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THYROID 
GLAND
DISEASE
These are common, affecting some 5% of
the population, predominantly females.
The thyroid axis is involved in the
regulation of cellular differentiation and
metabolism in virtually all nucleated cells,
so that disorders of thyroid function have
diverse manifestations. In addition,
structural diseases in the thyroid gland,
such as goitre, commonly occur without
abnormal thyroid function.

T3 and T4 circulate in plasma almost entirely 
(> 99%) bound to transport proteins, mainly
thyroxine-binding globulin (TBG). It is the
unbound or free hormones which diffuse into
tissues and exert diverse metabolic actions.
While it is possible to measure the concentration
of total or free T3 & T4 in plasma, the advantage
of the free hormone measurements is that they
are not influenced by changes in the
concentration of binding proteins; in pregnancy,
for example, TBG levels are increased and total
T3 & T4 may be raised, but free thyroid hormone
levels are normal.
PRESENTING PROBLEMS IN
THYROID DISEASE
The most common presentations of thyroid 
disease are thyrotoxicosis (i.e.
hyperthyroidism), hypothyroidism and goitre
(i.e. enlargement of the thyroid). In addition,
ready access to accurate tests of thyroid
function and an increasing tendency to screen
certain populations (e.g. elderly, hospitalised)
have led to the identification of patients with
abnormal results who are either asymptomatic
or have non-specific complaints such as
tiredness and weight gain.
THYROTOXICOSIS
Management
Definitive treatment of thyrotoxicosis depends 
on the underlying cause, and may include
antithyroid drugs, radioactive iodine or surgery.
In all patients with thyrotoxicosis a nonselective β-adrenoceptor antagonist (βblocker), such as propranolol (160 mg daily) or
nadolol (40-80 mg daily), will alleviate but not
abolish symptoms within 24-48 hours. Betablockers cannot be recommended for longterm treatment, but they are extremely useful
in the short term, e.g. for patients awaiting
hospital consultation or following I131 therapy.
Atrial fibrillation in thyrotoxicosis
Thyrotoxicosis is an important cause of atrial 
fibrillation; in one series of patients presenting
with atrial fibrillation the prevalence of
thyrotoxicosis was 26%, while atrial fibrillation
is present in about 10% of all patients with
thyrotoxicosis. The incidence increases with
age so that almost half of all males with
thyrotoxicosis over the age of 60 are affected.
Moreover, subclinical thyrotoxicosis is a risk 
factor for atrial fibrillation. Characteristically, the
ventricular rate is little influenced by digoxin, but
responds to the addition of a β-blocker.
Thrombo-embolic vascular complications are
particularly common in thyrotoxic atrial fibrillation
so that anticoagulation with warfarin is required,
unless contraindicated. Once thyroid hormone
and TSH concentrations have been returned to
normal, atrial fibrillation will spontaneously revert
to sinus rhythm in ∼50% of patients. In the
remainder, cardioversion will restore sinus
rhythm in up to 50%.
Thyrotoxic crisis ('thyroid storm)
This is a rare and life-threatening 
increase in the severity of the clinical
features of thyrotoxicosis. The most
prominent signs are fever, agitation,
confusion, tachycardia or atrial fibrillation
and, in the older patient, cardiac failure.
It is a medical emergency and, despite
early recognition and treatment, the
mortality rate is 10%.
Thyrotoxic crisis is most commonly 
precipitated by infection in a patient with
previously unrecognised or inadequately
treated thyrotoxicosis. It may also develop
shortly after subtotal thyroidectomy in an
ill-prepared patient or within a few days of
I131 therapy when acute irradiation
damage may lead to a transient rise in
serum thyroid hormone levels.
