BMJ 2014;349:g5128 doi: 10.1136/bmj.

g5128 (Published 21 August 2014)

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Clinical Review

CLINICAL REVIEW
Diagnosis and management of thyrotoxicosis
1

Bijay Vaidya consultant endocrinologist and honorary associate professor , Simon H S Pearce
2
professor of endocrinology and honorary consultant physician
Department of Endocrinology, Royal Devon and Exeter Hospital, and University of Exeter Medical School, Exeter EX2 5DW, UK; 2Endocrine Unit,
Royal Victoria Infirmary and Newcastle University, Newcastle upon Tyne, UK
1

Thyrotoxicosis is a common condition associated with excess

circulating thyroid hormones that may present in myriad ways
and thus will be encountered by practitioners in all medical
disciplines. In Europe, it affects around 1 in 2000 people
annually.1 Although thyrotoxicosis typically presents with
weight loss, heat intolerance, and palpitations, there are a large
variety of additional features, which manifest more variably
with advancing age and in people with milder disease. It is
important to determine the cause of the thyrotoxicosis, as this
determines treatment. Some experts distinguish between
thyrotoxicosis and hyperthyroidism by restricting the latter term
to describe the conditions associated with excess synthesis and
secretion of thyroid hormones from the thyroid gland.
This clinical review summarises the current evidence for the
diagnosis and management of adults with thyrotoxicosis.

What are the causes of thyrotoxicosis and

who gets it?
Table 1 lists the important causes of thyrotoxicosis and the
underlying pathogeneses. Graves disease is the most common
cause, accounting for about 75% of cases. It is typical in women
aged 30-50 years but can occur at any age in both sexes. People
with a history of other autoimmune disorders, those with a
family history of thyroid or other autoimmune disorders, and
smokers are at an increased risk of Graves disease.2 Several
case-controlled studies,3 4 but not all,5 have shown an increased
reporting of major adverse life events within the year before the
diagnosis of Graves disease, indicating that stress may act as
a trigger for the disease. Furthermore, observational studies
have shown an increased incidence of a new diagnosis or relapse
of Graves disease in the postpartum period, suggesting that
childbirth is an additional risk factor.6 Finally, people who are
recovering from immunosuppression such as during highly
active antiretroviral therapy for HIV are also at high risk of
developing Graves disease.7
Thyrotoxicosis due to toxic nodular goitre is more common in
people aged over 60 years. Those living in iodine deficient
regions are particularly at risk.

What is the underlying pathophysiology

of thyrotoxicosis?
Graves disease is an autoimmune disease mediated by
antibodies that stimulate the thyroid stimulating hormone (TSH)
receptor, leading to excess secretion of thyroid hormones and
hyperplasia of thyroid follicular cells, resulting in
hyperthyroidism and diffuse goitre (table 1). Both genetic and
environmental factors (for example, smoking, stress, and dietary
iodine) play important roles in the pathogenesis of Graves
disease.8
Hyperthyroidism in solitary toxic nodule and toxic multinodular
goitres results from over-secretion of thyroid hormones by one
or more nodules. Histologically these nodules are benign
follicular adenomas.
Thyroiditis (subacute, silent, or post partum) causes release of
preformed thyroid hormones into the circulation as a result of
inflammatory destruction of the thyroid follicles, resulting in
transient thyrotoxicosis.

Gestational hyperthyroidism occurs in the first trimester of

pregnancy owing to increased secretion of thyroid hormone in
response to placental human chorionic gonadotrophin, which
is structurally similar to TSH.9 Gestational hyperthyroidism is
particularly common in women with hyperemesis gravidarum,
which is associated with high levels of human chorionic
gonadotrophin.

Several drugs, including amiodarone, iodine, lithium, interferon

, highly active retroviral therapy, tyrosine kinase inhibitors,
and levothyroxine can cause thyrotoxicosis in different ways
(table 1).

What are the clinical features and

associated conditions?
Weight loss, heat intolerance, palpitations, tremor, anxiety, and
tiredness are common symptoms of thyrotoxicosis (box). Older
patients tend to have fewer symptoms; an observational study
of over 3000 consecutive patients with thyrotoxicosis found

Correspondence to: B Vaidya b.vaidya@exeter.ac.uk

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BMJ 2014;349:g5128 doi: 10.1136/bmj.g5128 (Published 21 August 2014)

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CLINICAL REVIEW

Summary points
It is important to determine the causes of thyrotoxicosis as some are self limiting
The test for antibodies to thyroid stimulating hormone receptor is more sensitive and specific than the test for antibodies to thyroid
peroxidase for the diagnosis of Graves disease
Stratification of the severity of Graves disease is good practice, allowing patients with a low probability of remission from treatment with
antithyroid drugs to be considered for radioiodine or thyroidectomy at an early stage
The block-replace regimen of antithyroid drugs must not be used to treat hyperthyroidism in pregnancy
Radioiodine treatment should be avoided in patients with active thyroid eye disease

