THYROID DISORDERS

Hypothyroidism

Measurement of antithyroid antibodies is unhelpful in the

diagnosis of hypothyroidism, but may indicate the cause. Antibodies to thyroglobulin or thyroid peroxidase (microsomal antibodies) are typically positive in Hashimotos thyroiditis.

Jayne A Franklyn

Special types of hypothyroidism

Abstract

Hashimotos thyroiditis
Hashimotos thyroiditis typically affects middle-aged and elderly
women. It is an autoimmune disorder; thyroid histology typically
reveals diffuse lymphocytic infiltration.

Hypothyroidism is a common clinical syndrome that results from deficiency

of the thyroid hormones thyroxine (T4) and tri-iodothyronine (T3). The diagnosis must be confirmed by biochemical testing. Primary hypothyroidism is
indicated by a rise in serum thyrotrophin (TSH). Hypothyroidism is readily
treated by T4 replacement, the aims of treatment being relief of symptoms
and restoration of serum TSH to the reference range.

Clinical features: patients present with goitre, hypothyroidism

or both. The thyroid can vary in size from barely palpable to
greatly enlarged, but is characteristically moderately enlarged,
firm and non-tender.

Keywords Hashimotos thyroiditis; hypothyroidism; thyrotrophin;

thyroxine

Associated conditions include vitiligo, pernicious anaemia, type

1 diabetes mellitus, Addisons disease and premature ovarian
failure. An increased incidence of Hashimotos thyroiditis is also
found in those with Downs or Turners syndromes.

Prevalence and causes

In the UK, the incidence of hypothyroidism is about 3.5/1000 in
females and 0.6/1000 in males.1 The cause (Table 1) may be
primary thyroid disease or, less commonly, disease of the pituitary or hypothalamus (secondary hypothyroidism).2

Idiopathic atrophic hypothyroidism

Idiopathic atrophic hypothyroidism is a common cause of hypothyroidism. The incidence increases with age, and it is ten
times more common in women than men. The aetiology of
atrophic hypothyroidism is less clear than that of Hashimotos
thyroiditis; however, lymphocytic infiltration of the thyroid and
an association with organ-specific autoimmune diseases suggest
an autoimmune cause.
Previous treatment for hyperthyroidism (radioiodine therapy,
partial thyroidectomy) may result in hypothyroidism.

Clinical features
The onset of hypothyroidism may be insidious and the symptoms
non-specific and vague. The presenting symptoms and signs are
diverse (Table 2) and reflect the widespread tissue actions of
thyroid hormones. In mild disease, symptoms and signs are often
absent.

Investigations

Congenital hypothyroidism
The prevalence of congenital hypothyroidism in the UK is 1/4000
to 1/3500 infants (three to four times more common than
phenylketonuria). In the UK and other developed countries, it is
diagnosed during routine screening of all infants by measurement of TSH or T4 in heel-prick blood in the first week of life.
Congenital hypothyroidism is usually caused by thyroid
agenesis, ectopic or hypoplastic thyroid tissue or dyshormonogenesis (usually an autosomal recessive disorder commonly due
to deficiency of thyroid peroxidase, which mediates thyroid
hormone synthesis). Neonatal screening programmes allow T4
therapy to be started within 2 weeks of birth. Most studies
indicate that normal intellectual development can be achieved.

Biochemical confirmation of the diagnosis is essential.2,3

A reduction in serum free or total thyroxine (T4) with increased
serum thyrotrophin (TSH) indicates primary hypothyroidism.
Elevated serum TSH in association with normal T4 is termed
subclinical hypothyroidism.
Measurement of serum free or total tri-iodothyronine (T3) is
unhelpful because T3 is often reduced only slightly, even in those
with overt hypothyroidism, because of increased peripheral
conversion of T4 to T3. Illnesses unrelated to the thyroid and
drug therapy are more common causes of reduced T3, particularly in hospitalized patients.
Secondary hypothyroidism (as a result of pituitary/hypothalamic disease) is indicated by reduced free and total T4, and a
serum TSH within or below the normal range; this biochemical
picture is also seen in patients with non-thyroidal illness, and in
those taking drugs such as corticosteroids or anticonvulsants. If
secondary hypothyroidism is suspected, further investigation of
hypothalamic/pituitary function is indicated.