Patients should be rehydrated and given a broad- 
spectrum antibiotic. Propranolol is rapidly effective
orally (80 mg 6-hourly) or intravenously (1-5 mg 6hourly). Sodium ipodate (500 mg per day orally)
will restore serum T3 levels to normal in 48-72
hours. This is a radiographic contrast medium
which not only inhibits the release of thyroid
hormones, but also reduces the conversion of T3 to
T4 and is, therefore, more effective than potassium
iodide or Lugol's solution. Dexamethasone (2 mg
6-hourly) and amiodarone have similar effects. Oral
carbimazole 40-60 mg daily inhibits the synthesis
of new thyroid hormone. If the patient is
unconscious or uncooperative, carbimazole can be
administered rectally with good effect, but no
preparation is available for parenteral use. After 1014 days the patient can usually be maintained on
carbimazole alone.
HYPOTHYROIDISM
Management
most patients do not require specialist review and will 
require life-long thyroxine therapy. It is customary to start
slowly and a dose of 50 μg per day should be given for 3
weeks, increasing thereafter to 100 μg per day for a
further 3 weeks and finally to a maintenance dose,
usually 100-150 μg per day. Thyroxine has a half-life of 7
days so it should always be taken as a single daily dose
and at least 6 weeks should pass before repeating
thyroid function tests and adjusting the dose, usually in
increments of 25 μg per day. Patients feel better within 23 weeks. Reduction in weight and periorbital puffiness
occurs quickly, but the restoration of skin and hair texture
and resolution of any effusions may take 3-6 months.
The correct dose of thyroxine in the long term is 
that which restores serum TSH to within the
reference range. To achieve this, serum T4 will
usually be in the upper part of the normal range
or even slightly raised, because the T3 required
for receptor activation is derived exclusively from
conversion of T4 within the target tissues without
the usual contribution from thyroid secretion.
Some physicians advocate combined
replacement with T4 & T3 but this approach
remains controversial and no ideal preparation
exists. Some patients remain symptomatic
despite normalisation of TSH and may wish to
take extra thyroxine which suppresses TSH
values. However, there is evidence that
suppressed TSH is a risk factor for osteoporosis
and atrial fibrillation so this approach cannot be
recommended.
It is important to measure thyroid function 
every 1-2 years once the dose of thyroxine is
stabilised. This encourages patient compliance
with therapy and allows adjustment for
variable underlying thyroid activity and other
changes in thyroxine requirements. In some
poorly compliant patients, thyroxine is taken
diligently or even in excess for a few days prior
to a clinic visit, resulting in the seemingly
anomalous combination of a high serum T4
. and high TSH
Thyroxine replacement in ischaemic
heart disease
Hypothyroidism and ischaemic heart disease 
are both common, so inevitably they will
sometimes occur together. Although angina
may remain unchanged in severity or
paradoxically disappear with restoration of
metabolic rate, exacerbation of myocardial
ischaemia, infarction and sudden death are
well-recognised complications of thyroxine
replacement, even using doses as low as 25
μg per day.
In patients with known ischaemic heart disease, 
thyroxine should be introduced at low dose and
increased very slowly under specialist
supervision. It has been suggested that T3 has
an advantage over T4 , since T3 has a shorter
half-life and any adverse effect will reverse more
quickly, but the more distinct peak in hormone
levels after each dose of T3 is a disadvantage.
Approximately 40% of patients with angina
cannot tolerate full replacement therapy despite
the use of β-blockers and vasodilators; coronary
artery surgery or balloon angioplasty can be
performed safely in such patients and, if
successful, allow full replacement dosage of
thyroxine in the majority.
Hypothyroidism in pregnancy
Most pregnant women with primary 
hypothyroidism require an increase in the dose of
thyroxine of ∼50 μg daily to maintain normal TSH
levels. This may reflect increased metabolism of
thyroxine by the placenta and increased serum
thyroxine-binding globulin during pregnancy,
resulting in an increase in the total thyroid
hormone pool to maintain the same free T4 & T3
concentrations. Recent research suggests that
inadequate maternal T4 therapy is associated
with impaired cognitive development in their
offspring. Serum TSH and free T4 should be
measured during each trimester and the dose of
thyroxine adjusted to maintain a normal TSH .