Sources and selection criteria

We searched Medline, Clinical Evidence, and the Cochrane library using various combinations of terms: thyrotoxicosis, hyperthyroidism,
Graves disease, subclinical hyperthyroidism, thyroiditis, antithyroid drugs, carbimazole, methimazole, propylthiouracil, amiodarone,
radioiodine, and thyroidectomy. We gave preference to high quality observational studies, randomised controlled trials, and systematic
reviews published in the past 10 years.

that more than half of patients aged 61 years or older had fewer
than three classic symptoms of thyrotoxicosis.10 Atrial fibrillation
is a commonly associated feature of thyrotoxicosis, particularly
in older patients. A recent epidemiological study of over 500
000 adults showed a 13% cumulative incidence of atrial
fibrillation over eight years among people with thyrotoxicosis
aged more than 65 years.11
Thyrotoxicosis is sometimes associated with acute muscle
paralysis and severe hypokalaemia, called thyrotoxic periodic
paralysis. It is most commonly seen in Asian men with
thyrotoxicosis and is often triggered by strenuous physical
activity, high carbohydrate load, alcohol, or infection.12

Rarely, patients with thyrotoxicosis present with thyroid storm,

which is a life threatening condition associated with tachycardia,
fever, agitation, altered mental state, features of cardiac failure,
and deranged liver function.13 Poor compliance to treatment,
surgery, infection, childbirth, and trauma are common
precipitating factors.

How do you determine the cause of

thyrotoxicosis?
Figure 1 shows an algorithm for the investigation of patients
presenting with symptoms of thyrotoxicosis.

The diagnosis of primary hyperthyroidism is usually based on

increased serum free thyroxine levels in the presence of fully
suppressed serum TSH (<0.05 mIU/L) levels. If the level of
free thyroxine is normal in the presence of suppressed TSH,
then the levels of free triiodothyronine must be checked to
exclude triiodothyronine (T3) thyrotoxicosis. This should be
considered as a mild form of hyperthyroidism and is commonly
seen in association with toxic multinodular goitre or a toxic
thyroid nodule but can also be a feature of mild Graves disease.
Low or suppressed TSH levels in the presence of normal free
thyroxine and free triiodothyronine levels is termed subclinical
hyperthyroidism.
Taking a careful clinical history and carrying out a physical
examination often provide clues as to the cause of thyrotoxicosis.
For example, ophthalmopathy, dermopathy, and acropachy are
hallmarks of Graves disease (fig 2). In the absence of these
features, the diagnosis of Graves disease can be confirmed by
checking the serum levels of antibodies to the TSH receptor. A
recent meta-analysis has shown that such antibodies measured
with immunoassay methods are highly sensitive and specific
for the diagnosis of Graves disease (third generation assay:
sensitivity 98%, specificity 99%).14 In contrast, thyroid
peroxidase antibodies are present only in about 75% of cases
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of Graves disease. If TSH receptor antibodies are not present,

a scan of radionuclide thyroid uptake (with radioactive
technetium or iodide) can be helpful to distinguish the different
causes of thyrotoxicosis (fig 3). In subacute thyroiditis,
inflammatory markers such as erythrocyte sedimentation rate
and C reactive protein are usually increased.15

When should general practitioners refer?

All patients with new onset thyrotoxicosis warrant assessment
in secondary care, to establish the cause and to agree on a
management plan. Prepregnancy consultation for counselling
and optimisation of treatment for those who are currently
receiving antithyroid drugs or who have received radioiodine
therapy or thyroidectomy in the past is also worthwhile.

What are the treatment options?

Graves disease

The treatment options for hyperthyroid Graves disease include

thionamide drugs, radioiodine, or thyroid surgery
(thyroidectomy). blockers (for example, propranolol modified
release 80 mg once or twice daily) are useful for the control of
symptoms in all patients with thyrotoxicosis but are
contraindicated in those with asthma. Anticoagulation is also
warranted in most patients with thyrotoxicosis who have atrial
fibrillation. A randomised controlled trial of antithyroid drugs,
thyroidectomy, or radioiodine in Graves disease showed no
significant difference in patient satisfaction with the three
treatment options.16 Each modality has its own advantages and
drawbacks, and patient preference is often a deciding factor.

