THYROID DISORDERS
Hypothyroidism
Jackie Gilbert
Abstract
Hypothyroidism results from deficiency of the thyroid hormones
thyroxine (T4) and triiodothyronine. Symptoms are diverse and not
specific to thyroid disease. The most common causes are chronic
autoimmune thyroid disease and destructive treatments for hyperthy-
roidism. The diagnosis is confirmed biochemically by a reduction in
serum free T4 with increased serum thyroid-stimulating hormone
(TSH; thyrotrophin). Subclinical hypothyroidism is a biochemical diag-
nosis and describes an elevated serum TSH with normal free thyroid
hormones. Hypothyroidism is treated by T4 replacement, the aims of
treatment being relief of symptoms and restoration of serum TSH to
the reference range.
Keywords Autoimmune; hypothyroidism; liothyronine; MRCP;
subclinical hypothyroidism; thyroid-stimulating hormone; thyroxine
Introduction
In the UK, the prevalence of spontaneous hypothyroidism is 1
e2%. It is more common with increasing age and 10 times more
common in women than men.1 The most common cause is
chronic autoimmune disease, namely goitrous autoimmune
thyroiditis (Hashimoto’s thyroiditis) and atrophic autoimmune
thyroiditis. Other causes (Table 1) include destructive treatments
for hyperthyroidism, i.e. radioactive iodine or surgery, and drugs
such as thionamides, lithium, amiodarone and interferon-a.
Congenital hypothyroidism affects approximately one in 3500
e4000 newborns.
Iodine deficiency is a common cause of hypothyroidism
worldwide. A UK-based study measuring iodine status in 14e15-
year-old schoolgirls revealed mild iodine deficiency according to
World Health Organization criteria. However, a more recent
study of schoolchildren aged 8e10 years found that this age
group was not at risk of iodine deficiency; this may be because of
higher milk consumption in this younger age group.
Clinical features
The presenting symptoms and signs of hypothyroidism (Table 2)
are diverse, reflecting the widespread tissue actions of thyroid
hormones. Notably, the symptoms are not specific to
hypothyroidism.
Investigations
The diagnosis must be confirmed biochemically. A reduction in
serum free thyroxine (T4) with increased serum thyroid-
Jackie Gilbert PhD FRCP is a Consultant in Endocrinology and
General Internal Medicine at King’s College Hospital NHS
Foundation Trust, London and an Honorary Senior Lecturer at King’s
College London, UK. Research interest e autoimmune thyroid
disease. Competing interests: none declared.
MEDICINE 45:8
Key points
C Primary hypothyroidism has a prevalence of 1e2% in the UK;
the most common cause is autoimmune thyroiditis
C Subclinical hypothyroidism is found in 5e10% of the
population
C Symptoms of hypothyroidism are non-specific so the diag-
nosis must be confirmed biochemically
C Synthetic levothyroxine monotherapy remains the treatment of
choice for hypothyroidism
stimulating hormone (TSH; thyrotrophin)) indicates primary
hypothyroidism.
Measurement of serum free triiodothyronine (T3) is unhelpful
because T3 can be marginally reduced even in individuals with
overt hypothyroidism. This is because of increased peripheral
conversion of T4 to T3. Non-thyroidal illness and drug therapy
are more common causes of reduced T3, particularly in hospital
inpatients.
Secondary hypothyroidism (as a result of pituitary/hypotha-
lamic disease) is indicated by reduced free T4 and a non-elevated
serum TSH. Non-thyroidal illness can also produce this
biochemical picture, as can drugs such as corticosteroids or an-
ticonvulsants. If secondary hypothyroidism is suspected, further
investigation of hypothalamic/pituitary function is indicated.
Measurement of antithyroid antibodies may indicate the
aetiology. Antibodies to thyroglobulin or thyroid peroxidase
(microsomal antibodies) are typically positive in Hashimoto’s
thyroiditis.
Subclinical hypothyroidism
This is a biochemical diagnosis and describes the finding of
elevated serum TSH with normal free thyroid hormones.2 The
elevated serum TSH is a sensitive indicator of a degree of thyroid
failure and there is an inverse relationship with free T4
concentrations.
Causes of primary hypothyroidism
Common
C Autoimmune Hashimoto’s thyroiditis
C Autoimmune atrophic thyroiditis
C Previous treatment with surgery or radioactive iodine
C Iodine deficiency (common worldwide)
C Drugs: anti-thyroid drugs, lithium, amiodarone, interferon-a
C Destructive thyroiditis
Uncommon
C Agenesis
C Dyshormonogenesis
C Infiltrative disorders
Secondary hypothyroidism
C Pituitary or hypothalamic disease
Table 1
506 Ó 2017 Elsevier Ltd. All rights reserved.
 THYROID DISORDERS