Myxoedema coma
This is a rare presentation of hypothyroidism in 
which there is a depressed level of
consciousness, usually in an elderly patient who
appears myxoedematous. Body temperature
may be as low as 25°C, convulsions are not
uncommon and cerebrospinal fluid (CSF)
pressure and protein content are raised. The
mortality rate is 50% and survival depends upon
early recognition and treatment of
hypothyroidism and other factors contributing to
the altered consciousness level, e.g. drugs such
as phenothiazines, cardiac failure, pneumonia,
dilutional hyponatraemia and respiratory failure.
Myxoedema coma is a medical emergency and 
treatment must begin before biochemical confirmation of
the diagnosis. Thyroxine is not usually available for
parenteral use so triiodothyronine is given as an
intravenous bolus of 20 μg followed by 20 μg 8-hourly
until there is sustained clinical improvement. In survivors
there is a rise in body temperature within 24 hours and,
after 48-72 hours, it is usually possible to substitute oral
thyroxine in a dose of 50 μg per day. Unless it is
apparent that the patient has primary hypothyroidism,
e.g. thyroidectomy scar or goitre, the thyroid failure
should be assumed to be secondary to hypothalamic or
pituitary disease and treatment given with hydrocortisone
100 mg i.m. 8-hourly, pending the results of T4, TSH and
cortisol concentration. Other measures include slow
rewarming, cautious use of intravenous fluids, broadspectrum antibiotics and high-flow oxygen. Occasionally,
assisted ventilation may be necessary.
ASYMPTOMATIC ABNORMAL THYROID FUNCTION
TEST RESULTS
Subclinical thyrotoxicosis: 
The serum TSH is undetectable and the serum 
T3&T4 lie in the upper parts of their respective
reference ranges. This combination is most often
found in older patients with multinodular goitre.
These patients are at increased risk of atrial
fibrillation and osteoporosis and hence the
consensus view is that such patients have mild
thyrotoxicosis and require therapy, usually with
I131. Otherwise, annual review is essential as the
conversion rate to overt thyrotoxicosis with
elevated T4 &/or T3 concentrations is 5% each
year.
Subclinical hypothyroidism
The serum TSH is raised and the serum T4&T3 
concentrations are usually in the lower part of their
respective reference ranges. It may persist for many
years, although there is a risk of progression to overt
thyroid failure, particularly if antibodies to thyroid
peroxidase are present in the serum or if the TSH rises
above 10 mU/l. In patients with non-specific symptoms a
trial of thyroxine therapy may be appropriate. In those
with positive autoantibodies or TSH > 10 mU/l it is better
to treat the thyroid failure early rather than risk loss to
follow-up and subsequent presentation with profound
hypothyroidism. Thyroxine should be given in a dose
sufficient to restore the serum TSH concentration to
normal.
Non-thyroidal illness ('sick euthyroidism)
In patients with systemic illness (e.g. myocardial 
infarction, pneumonia) there is decreased peripheral
conversion of T4 to T3 and alterations of binding proteins
and their affinity for thyroid hormones. In addition, serum
TSH concentrations may be subnormal as a result of the
illness itself or the use of drugs such as dopamine or
corticosteroids. The most common combination is a low
serum TSH, raised T4 and normal or low T3, but many
patterns of thyroid function tests can be seen, dependent
upon the type of assay used. During convalescence,
serum TSH concentrations may increase to levels found
in primary hypothyroidism. It follows that biochemical
assessment of thyroid function should not be undertaken
in patients with non-thyroidal illness, unless there is good
evidence of concomitant thyroid disease, e.g. goitre,
exophthalmos. If an abnormal result is found, treatment
should only be given with specialist advice and the tests
should be repeated after recovery.