Thionamide drugs
The thionamide drugs, propylthiouracil, carbimazole, and its
active metabolite methimazole, have been in use to treat
thyrotoxicosis for more than 60 years. A meta-analysis of
randomised controlled trials showed long term remission of
hyperthyroid Graves disease in about 50% of those treated with
thionamide drugs for a prolonged period.17 Carbimazole or
methimazole are preferred in most situations, as a small risk of
serious liver injury (about 1 in 10 000 adults) has recently been
highlighted during propylthiouracil use.18 In addition,
carbimazole or methimazole can be taken once daily rather than
every eight or 12 hours as is the case for propylthiouracil, and
the longer half life leads to more rapid control.
Thionamides reduce levels of circulating thyroid hormones by
acting as a preferential substrate for iodination by thyroid
peroxidase, the key enzyme in thyroid hormone synthesis. Most
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BMJ 2014;349:g5128 doi: 10.1136/bmj.g5128 (Published 21 August 2014)

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CLINICAL REVIEW

Common symptoms and signs of thyrotoxicosis

Symptoms
Weight loss
Palpitations
Breathlessness
Tremor
Tiredness
Heat intolerance
Excessive sweating
Increased bowel action
Anxiety
Nervousness
Muscle weakness
Menstrual disturbances (oligomenorrhoea and amenorrhoea)
Loss of libido

Signs
Weight loss
Tachycardia
Atrial fibrillation
Fine tremor
Skin erythema
Sweaty palms and palmar erythema
Onycholysis
Prominent eyes and eyelid retraction
Muscle weakness
Systolic hypertension, wide pulse pressure
Thyroid bruit
Signs of cardiac failure

patients with hyperthyroid Graves disease are rendered

euthyroid (as judged by normal free thyroid hormone levels)
by 4-8 weeks treatment with methimazole (15-30 mg daily) or
carbimazole (20-40 mg daily). Patients with severe
hyperthyroidism (free thyroxine >70 pmol/L), large goitre, or
recent exposure to iodide (including contrast media used for
computed tomography) may need to be treated for longer, or
with larger thionamide doses.

After euthyroidism is achieved, two different regimens can be

employed. In the first regimen, termed block-replace, the dose
of thionamide is kept constant (for example, carbimazole 40
mg daily), thus blocking thyroid hormone production, and
levothyroxine is then added in a suitable dose to maintain
euthyroidism (for example, 100 g daily for women, 125 g
daily for men). In the second regimen, termed titrated, the
thionamide dose is progressively lowered at regular intervals
to allow endogenous synthesis of thyroid hormone to continue
in a regulated fashion. Table 2 lists the advantages and
disadvantages of the two methods. In both regimens the
remission rate is approximately 50% if treatment is continued
for between six and 18 months and then stopped.19 The most
important disadvantage of treatment with either regimen is the
uncertainty of whether patients will relapse after treatment is
stopped and the potential adverse effects of the drugs.

A pruritic rash, which is often transient, is seen in about 5% of

patients taking antithyroid drugs. The much rarer but
occasionally lethal problem of thionamide induced
agranulocytosis occurs in about 1 in 300 people.20 It usually
presents with sore throat, mouth ulcers, and high fever. All
patients embarking on antithyroid drug treatment should receive
clear verbal and written information about this adverse effect
with advice to stop the drug and have a blood test for full blood
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count if they develop these warning symptoms. Agranulocytosis

occurs most commonly in the first three months of treatment
(median 30 days) and is rare after six months.21 22 An
observational study of more than 5000 Japanese patients found
agranulocytosis in 0.8% of patients who started treatment with
30 mg methimazole compared with 0.2% of those starting with
15 mg,23 suggesting that drug dose is an important risk factor.

Whether using titrated or block-replace regimens, trials have

shown that prolonged treatment beyond 18 months has no
advantage in remission rates,19 and the drugs should generally
be stopped at this stage, with testing of thyroid function at 4-6
weeks to detect early relapse. The ideal patients to treat with
antithyroid drugs for Graves disease are those with a high
chance of remission after treatment. Thus women, age over 40
years, small thyroid size, no extrathyroidal manifestations, mild
hyperthyroxinaemia, or triiodothyronine thyrotoxicosis at
presentation and a low titre of TSH receptor antibodies are most
likely to have a successful outcome from drug treatment.24 After
relapse, a long term, small dose of thionamide is an acceptable
option where definitive treatment with radioiodine or surgery
is not feasible.

Radioiodine
Radioiodine (iodine-131) is a and radiation emitter, which
is rapidly concentrated by the thyroid after oral ingestion. The
radiation has a 2 mm radius of activity and induces DNA
damage leading to death of thyroid cells. Six weeks to six
months after radioiodine treatment most patients with Graves
disease are rendered sequentially euthyroid and then
hypothyroid.25 A pragmatic fixed dose that results in
euthryoidism or hypothyroidism in 70-90% of patients is
recommended, as attempts to use dosimetry to estimate the
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BMJ 2014;349:g5128 doi: 10.1136/bmj.g5128 (Published 21 August 2014)