thereafter. Potential deleterious health effects of iatrogenic

Clinical features of hypothyroidism thyrotoxicosis include atrial fibrillation and osteoporosis.
General Haematological L-T4 therapy should be initiated more cautiously in patients
C Lethargy C Macrocytic anaemia who are elderly and/or have a history of ischaemic heart disease
C Weight gain C Pernicious anaemia as it can worsen angina and myocardial infarction as a result of
C Cold intolerance C Normocytic anaemia increased heart rate and cardiac work. T4 should be started at a
C Goitre C Iron deficiency anaemia low dose (e.g. 25 mg) daily, increasing the dose cautiously every
Cardiovascular Dermatological 4 weeks until euthyroidism has been achieved. Ultimately,
C Bradycardia C Dry skin effective T4 replacement is beneficial because it corrects the
C Cardiac failure C Myxoedema hypercholesterolaemia of hypothyroidism and improves cardiac
C Angina C Alopecia function.
C Pericardial effusions C Vitiligo Evidence for the benefit of thyroid hormone treatment in
Gastrointestinal Reproductive subclinical hypothyroidism is inconsistent. Epidemiological
C Constipation C Menorrhagia studies have shown an association between subclinical hypo-
C Ileus C Infertility thyroidism and coronary heart disease in younger people (<65
Neuromuscular Developmental years) and those with a TSH >10 mU/litre. However recent ev-
C Myalgia C Growth retardation idence suggests that higher serum TSH and lower free T4 con-
C Hoarse voice C Mental retardation centrations within the euthyroid range in older people are
C Slow relaxing reflexes C Delayed puberty associated with lower risks of adverse events, including
C Carpal tunnel syndrome Metabolic mortality.
C Depression C Hyperlipidaemia L-T4 absorption can be impaired by other drugs and supple-
C Psychosis ments, such as calcium- and iron-containing preparations
(Table 3). It is recommended that a minimum of 4 hours is
Table 2 maintained between ingestion of these medications. Higher doses
of L-T4 may be required with co-prescription of drugs that induce
Subclinical hypothyroidism is found in 5e10% of the popu- increased L-T4 metabolism.
lation, being more common in women and increasing with age. It Most patients demonstrate a satisfactory response to L-T4
can progress to overt hypothyroidism, particularly if patients treatment. However, it is acknowledged that a proportion of in-
have elevated concentrations of thyroid antibodies.3 The most dividuals taking L-T4 are not satisfied with therapy and have
common aetiology is chronic autoimmune thyroiditis. The term persistent symptoms despite a normal serum TSH. Such patients
‘subclinical’ suggests that patients should be asymptomatic. should be thoroughly evaluated for other potentially modifiable
However, symptoms can be challenging to assess, especially in conditions (Table 4).
patients who present with non-specific complaints such as Combination L-T4/liothyronine (L-T3) therapy should not be
tiredness. TSH testing should be repeated every 6e12 months to used routinely for patients with hypothyroidism as there is
document any biochemical progression. insufficient evidence to show that combination therapy is supe-
An exception is during the pre-conception period or preg- rior to L-T4 monotherapy. L-T3 should be reserved for use by
nancy, when T4 treatment should be initiated if serum TSH is accredited endocrinologists for individual patients.5 Limited data
only mildly elevated because of an association of mild hypo- suggest that psychological well-being and preference for L-T4/L-
thyroidism with neurodevelopment abnormalities in childhood. T3 combination therapy can be influenced by polymorphisms in
thyroid hormone pathway genes, specifically in thyroid hormone
TSH reference range transporters and deiodinases. Genetic testing for these specific
deiodinase polymorphisms is currently available only in the
There is controversy regarding the upper limit of the reference
research setting.
range for serum TSH. Reference ranges are derived from a
reference population comprising a large group of individuals who
do not have thyroid disease and are otherwise well. For serum Drugs and supplements that interact with L-T4
TSH, the reference range in individuals without thyroid disease is
typically cited as 0.4e4.0 mU/litre.4 Reduced thyroxine absorption
C Sucralfate
Management C Proton pump inhibitors
C Cimetidine
Synthetic levothyroxine (L-T4) monotherapy remains the treat- C Calcium salts
ment of choice for hypothyroidism, the aim of therapy being to C Ferrous sulphate
restore physical and psychological well-being while maintaining C Aluminium hydroxide
normal laboratory reference range concentrations of serum TSH. Increased thyroxine metabolism
L-T4 can be initiated at a dose of 1.6 micrograms/kg body C Rifampicin
weight. After initiation of therapy, TSH should be monitored 6 C Phenytoin
e8-weekly and the dose of L-T4 should be adjusted until a stable C Carbamazepine
TSH concentration has been achieved; after this TSH can be
checked 4e6-monthly for the first year and then annually Table 3