AUTOIMMUNE THYROID DISEASE
Thyroid diseases are amongst the most 
prevalent antibody-mediated autoimmune
diseases and are associated with other organspecific autoimmunity. Autoantibodies may
produce inflammation and destruction of thyroid
tissue resulting in hypothyroidism, goitre (in
Hashimoto's thyroiditis) or sometimes even
transient thyrotoxicosis ('Hashitoxicosis'), or they
may stimulate the TSH receptor to cause
thyrotoxicosis (in Graves' disease). There is
overlap between these conditions, since some
patients have multiple autoantibodies.
GRAVES' DISEASE
The most common manifestation is 
thyrotoxicosis with or without a diffuse goitre.
Graves' disease also causes ophthalmopathy
and rarely pretibial myxoedema. These
features usually occur in thyrotoxic patients,
but can occur in the absence of thyroid
dysfunction. Graves' disease can occur at any
age but is unusual before puberty and most
commonly affects women aged 30-50 years.
Pathophysiology
The thyrotoxicosis results from the production of 
IgG antibodies directed against the TSH
receptor on the thyroid follicular cell, which
stimulate thyroid hormone production and, in the
majority, goitre formation. These antibodies are
termed thyroid-stimulating immunoglobulins or
TSH receptor antibodies (TRAb) and can be
detected in the serum of 80-95% of patients with
Graves' disease. The concentration of TRAb in
the serum is presumed to fluctuate to account
for the natural history of Graves' thyrotoxicosis.
The ultimate thyroid failure seen in some
patients is thought to result from the presence of
blocking antibodies against the TSH receptor,
and from tissue destruction by cytotoxic
antibodies and cell-mediated immunity.
Management
Graves' ophthalmopathy
This condition is immunologically mediated, but 
the autoantigen that causes the local
accumulation of lymphocytes has not been
identified. Within the orbit (and the dermis) there
is cytokine-mediated proliferation of fibroblasts
which secrete hydrophilic glycosaminoglycans.
The resulting increased interstitial fluid content,
combined with a chronic inflammatory cell
infiltrate, causes marked swelling and ultimately
fibrosis of the extraocular muscles and a rise in
retrobulbar pressure. The eye is displaced
forwards (proptosis, exophthalmos) and in more
severe cases there is optic nerve compression.
The majority of patients require no treatment 
other than reassurance. Methylcellulose eye
drops and gel counter the gritty discomfort of dry
eyes, and tinted glasses or side shields attached
to spectacle frames reduce the excessive
lacrimation triggered by sun or wind. Severe
inflammatory episodes are treated with oral
glucocorticoids (e.g. prednisolone 60 mg daily)
and sometimes orbital irradiation. Loss of visual
acuity is an indication for urgent surgical
decompression of the orbit. In 'burnt out'
disease, surgery to the eyelids and/or ocular
muscles may improve conjunctival exposure,
cosmetic appearance and diplopia.
HASHIMOTO'S THYROIDITIS
The nomenclature of autoimmune hypothyroidism can be 
confusing. Some authorities reserve the term 'Hashimoto's
thyroiditis' for patients with positive thyroid peroxidase
autoantibodies and a firm goitre who may or may not be
hypothyroid, and use the term 'spontaneous atrophic
hypothyroidism' for hypothyroid patients without a goitre in
whom TSH receptor-blocking antibodies may be more
important than antiperoxidase antibodies. However, these
syndromes can both be considered as variants of
Hashimoto's thyroiditis since both are characterised by
destructive lymphoid infiltration of the thyroid, ultimately
leading to a varying degree of fibrosis which accounts for the
varying degree of thyroid enlargement. In association with
the lymphoid thyroid infiltration there is an increased risk of
thyroid lymphoma, although this is an exceedingly rare
complication.
Hashimoto's thyroiditis increases in incidence with age 
and affects ∼3.5 per 1000 women and 0.8 per 1000 men
each year. Many present with a small or moderately
sized diffuse goitre, which is characteristically firm or
rubbery in consistency. The goitre may be soft, however,
and impossible to differentiate from simple goitre by
palpation alone. Around 25% of patients are hypothyroid
at presentation. In the remainder, serum T4 is normal
and TSH normal or raised, but these patients are at risk
of developing overt hypothyroidism in future years.