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CLINICAL REVIEW

optimal individual dose of radioiodine does not improve

outcome.26 Current UK guidance suggests doses of 370 to 550
MBq for routine use in Graves disease.27 Patients with large
goitres, however, may need higher or repeated doses to achieve
euthyroidism. Although radioiodine is commonly used in
Graves disease after a recurrence or side effects from
antithyroid drugs,28 it should also be considered as the preferred
treatment for those with severe Graves disease (particularly
young patients aged less than 40 years, men, and those with a
large goitre), who are unlikely to achieve long term remission
with antithyroid drugs.24 Radioiodine is also a good treatment
for patients who want a predictable cure and for whom the high
probability of subsequent lifelong levothyroxine treatment is
an acceptable consequence. A recent analysis found that early
use of radioiodine is the cheapest long term management
strategy for Graves disease.29

In the month after radioiodine treatment there is a small risk of

thyrotoxicosis being exacerbated (or even a thyroid storm being
precipitated) due to the release of preformed hormone. To reduce
this risk it is recommended that patients with large goitres,
severe thyrotoxicosis, ischaemic heart disease, heart failure, or
arrhythmia should be pretreated with thionamide until they are
euthyroid.27 30 A meta-analysis showed that to obtain optimal
outcomes from radioiodine, methimazole or carbimazole should
be stopped at least a week before radioiodine therapy.31
However, it is widely believed that propylthiouracil should be
stopped at least two weeks beforehand. Antithyroid drugs can
be restarted two weeks after the radioiodine dose, if ongoing
control of thyrotoxicosis is critical. Patients should be monitored
with regular thyroid function tests for early detection of
radioiodine induced hypothyroidism.
Radioiodine is absolutely contraindicated in pregnancy and
lactation, and patients are advised to avoid a new pregnancy for
six months after treatment.27 Patients receiving a standard dose
of radioiodine in the United Kingdom are also advised to take
several precautions to minimise the perceived deleterious effects
of ionising radiation to others.27 For example, close and
prolonged contact with children and pregnant women should
be avoided for about three weeks (after a 400 MBq dose).
Several studies have looked at the risk of cancer after the
therapeutic use of radioiodine and the data are strongly
reassuring that cancers at all major sites are no different or less
common in patients treated with radioiodine than in the
background population.32 33

Radioiodine is relatively contraindicated in those with active

inflammatory Graves ophthalmopathy, as the release of thyroid
antigen and subsequent hypothyroidism may be associated with
deterioration of eye disease.34 35 The risk of deterioration of eye
disease is, however, small in patients with inactive
ophthalmopathy as long as thyroxine replacement is prompt.36
The risk of ophthalmopathy is much higher in smokers, but can
be abrogated by a short course of prednisolone.37

Thyroid surgery
Total (or near total) thyroidectomy is a highly effective and
predictable treatment for Graves disease. Patients with Graves
disease who have relapsed after adequate medical treatment,
those with active Graves ophthalmopathy, or those with a
cosmetically undesirable goitre are all well suited to surgical
intervention. Long term complications of thyroidectomy include
hypocalcaemia as a result of hypoparathyroidism, which is most
often transient, and vocal cord paresis due to operative
compromise of the recurrent laryngeal nerve. Patients need to
be rendered euthyroid before surgery, and where thionamide
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antithyroid drugs cannot be used, iodine loading with potassium

iodide, Lugols iodine, or oral cholecystographic contrast media
(iopanoic acid 1 g daily) for 5-10 days is sufficient to achieve
euthyroidism in almost all cases.38

Toxic multinodular goitre and solitary toxic

nodule
Antithyroid drugs do not lead to long term remission of
thyrotoxicosis in toxic multinodular goitre or solitary toxic
nodules. Therefore radioiodine is the treatment of choice for
most patients with these conditions. When treatment with
radioiodine is not possible, the alternatives are a long term small
dose of carbimazole (or methimazole) or thyroid surgery.

Thyroiditis
Thyrotoxicosis associated with thyroiditis is transient, often
progresses through a hypothyroid phase, and then resolves
spontaneously. Antithyroid drugs are ineffective and should be
avoided. Treatment is often limited to symptom control with
blockers. In subacute thyroiditis, non-steroidal anti-inflammatory
drugs and occasionally systemic glucocorticoids may be required
to control pain.

Drug induced thyrotoxicosis

Amiodarone induced thyrotoxicosis may result from
autoimmunity (type 1) or a destructive thyroiditis with release
of preformed thyroid hormones (type 2). Close liaison with a
cardiologist is recommended to best manage these patients. The
most common form in the United Kingdom is type 2 amiodarone
induced thyroiditis, and a recent randomised controlled trial
found that the most effective treatment for this was
prednisolone.39 Type 1 amiodarone induced thyrotoxicosis is
treated with antithyroid drugs.
Treatment of thyrotoxicosis associated with other drugs, such
as lithium, interferon , highly active antiretroviral therapy, and
tyrosine kinase inhibitors depends on whether the underlying
mechanism is autoimmunity or destructive thyroiditis. More
often than not these conditions are self limiting, and timely
investigation saves patients from unnecessary treatment.
Consultation between the specialist prescribing the drug in
question and an endocrinologist is recommended.