Iodine-deficient hypothyroidism
Marked iodine deficiency is not evident in developed countries
such as the UK (except in some taking a strict vegan diet) since
there is adequate iodine in diet, especially in dairy products.
However, iodine deficiency is a major cause of goitre and hypothyroidism worldwide, and can be eradicated by effective
iodine supplementation programmes. Iodine deficiency is typically found in mountainous regions of developing countries.
Most iodine-deficient individuals have a goitre (termed endemic
goitre in areas of high prevalence), but are euthyroid with
normal or elevated serum TSH.

Jayne A Franklyn MD PhD FRCP FMedSci is the William Withering Professor

of Medicine at the University of Birmingham and an Endocrinologist at
the Queen Elizabeth Hospital, Birmingham, UK. Competing interests:
none declared.

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Causes of hypothyroidism

Clinical features of hypothyroidism

Primary thyroid failure

Common
C
Autoimmune (Hashimotos) thyroiditisa
C
Idiopathic atrophya
C
Previous treatment with radioiodine or thyroidectomya
C
Iodine deficiency (common worldwide)
C
Antithyroid drugs
C
Other drugs (e.g. lithium, amiodarone)
C
Subacute and silent thyroiditis
Uncommon
C
Dyshormonogenesis
C
Agenesis
C
Infiltrative disease
Secondary thyroid failure
C
Disease of the hypothalamus or pituitary

General
C
Tirednessa
C
Weight gaina
C
Cold intolerancea
C
Goitrea
C
Hyperlipidaemiaa
Haematological
C
Iron-deficiency anaemia
C
Macrocytic anaemia
C
Pernicious anaemia
C
Normochromic, normocytic anaemia
Cardiovascular/respiratory
C
Bradycardiaa
C
Angina
C
Cardiac failure
C
Pericardial effusions
C
Pleural effusions
C
Erythema ab igne
Dermatological
C
Dry skina
C
Myxoedema (local infiltration with hyaluronic acid and
muciopolysaccharides)
C
Vitiligo
C
Alopecia
Neuromuscular
C
Aches and painsa
C
Carpal tunnel syndrome
C
Myalgia and muscle stiffness
C
Hoarseness
C
Deafness
C
Cerebellar ataxia
C
Delayed relaxation of reflexesa
C
Depression
C
Psychosis (myxoedema madness)
Gastrointestinal
C
Constipation
C
Ileus
C
Ascites
Reproductive
C
Infertility
C
Menorrhagia
C
Galactorrhoea and hyperprolactinaemia
Developmental
C
Growth retardation
C
Mental retardation
C
Delayed puberty

These conditions together account for 90% of cases in developed

countries.

Table 1

Cretinism: severe maternal iodine deficiency is associated with

neurological damage to the fetus and subsequent mental retardation (neurological cretinism) that is not improved by iodine or
thyroid hormone supplementation in pregnancy or neonatal life.
Iodine deficiency in late, rather than early, pregnancy or in infancy
results in neonatal hypothyroidism, which predominantly affects
somatic development (myxoedematous cretinism), with marked
growth retardation. In contrast to neurological cretinism, treatment of neonatal hypothyroidism with iodine supplementation or
T4 has some benefit.
Iatrogenic hypothyroidism
Iodine: long-term therapy with iodine (e.g. in expectorants or
kelp preparations) occasionally results in hypothyroidism.
Iodine-containing drugs (particularly the anti-arrhythmic amiodarone) can also cause hypothyroidism, particularly in patients
with a history of thyroid disorders or who are positive for thyroid
antibodies.
In euthyroid individuals, amiodarone treatment is associated
with a modest increase in serum T4 concentration and a decrease
in serum T3; TSH is largely unaffected. Development of hypothyroidism is confirmed by reduced T4 and increased TSH
concentrations.
Lithium carbonate causes various abnormalities, including goitre and hypothyroidism, most commonly in those positive for
thyroid antibodies. A regular (6-monthly or 12-monthly) check of
thyroid function is therefore important.

Most common features.