Thyroid peroxidase antibodies are present in the serum
in > 90% of patients with Hashimoto's thyroiditis. In those
under the age of 20 years, antinuclear factor (ANF) may
also be positive. Thyroxine therapy is indicated not only
for hypothyroidism, but also sometimes for goitre
shrinkage. In this context, the dose of thyroxine should
be sufficient to suppress serum TSH to low but
detectable levels.
SUBACUTE (DE QUERVAIN'S)
THYROIDITIS
In its classical painful form, subacute thyroiditis 
is a virus-induced (e.g. Coxsackie, mumps or
adenovirus) transient inflammation of the thyroid
gland. There is pain in the region of the thyroid
that may radiate to the angle of the jaw and the
ears, and is made worse by swallowing,
coughing and movement of the neck. The
thyroid is usually palpably enlarged and tender.
Systemic upset is common. Affected patients are
usually females aged 20-40 years.
Painless transient thyroiditis also occurs, 
sometimes after viral infection and sometimes in
patients with underlying autoimmune disease.
In both painless and painful varieties, inflammation 
in the thyroid gland is associated with release of
colloid and stored thyroid hormones, but also with
damage to follicular cells and impaired synthesis of
new thyroid hormones. As a result, T4&T3 levels are
raised for 4-6 weeks until the pre-formed colloid is
depleted. Thereafter, there is usually a period of
hypothyroidism of variable severity before the
follicular cells recover and normal thyroid function is
restored within 4-6 months. In the thyrotoxic phase,
the iodine uptake is low because the damaged
follicular cells are unable to trap iodine and because
endogenous TSH secretion is suppressed. Low-titre
thyroid autoantibodies appear transiently in the
serum, and the erythrocyte sedimentation rate
(ESR) is usually raised. High titre autoantibodies
suggest an underlying autoimmune pathology and
risk of recurrence and ultimate progression to
hypothyroidism.
The pain and systemic upset usually respond to 
simple measures such as non-steroidal antiinflammatory drugs (NSAIDs). Occasionally,
however, it may be necessary to prescribe
prednisolone 40 mg daily for 3-4 weeks. The
thyrotoxicosis is mild and treatment with
propranolol or nadolol is usually adequate.
Antithyroid drugs are of no benefit because
thyroid hormone synthesis is impaired rather
than enhanced. Careful monitoring of thyroid
function and symptoms is required so that
thyroxine can be prescribed temporarily in the
hypothyroid phase. Care must be taken to
identify patients presenting with hypothyroidism
who are in the later stages of a transient
thyroiditis, since they are unlikely to require lifelong thyroxine therapy.
POST-PARTUM THYROIDITIS
The maternal immune response, which is 
modified during pregnancy to allow survival of
the fetus, is enhanced after delivery and may
unmask previously unrecognised subclinical
autoimmune thyroid disease. Surveys have
shown that transient biochemical disturbances of
thyroid function, i.e. thyrotoxicosis,
hypothyroidism and thyrotoxicosis followed by
hypothyroidism, occur in 5-10% of women within
6 months of delivery.
Those affected are likely to have antithyroid 
peroxidase antibodies in the serum in early
pregnancy. Symptoms of thyroid dysfunction are
rare and there is no association between
postnatal depression and abnormal thyroid
function tests. However, symptomatic
thyrotoxicosis presenting for the first time within
6 months of childbirth is likely to be due to postpartum thyroiditis and the diagnosis is confirmed
by a negligible radio-isotope uptake. The clinical
course and treatment are similar to painless
subacute thyroiditis (see above). Post-partum
thyroiditis tends to recur after subsequent
pregnancies and eventually patients progress
over a period of years to permanent
hypothyroidism.