Special situations
Pregnancy and lactation

Graves disease is the commonest cause of hyperthyroidism

presenting in pregnancy; however, it needs to be distinguished
from gestational hyperthyroidism mediated by human
chorionic gonadotrophin. The latter is characterised by the
absence of ophthalmopathy or a large goitre, absent TSH
receptor antibodies, and spontaneous resolution of
hyperthyroidism by 20 weeks of gestation.

Antithyroid drugs are the mainstay of treatment for hyperthyroid

Graves disease in pregnancy, and a titrated dose regimen is
mandatory as block-replace regimens are associated with a risk
of fetal hypothyroidism and goitre. There is evidence for a small
risk of embryopathy with all antithyroid drugs. A nationwide
birth cohort study from Denmark showed birth defects in 9.1%
of offspring of mothers treated with carbimazole or
methimazole, compared with 8.0% treated with propylthiouracil
and 5.4% in untreated women with a previous diagnosis of
hyperthyroidism.40 The spectrum of congenital abnormalities
seems different, with aplasia cutis, choanal atresia,
tracheo-oesophageal fistula, and omphalocoele with carbimazole
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CLINICAL REVIEW

or methimazole but potentially less severe facial, neck, urinary

tract, and cardiac malformations with propylthiouracil. This
risk of congenital defects with antithyroid drugs also has to be
balanced against the much rarer risk of serious maternal
hepatotoxicity with propylthiouracil.41 Current guidelines
recommend that propylthiouracil is preferred during the first
trimester of pregnancy.9 42 Given the uncertainties relating to
birth defects, a full discussion with prospective mothers is
warranted. If women of childbearing age present with
hyperthyroid Graves disease and express the wish for future
pregnancy, the advantages of early definitive treatment with
radioiodine or surgery should be discussed.
Breast feeding is safe with all three antithyroid drugs (daily
doses of up to 20 mg methimazole or carbimazole or 300 mg
propylthiouracil); however, because of the small risk of severe
liver toxicity associated with propylthiouracil, the current
guidelines recommend methimazole or carbimazole as the
preferred antithyroid drugs for lactating women.42

Thyroid eye disease

Radioiodine should be avoided in active Graves

ophthalmopathy. Antithyroid drugs in a block-replace regimen
is probably the optimal treatment until the ophthalmopathy
becomes inactive.43 44 If this cannot be tolerated then total
thyroidectomy is a good option. Patients with ophthalmopathy
may need specific treatment and should be referred early to
specialist services.45

Subclinical hyperthyroidism

1
2
3
4
5
6
7
8
9
10
11
12
13
14

15
16

Subclinical hyperthyroidism refers to a state of low or

suppressed serum TSH levels with normal circulating free
thyroxine and free triiodothyronine levels. It occurs in 2-3% of
patients over the age of 80 years,46 with around 0.7% having
the more important abnormality of suppression of serum TSH
levels to <0.1 mIU/L. Prospective studies have shown that more
than 50% of patients with subclinical hyperthyroidism, and
particularly those with a low but not suppressed TSH level
(range 0.1-0.4 mIU/L), have a transient abnormality.47 A low
or suppressed TSH level may also be caused by several drugs,
including opiates, levodopa, anti-inflammatory doses of
glucocorticoid, metformin, and levothyroxine. In addition,
persistently low or suppressed serum TSH levels can presage
more major systemic illness, such as chronic infection or covert
cancer. Although epidemiological studies show that a low serum
TSH level is associated with an increased risk of atrial
fibrillation,48 49 and in some studies excess vascular mortality,47 49
only a few patients have evidence of intrinsic thyroid disease.
Current opinion favours consideration of antithyroid treatment
in patients aged more than 65 years with a persistently
suppressed TSH level (<0.1 mIU/L), particularly in the presence
of atrial fibrillation or other cardiac problems.50 In people with
untreated subclinical hyperthyroidism, thyroid function tests
should be carried out annually to detect progression to overt
thyrotoxicosis.

17

We thank Mike Ramell (general practitioner) for his helpful comments

on the manuscript.

31

Contributors: Both authors contributed equally to the planning, writing,

and revision of this article. Both are guarantors.

32

Competing interests: We have read and understood BMJ policy on

declaration of interests and declare the following interests: SHSP has
received speaker fees from Merck-Serono and ViroPharma.
Provenance and peer review: Commissioned; externally peer reviewed.