MEDICINE 45:8 507 Ó 2017 Elsevier Ltd. All rights reserved.

 THYROID DISORDERS

Hypothyroid crisis/coma
Causes of persistent symptoms in euthyroid patients
taking L-T4 therapy Hypothyroid crisis is an uncommon complication of hypothy-
roidism, typically seen in elderly individuals and often caused
Endocrine/autoimmune by infection. A reduced level of consciousness is common. Other
C Adrenal insufficiency features include hypothermia, hypotension, heart failure,
C Diabetes mellitus hyponatraemia and hypoventilation with hypoxia and
C Coeliac disease hypercapnia.
C Obesity Treatment comprises multisystem support including intrave-
Haematological nous fluids, antibiotics, ventilation and slow rewarming with
C Anaemia thyroid hormone replacement. Intravenous T3 is traditionally
Nutritional
given because of its rapid action. T4 can be administered in
C Iron deficiency
conjunction with this by mouth or nasogastric tube. Glucocorti-
C Vitamin B12 deficiency
coid replacement (parenteral hydrocortisone 50e100 mg three to
C Folate deficiency
four times daily) is given in conjunction with T3 in patients in
Drugs
C Statins
whom hypoadrenalism may be present. A
C Opiates
C b-Adrenoceptor blockers KEY REFERENCES
C Alcohol excess 1 Vanderpump MP. The epidemiology of thyroid disease. Br Med Bull
Rheumatological 2011; 99: 39e51.
C Polymyalgia rheumatica 2 Cooper DS, Biondi B. Subclinical thyroid disease. Lancet 2012;
C Fibromyalgia 379: 1142e54.
Other
3 Vanderpump MP, Tunbridge WM, French JM, et al. The incidence
C Stress
of thyroid disorders in the community: a twenty-year follow-up of
C Sleep deprivation
the Whickham Survey. Clin Endocrinol (Oxf) 1995; 43: 55e68.
C Chronic fatigue syndrome
4 Association of Clinical Biochemistry, British Thyroid Association
C Depression and anxiety
and British Thyroid Foundation. UK guidelines for the use of thyroid
Table 4 function tests. 2006, www.british-thyroid-association.org.
5 Royal College of Physicians. The diagnosis and management of
primary hypothyroidism e revised statement. 2011, http://www.
Hypothyroidism and pregnancy british-thyroid-association.org/current-bta-guidelines (accessed 12
In neonates and children, during pregnancy, or in women trying Dec 16).
to conceive, a mildly increased serum TSH should always be
FURTHER READING
treated as mild thyroid failure; this is associated with adverse
Alexander EK, Pearce EN, Brent GA, et al. 2016 Guidelines of the
outcomes for both mother and fetus.
American Thyroid Association for the diagnosis and management
The serum TSH reference range in pregnancy is 0.4e2.5 mU/
of thyroid disease during pregnancy and the postpartum. Thyroid
litre in the first trimester and 0.4e3.0 mU/litre in the second and
2017; 27: 315e89.
third trimesters, or should be based on the trimester-specific
Okosieme O, Gilbert J, Abraham P, et al. Management of primary
reference range for the particular population if these are avail-
hypothyroidism: statement by the British Thyroid Association Ex-
able. These reference ranges should be achieved where possible
ecutive Committee. Clin Endocrinol (Oxf) 2016; 84: 799e808.
with appropriate doses of L-T4 before conception and most
Vanderpump MP, Lazarus JH, Smyth PP, et al. British Thyroid Asso-
importantly in the first trimester. L-T4/L-T3 combination therapy
ciation UK Iodine Survey Group. Iodine status of UK schoolgirls: a
is not recommended in pregnancy.
cross-sectional survey. Lancet 2011; 377: 2007e12.