SIMPLE DIFFUSE GOITRE
This form of goitre usually presents between the ages of
15 and 25 years, often during pregnancy, and tends to
be noticed, not by the patient, but by friends and
relatives. Occasionally, there is a tight sensation in the
neck, particularly when swallowing. The goitre is soft and
symmetrical and the thyroid is enlarged to two or three
times its normal size. There is no tenderness,
lymphadenopathy or overlying bruit. Concentrations of
T3&T4 and TSH are normal and no thyroid
autoantibodies are detected in the serum. No treatment
is necessary and in most cases the goitre regresses. In
some, however, the unknown stimulus to thyroid
enlargement persists and, as a result of recurrent
episodes of hyperplasia and involution during the
following 10-20 years, the gland becomes multinodular
with areas of autonomous function.

MULTINODULAR GOITRE
Patients with thyroid enlargement in the absence of thyroid 
dysfunction or positive autoantibodies (i.e. with 'simple
goitre', see above) as young adults may progress to develop
nodules. These nodules grow at varying rates and secrete
thyroid hormone 'autonomously', thereby suppressing TSHdependent growth and function in the rest of the gland.
Ultimately, complete suppression of TSH occurs in about
25% of cases, with T3&T4 levels often within the normal
range but sometimes elevated. Opinions differ as to whether
the nodules represent multiple adenomas or focal
hyperplasia. There are reports that the prevalence of foci of
thyroid cancer is increased in multinodular goitres, but for
practical purposes patients can be reassured that it is a
benign condition and malignancy need only be considered in
patients with a large 'dominant' nodule that is 'cold' (i.e. does
not take up radioisotope).
Clinical features and investigations
Multinodular goitre is usually diagnosed in 
patients presenting with thyrotoxicosis, a large
goitre with or without tracheal compression, or
sudden painful swelling caused by haemorrhage
into a nodule or cyst. The goitre is nodular or
lobulated on palpation and may extend
retrosternally; however, not all mutinodular
goitres causing thyrotoxicosis are easily
palpable. Very large goitres may cause
mediastinal compression with stridor, dysphagia
and obstruction of the superior vena cava.
Hoarseness due to recurrent laryngeal nerve
palsy can occur, but is far more suggestive of
thyroid carcinoma.
The diagnosis is confirmed by a radioisotope 
thyroid scan and/or ultrasonography. In patients
with large goitres a flow-volume loop is a good
screening test for significant tracheal
compression. If intervention is contemplated, a
chest X-ray may be helpful, but CT or MRI of the
thoracic inlet is optimal to quantify the degree of
tracheal displacement or compression and the
extent of retrosternal extension. In those with a
'dominant', 'cold' nodule, fine needle aspiration is
indicated to exclude thyroid cancer .
Management
If the goitre is small, no treatment is necessary 
but annual review should be arranged as the
natural history is progression to a toxic
multinodular goitre. Partial thyroidectomy is
indicated for large goitres which cause
mediastinal compression or which are
cosmetically unattractive. I131 can result in a
significant reduction in thyroid size and may be
of value in elderly patients. Unfortunately,
recurrence 10-20 years later is not uncommon.
Thyroxine is of no benefit in shrinking
multinodular goitres and may serve only to
aggravate any associated thyrotoxicosis.
In toxic multinodular goitre treatment is usually 
with I131. The iodine uptake is lower than in
Graves' disease so a higher dose is employed
(555-1850 MBq, 15-50 mCi) and hypothyroidism
is less common. In thyrotoxic patients with a
large goitre, partial thyroidectomy may be
indicated. Long-term treatment with antithyroid
drugs is not usually appropriate as relapse is
invariable after drug withdrawal . Asymptomatic
patients with subclinical thyrotoxicosis are
increasingly being treated with I131 on the
grounds that a suppressed TSH is a risk factor
for atrial fibrillation and, particularly in postmenopausal women, osteoporosis.