Depression
Reduced cardiac output
Lethargy
Dry hair
‘Puffy’ appearance
Possible goitre
Feels cold
Bradycardia
Weight gain
Coarse skin
Muscle weakness
Cold feet
Fig. 7.12 Signs and symptoms of hypothyroidism.
judged in patients with an intact pituitary by measuring the plasma TSH levels. The aim of treatment is to
keep the plasma thyroxine at a level where TSH is just
suppressed below about 4 mU/L. This usually requires
‘titration’ of the dose of thyroxine (i.e. a process of trial
and error).
Interesting fact
One of the simplest and most effective measures put in
place to improve public health across the world has been
the addition of iodine to table salt to prevent the intellectual impairment caused by thyroxine deficiency. Since
the early 20th century, salt manufacturers have added
iodine, usually in the form of potassium iodide, to table
salt. Although the World Health Organization strongly
supports the iodisation of salt, it is not a universally popular measure. Many conspiracy theorists dislike food supplementation measures and have started rumours that
iodised salt causes AIDS.
THE THYROID GLAND
87THE ENDOCRINE SYSTEM
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