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19
20

21
22
23
24
25
26
27
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30

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Wartofsky L. Radioiodine therapy for Graves disease: case selection and restrictions
recommended to patients in North America. Thyroid 1997;7:213-6.
De Rooij A, Vandenbroucke JP, Smit JW, Stokkel MP, Dekkers OM. Clinical outcomes
after estimated versus calculated activity of radioiodine for the treatment of hyperthyroidism:
systematic review and meta-analysis. Eur J Endocrinol 2009;161:771-7.
Radioiodine in the management of benign thyroid disease. 2014. www.rcplondon.ac.uk/
publications/radioiodine-management-benign-thyroid-disease.
Vaidya B, Williams GR, Abraham P, Pearce SH. Radioiodine treatment for benign thyroid
disorders: results of a nationwide survey of UK endocrinologists. Clin Endocrinol
2008;68:814-20.
Patel NN, Abraham P, Buscombe J, Vanderpump MP. The cost effectiveness of treatment
modalities for thyrotoxicosis in a UK center. Thyroid 2006;16:593-8.
Bahn RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, et al. Hyperthyroidism
and other causes of thyrotoxicosis: management guidelines of the American Thyroid
Association and American Association of Clinical Endocrinologists. Endocr Pract
2011;17:456-520
Walter MA, Briel M, Christ-Crain M, Bonnema SJ, Connell J, Cooper DS, et al. Effects of
antithyroid drugs on radioiodine treatment: systematic review and meta-analysis of
randomised controlled trials. BMJ 2007;334:514.
Ron E, Doody MM, Becker DV, Brill AB, Curtis RE, Goldman MB, et al. Cancer mortality
following treatment for adult hyperthyroidism. Cooperative Thyrotoxicosis Therapy
Follow-up Study Group. JAMA 1998;280:347-55.
Franklyn JA, Maisonneuve P, Sheppard M, Betteridge J, Boyle P. Cancer incidence and
mortality after radioiodine treatment for hyperthyroidism: a population-based cohort study.
Lancet 1999;353:2111-5.
Bartalena L, Marcocci C, Bogazzi F, Manetti L, Tanda ML, DellUnto E, et al. Relation
between therapy for hyperthyroidism and the course of Graves ophthalmopathy. N Engl
J Med 1998;338:73-8.

Patient consent: Obtained.

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Questions for future research

Is the block-replace regimen superior to the titration regimen for the treatment of Graves disease with antithyroid drugs?
What is the safest treatment for women with Graves disease who are pregnant or planning pregnancy?
What is the most appropriate management strategy for asymptomatic mild hyperthyroidism and subclinical hyperthyroidism?
Will new treatments with immunomodulatory biological agents or thyroid stimulating hormone receptor antagonists become an alternative
or a useful adjunct to thionamide antithyroid drugs for Graves disease?

Ongoing research
Selenium supplementation versus placebo in patients with Graves hyperthyroidism. Copenhagen University Hospital Rigshospitalet,
Denmark (www.clinicaltrials.gov/ct2/show/NCT01611896?term=hyperthyroidism&rank=4)
Post-radioiodine Graves management: the PRAGMA Study. Newcastle upon Tyne Hospitals NHS Trust, UK (www.clinicaltrials.gov/ct2/
show/NCT01885533?term=hyperthyroidism&rank=78)
Short term prednisolone to treat moderate and severe subacute thyroiditis. Xinqiao Hospital of Chongqing, China (www.clinicaltrials.
gov/ct2/show/NCT01837433?term=thyroiditis&rank=10)

Tips for non-specialists

Patients aged more than 70 years with thyrotoxicosis often manifest minimal classic symptoms and signs. They sometimes present with
apathy, lethargy, and depression mimicking a depressive disorder (apathetic thyrotoxicosis)
Diagnosis of thyrotoxicosis should be considered in patients presenting with unexplained weight loss or atrial fibrillation
Rapid onset of thyrotoxic symptoms over one day or two days signals thyroiditis as the likely diagnosis rather than Graves disease
If blockers are contraindicated, diltiazem may be used to reduce tachycardia in thyrotoxicosis

Additional educational resources

Resources for healthcare professionals
Thyroid disease manager (www.thyroidmanager.org/)a web based comprehensive and up to date textbook with chapters on different
thyroid disorders (free registration is required to access chapters)
NICE clinical knowledge summaries (http://cks.nice.org.uk/hyperthyroidism#!topicsummary)this website is particularly useful for primary
care practitioners and contains current evidence based best practice guidance on the management of more than 300 common conditions,
including hyperthyroidism
American Thyroid Association and American Association of Clinical Endocrinologists guidelines on management of hyperthyroidism
(http://thyroidguidelines.net/sites/thyroidguidelines.net/files/file/THY_2010_0417.pdf)a useful evidence based guideline on management
of hyperthyroidism
The Endocrine Society clinical practice guideline on management of thyroid dysfunction during pregnancy and post partum (http://press.
endocrine.org/doi/pdf/10.1210/jc.2011-2803)a comprehensive guideline on management of thyroid disorders (including hyperthyroidism)
in pregnancy