TEST YOURSELF
To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the
end of the issue or online here.

Question 1 What is an optimum initial dose of thyroxine?

A Levothyroxine 25 micrograms
A 27-year-old woman was diagnosed with primary hypothy-
B Levothyroxine 50 micrograms
roidism. She had no significant past medical history and was not
C Levothyroxine 75 micrograms
taking regular medication.
D Levothyroxine 100 micrograms
On examination, weight was 62 kg, body mass index 26 kg/m2,
E Levothyroxine 175 micrograms
pulse 75 beats/minute and blood pressure 115/70 mmHg.

MEDICINE 45:8 508 Ó 2017 Elsevier Ltd. All rights reserved.

 THYROID DISORDERS
Question 2
A 55-year-old woman was treated with thyroxine for primary
hypothyroidism. Her thyroid function tests were confirmed to be
within the reference range one year previously. Since then, she
has commenced the following medications; atenolol, calcium
carbonate, codeine, furosemide and ibuprofen. Recent thyroid
function tests had demonstrated the following results, on both
initial samples and retesting.
Investigations
 Free thyroxine 14.5 pmol/litre (9e25)
 Thyroid-stimulating hormone 10.3 mU/litre (0.3e5.0)
Which of the following medications/supplements is most
likely to be adversely affecting thyroxine absorption?
A Atenolol
B Calcium carbonate
C Codeine
D Furosemide
E Ibuprofen
MEDICINE 45:8
Question 3
A 45-year-old woman presented with tiredness, weight gain and
muscle aches and pains. There was no significant previous history,
and she was taking no drugs. She was separated from her husband.
On clinical examination, heart rate was 78 beats/minute and blood
pressure 138/90 mmHg. Areas tender to palpation were found in
the arm muscles, but there were no other abnormal findings.
Investigations
 Serum free thyroxine 15.0 pmol/litre (10.0e22.0)
 Serum thyroid-stimulating hormone 8.0 mU/litre (0.4e5.0)
Similar thyroid function test results were obtained on repeat
testing after a 3 month interval.
What is the most likely diagnosis?
A Chronic autoimmune thyroiditis
B Pituitary tumour
C Non-thyroidal illness
D Subclinical hypothyroidism
E Iodine deficiency
509 Ó 2017 Elsevier Ltd. All rights reserved.