Table 2

Management
Patients with symptomatic hypothyroidism require T4, which is
available as levothyroxine, usually in tablets of 25, 50 or 100 mg.
A T4 dose of 100e150 mg/day is effective in most patients; divided
doses are unnecessary in view of its long half-life (7 days).
Symptomatic improvement is seen within 2e3 weeks of starting

MEDICINE 41:9

therapy, although 6e8 weeks treatment at full dose may be

required for serum TSH to return to normal. TSH measurements
should not be undertaken until 6e8 weeks after changing dose.
There is no evidence of advantage in combination T4 and T3
treatment.4

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THYROID DISORDERS

spontaneously, particularly in the elderly. Whether such patients

require T4 for their compensated hypothyroidism remains unclear.9 However, the slowly progressive nature of the thyroid
failure, particularly in those who have been treated with radioiodine or who are thyroid antibody-positive, as well as possible
associations with hypercholesterolaemia and with ischaemic heart
disease,10 favours T4 treatment in patients whose serum TSH is
consistently more than 10 mU/litre. When TSH is only slightly
raised (5e10 mU/litre), there is little evidence that treatment is
beneficial;2,9,11 TSH testing should be repeated every 6e12 months
to document any progression. An exception is in the preconception period or in pregnancy, when T4 should be initiated
if serum TSH is only mildly elevated because of an association of
mild hypothyroidism with subtle neurodevelopment abnormalities in childhood.12

Monitoring T4 therapy: the aim of T4 therapy is to restore serum

T4 and TSH to normal levels.2,3 Suppression of TSH with serum T4
at the upper end of the normal range or slightly elevated is
sometimes observed in those taking standard doses.5 These
biochemical findings are indicative of over-treatment and indicate
a need for dose reduction; there is evidence for long-term cardiovascular and osteoporosis risks associated with over-treatment.6,7
There is evidence that up to 25% of patients in the community
taking T4 for hypothyroidism are under-treated, so adequacy of
therapy and adherence with treatment should be checked by
annual TSH measurement. In non-adherent patients who take T4
for a few days before testing, thyroid function tests typically
reveal normal or even elevated T4 with paradoxically raised TSH.
In most patients, dose requirements for T4 do not change, but
pregnancy often necessitates a dose increase to maintain normal
serum TSH.8 Therapy with some drugs also alters T4 dose requirements because of effects on T4 absorption or metabolism
(Table 3).

Myxoedema coma
Myxoedema coma is an uncommon complication of hypothyroidism, typically seen in the elderly and often precipitated by
infection, therapy with sedative drugs or cold weather. Coma
does not occur in all patients, but reduction of consciousness
level is common as is hypothermia. Other features include hypotension, heart failure, hyponatraemia, and hypoventilation
with hypoxia and hypercapnia.
Treatment comprises general supportive measures, including
intravenous fluids, antibiotics, ventilation and slow re-warming, in
addition to thyroid hormone replacement. Traditionally, intravenous boluses of T3, 100 mg followed by 20 mg three times daily, are
given. T3 is given because of its rapid action; T4 administered by
mouth or nasogastric tube can be substituted after 2e3 days if there
is clinical improvement. Glucocorticoid replacement (hydrocortisone, 100 mg three times daily) is given in conjunction with T3 in
patients in whom secondary hypoadrenalism is a possibility. A

Duration of therapy: mild hypothyroidism occurring within the

first 6 months after therapy for hyperthyroidism, or as part of
subacute or silent thyroiditis, may be temporary.2 If the symptoms are sufficiently severe to require treatment with T4,
consider stopping treatment after 6 months for a period of 6
weeks so that serum TSH can be measured in the absence of T4
therapy. Hypothyroidism diagnosed in other circumstances is
lifelong, so withdrawal of T4 therapy is inappropriate.

Special situations
Ischaemic heart disease
Caution should be exercised in the elderly and those with a history
of heart disease; initiation of T4 therapy may precipitate worsening
angina, myocardial infarction and even death as a consequence of
the resulting increase in heart rate and cardiac work. In those
with severe ischaemic heart disease who are found to be hypothyroid, it is important to start T4 at a low dose (25 mg daily or on
alternate days), increasing the dose cautiously every 4 weeks until
euthyroidism is achieved. Ultimately, effective T4 replacement is
beneficial because it corrects the hypercholesterolaemia of hypothyroidism and improves cardiac function.

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