Resources for patients

NHS Choices (www.nhs.uk/Conditions/Thyroid-over-active/)provides information on a wide range of health problems, including
thyrotoxicosis
British Thyroid Foundation (www.btf-thyroid.org/) and Thyroid Eye Disease Charitable Trust (www.tedct.co.uk/) national charities and
patient support organisations for patients with thyroid diseases, including thyrotoxicosis and thyroid eye disease
British Thyroid Association (www.british-thyroid-association.org/info-for-patients/) and American Thyroid Association (www.thyroid.org/
patient-thyroid-information/)both websites provide information on different thyroid disorders in a separate section dedicated for patients
and families

A patients perspective
At the age of 23 I started to eat more, my bowels opened more frequently, and I felt tired. I put this down to working out too much at the
gym. I also noticed that I had lost a few kilograms in weight over a few months, but I had no palpitations. One day, after two months off from
the gym, I could not lift the weight that I used to. Then I experienced weakness of my lower limbs, such that I struggled to stand and walk.
It took me a few days to recover. I thought this was due to the exercise that I had done being too much. However, three months later I had
a few episodes of weakness in my lower limbs at night. I did not seek any medical advice until an episode when I fell over in the bath, which
returned to normal within 12 hours. My GP had no idea about the cause. I had further episodes after that but the GP was not able to explain
what was happening. My friends dad, who is a neurosurgeon, suggested that I may be suffering from thyrotoxic periodic paralysis. After the
blood test for my thyroid function showed thyrotoxicosis, I was treated with carbimazole and propranolol. After the treatment, my appetite
has returned back to normal, my bowels do not open as frequently, and I feel a lot less tired. The muscle weakness episodes have also
disappeared.
Male Chinese student, Exeter, United Kingdom
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Acharya SH, Avenell A, Philip S, Burr J, Bevan JS, Abraham P. Radioiodine therapy (RAI)
for Graves disease (GD) and the effect on ophthalmopathy: a systematic review. Clin
Endocrinol 2008;69:943-50.
Perros P, Kendall-Taylor P, Neoh C, Frewin S, Dickinson J. A prospective study of the
effects of radioiodine therapy for hyperthyroidism in patients with minimally active graves
ophthalmopathy. J Clin Endocrinol Metab 2005;90:5321-3.

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37
38
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Bartalena L, Marcocci C, Bogazzi F, Panicucci M, Lepri A, Pinchera A. Use of

corticosteroids to prevent progression of Graves ophthalmopathy after radioiodine therapy
for hyperthyroidism. N Engl J Med 1989;321:1349-52.
Panzer C, Beazley R, Braverman L. Rapid preoperative preparation for severe hyperthyroid
Graves disease. J Clin Endocrinol Metab 2004;89:2142-4.
Eskes SA, Endert E, Fliers E, Geskus RB, Dullaart RP, Links TP, et al. Treatment of
amiodarone-induced thyrotoxicosis type 2: a randomized clinical trial. J Clin Endocrinol
Metab 2012;97:499-506.

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CLINICAL REVIEW

What to tell patients with newly diagnosed Graves disease who are starting antithyroid drugs
It takes at least 5-10 days of treatment before any improvement in symptoms of thyrotoxicosis will be noticed
Agranulocytosis is a rare but serious side effect of antithyroid drugs and usually presents with sore throat, mouth ulcers, and high fever.
If these symptoms develop, you must stop the drug and have a blood test for a full blood count
If you have lost weight, expect to gain it again after treatment. Your appetite may be increased at diagnosis and you should curb your
food intake quickly once the thyroid condition comes under control
Continuing to smoke increases the risk of thyroid eye disease, delays the onset of action of antithyroid drugs, and increases the risk of
relapse of thyrotoxicosis after stopping treatment
Taking antithyroid drugs (in particular, carbimazole or methimazole) in early pregnancy is associated with birth defects in offspring. Tell
your doctor if you are planning a pregnancy
40
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Andersen SL, Olsen J, Wu CS, Laurberg P. Birth defects after early pregnancy use of
antithyroid drugs: a Danish nationwide study. J Clin Endocrinol Metab 2013;98:4373-81.
Taylor PN, Vaidya B. Side effects of anti-thyroid drugs and their impact on the choice of
treatment for thyrotoxicosis in pregnancy. Eur Thyroid J 2012;1:176-85.
Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, et al.
Guidelines of the American Thyroid Association for the diagnosis and management of
thyroid disease during pregnancy and postpartum. Thyroid 2011;21:1081-125.
Laurberg P, Berman DC, Andersen S, Bulow Pedersen I. Sustained control of Graves
hyperthyroidism during long-term low-dose antithyroid drug therapy of patients with severe
Graves orbitopathy. Thyroid 2011;21:951-6.
Elbers L, Mourits M, Wiersinga W. Outcome of very long-term treatment with antithyroid
drugs in Graves hyperthyroidism associated with Graves orbitopathy. Thyroid
2011;21:279-83.
Bartalena L, Baldeschi L, Dickinson AJ, Eckstein A, Kendall-Taylor P, Marcocci C, et al.
Consensus statement of the European group on Graves orbitopathy (EUGOGO) on
management of Graves orbitopathy. Thyroid 2008;18:333-46.
Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al.
Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994):

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47
48
49
50

National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab
2002;87:489-99.
Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up
of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin
Endocrinol 1991;34:77-83.
Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, et al. Low serum
thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J
Med 1994;331:1249-52.
Vadiveloo T, Donnan PT, Cochrane L, Leese GP. The Thyroid Epidemiology, Audit, and
Research Study (TEARS): morbidity in patients with endogenous subclinical
hyperthyroidism. J Clin Endocrinol Metab 2011;96:1344-51.
Mitchell AL, Pearce SH. How should we treat patients with low serum thyrotropin
concentrations? Clin Endocrinol 2010;72:292-6.

Cite this as: BMJ 2014;349:g5128

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Tables
Table 1| Important causes and underlying mechanisms of thyrotoxicosis in adults
Causes

Underlying mechanisms

Graves disease

Autoimmunity; stimulation of thyrocytes by TSH receptor antibodies

Toxic multinodular goitre

Autonomous thyroid nodules

Toxic nodule

Autonomous thyroid nodule

Thyroiditis:
Subacute thyroiditis

Release of preformed thyroid hormones; possibly viral infection

Silent thyroiditis

Release of preformed thyroid hormones

Postpartum thyroiditis

Release of preformed thyroid hormones; autoimmunity

Drugs:
Levothyroxine/triiodothyronine

Exogenous ingestion of thyroid hormones; iatrogenic or factitious

Amiodarone

Release of preformed thyroid hormones (type 2; thyroiditis) or excess thyroid hormone production
(type 1; Jod-Basedow phenomenon)

Lithium

Release of preformed thyroid hormones (thyroiditis) or autoimmunity

Interferon

Release of preformed thyroid hormones (thyroiditis) or autoimmunity

Highly active antiretroviral therapy

Autoimmunity or release of preformed thyroid hormones (thyroiditis)

Tyrosine kinase inhibitors

Release of preformed thyroid hormones (thyroiditis) or autoimmunity

human chorionic gonadotrophin mediated hyperthyroidism:

Gestational hyperthyroidism

Stimulation of thyrocytes by human chorionic gonadotrophin

Choriocarcinoma

Stimulation of thyrocytes by human chorionic gonadotrophin

Hydatidiform mole

Stimulation of thyrocytes by human chorionic gonadotrophin

Struma ovarii

Ovarian teratoma with autonomous thyroid tissue

Non-autoimmune familial hyperthyroidism

Constitutive activation of TSH receptor due to germline mutation

TSH secreting pituitary adenoma

Stimulation of thyrocytes by excess TSH secreted by pituitary adenoma

TSH=thyroid stimulating hormone.

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Table 2| Considerations in administering the block-replace versus titrated regimens of antithyroid drugs
Factors

Block-replace

Titrated dose

Stability

Easier to maintain stable euthyroidism

Prone to fluctuating hypothyroidism and hyperthyroidism

Monitoring

Fewer thyroid function tests and clinic visits

More thyroid function tests and clinic visits

Side effects

High risk

Low risk

Optimal remission*

Ranges from 6-12 months

Ranges from 12-18 months

Ease of use

More complex regimen with less likelihood of compliance and more Simpler regimen with better compliance and less prone to drug
prone to drug errors
errors

Prediction of remission

Not possible to predict remission by dose changes

Prediction of early remission by successful dose reduction

Cost of drugs

High

Low

*No significant difference in early or late remission rates between either regimen.

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Figures

Fig 1 Algorithm for investigation of thyrotoxicosis. TSH=thyroid stimulating hormone. *Patients might also have
non-autoimmune familial hyperthyroidism

Fig 2 Extrathyroidal manifestations of Graves disease: (A) thyroid eye disease with periorbital swelling, eyelid retraction,
and exophthalmos (the patient also has a bilateral, symmetrical goitre); (B) thyroid associated dermopathy (pretibial
myxoedema) with non-pitting oedema as a result of diffuse waxy induration of skin on both legs; and (C) thyroid acropachy
(arrow) with clubbing and swelling of the finger

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Fig 3 Radionuclide uptake scans in thyrotoxicosis from different causes: (A) bilaterally symmetrical diffusely increased
uptake in Graves disease (patients with non-autoimmune familial hyperthyroidism show similar results); (B) asymmetrical
patchy uptake in toxic multinodular goitre; (C) localised focal uptake in solitary toxic nodule (note diminished uptake in rest
of thyroid); and (D) absence of uptake during thyrotoxic phase of subacute, painless, or postpartum thyroiditis (patients
with thyrotoxicosis due to exogenous levothyroxine ingestion show similar results)

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