REVIEWS

Diagnosis and management of Graves disease:

a global overview
Luigi Bartalena
Abstract | Graves disease is an autoimmune disorder characterized by goitre, hyperthyroidism and, in
25% of patients, Graves ophthalmopathy. The hyperthyroidism is caused by thyroid hypertrophy and
stimulationoffunction, resulting from interaction of anti-TSH-receptor antibodies (TRAb) with the TSH receptor
on thyroid follicular cells. Measurements of serum levels of TRAb and thyroid ultrasonography represent
the most important diagnostic tests for Graves disease. Management of the condition currently relies on
antithyroid drugs, which mainly inhibit thyroid hormone synthesis, or ablative treatments ( 131I-radiotherapy
or thyroidectomy) that remove or decrease thyroid tissue. None of these treatments targets the disease
process, and patients with treated Graves disease consequently experience either a high rate of recurrence,
if receiving antithyroid drugs, or lifelong hypothyroidism, after ablative therapy. Geographical differences in
the use of these therapies exist, partially owing to the availability of skilled thyroid surgeons and suitable
nuclear medicine units. Novel agents that might act on the disease process are currently under evaluation
inpreclinical or clinical studies, but evidence of their efficacy and safety is lacking.
Bartalena, L. Nat. Rev. Endocrinol. 9, 724734 (2013); published online 15 October 2013; doi:10.1038/nrendo.2013.193

Introduction
Graves disease is an autoimmune disorder and the most
common cause of hyperthyroidism in areas with suffi
cient iodine intake, where its prevalence is about 0.5%1
and the number of incidences is around 21 per 100,000 per
year.2 Individuals of any age can be affected, but women
aged 4060years have the highest risk of developing the
disease.3 Genetic factors account for up to 80% of the risk
of developing Graves disease;4 the other 20% are associ
ated with environmental risk factors, such as cigarette
smoking, sex hormones, pregnancy, stress, infections and
adequate iodine intake.5,6 These factors contribute to the
onset of Graves disease in genetically predisposed indivi
duals by breaking the mechanisms that result in immune
tolerance.5,6 The immunopathogenesis of Graves disease is
complex, but antibodies against the TSH receptor (TRAb)
are ultimately responsible for hyperthyroidism.7 These
antibodies bind to TSH receptors on the surface of thyroid
follicular cells, leading to continuous and uncontrolled
thyroid stimulation, associated with excess synthesis of
the thyroid hormones T4 and T3, and thyroid hypertrophy.
The aim of this Review is to provide an overview of the
current approaches to diagnosis and treatment of Graves
disease. Past and present geographical differences in the
management of Graves disease will also be highlighted.
Department of Clinical Diagnosis of Graves disease
and Experimental The clinical signs and symptoms of Graves disease are
Medicine, University
ofInsubria, Endocrine
shared by other forms of thyrotoxicosis. 8 However,
Unit, Ospedale di Graves disease is associated with unique extrathyroidal
Circolo, Viale Borri, 57,
21100 Varese, Italy.
luigi.bartalena@ Competing interests
uninsubria.it The author declares no competing interests.
manifestations, including orbital disease (Graves
ophthalmopathy),911 skin changes (thyroid dermopathy)
and, rarely, fingertip and nail abnormalities (thyroid
acropachy).12 Diagnosis of Graves disease is straight
forward when these characteristic symptoms occur in
conjunction with hyperthyroidism and diffuse goitre.
However, in patients without obvious hyperthyroidism or
ocular signs, and nodular or absent goitre, Graves disease
needs to be differentiated from other possible causes of
hyperthyroidism, such as toxic adenoma or toxic multi
nodular goitre. Graves disease is particularly difficult to
diagnose in elderly patients, in whom hyperthyroidism
is often associated with few symptoms and signs,13 and
in rare patients with Graves ophthalmopathy who do not
have hyperthyroidism (so-called euthyroid Graves disease
or euthyroid ophthalmic disease).14 The latter have typical
clinical and radiological signs of Graves ophthalmopathy
and in many instances develop classic Graves disease over
months to years.14
Laboratory tests
In 2011, a large international questionnaire-based survey
was carried out to investigate the management of Graves
disease among members of the Endocrine Society, the
American Thyroid Association (ATA) and the American
Association of Clinical Endocrinologists (AACE).15 Most
respondents were from North America (63%), and the
rest were from Europe (12.9%), South America (11.3%),
Asia and Oceania (9.5%) or the Middle East and Africa
(3.4%).15 This survey showed that measurement of serum
levels of TSH and free T4 are concomitantly requested by
90% of endocrinologists if hyperthyroidism is suspected.

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This approach is in line with the ATA and AACE guide
lines on diagnosis of hyperthyroidism;16 thus, the finding
of increased levels of free T4 and decreased levels of TSH
is usually sufficient to confirm the diagnosis of Graves
disease. Serum levels of free T3 or total T3 are also com
monly increased in patients with hyperthyroidism,
but measurement of free T3 or total T3 levels was only
requested by 40% of the endocrinologists in the above
survey (with no geographical differences in whether or
not this additional test was requested).15 However, 24%
of patients with hyperthyroidism have normal serum
levels of free T4 and increased serum levels of free T3
or total T3 (so-called T3 thyrotoxicosis).8 Thus, in the
initial assessment of thyroid status in a patient with sus
pected hyperthyroidism, concomitant determination of
the serum levels of free T4, free T3 (ortotal T3) and TSH
isadvised.
Determination of the serum levels of TRAb is a useful
laboratory test to determine whether Graves disease is the
cause of hyperthyroidism. Whereas antibodies against
thyroglobulin and thyroid peroxidase (TPO) are found
in patients with Hashimoto thyroiditis as well as in those
with Graves disease, modern immunoassays and bioassays
for TRAb with high sensitivity and specificity, enable the
precise aetiology of hyperthyoidism to be identified.1721
Whereas early TRAb assays were expensive and time-
consuming, automated TRAb assays developed over the
past 510years are comparable to anti-TPO antibody
assays in terms of ease of use and cost.22 A meta-analysis
published in 2012 indicated that the pooled sensitiv
ity and specificity values for third-generation TRAb
assays are 98.3% and 99.2%, respectively.23 The likeli
hood that a patient has Graves disease is 1,3673,420-
fold greater if they are TRAbpositive than if they are are
TRAb-negative.23
The ATA and AACE guidelines from 2011 suggest
that measurement of serum TRAb levels should be util
ized when measurement of radioactive iodine uptake or
thyroid scintigraphy is not available or contraindicated.16
However, other researchers disagree with this restric
tion on the diagnostic use of TRAb measurement.2426
In the 2011 survey,15 the measurement of serum levels of
TRAb for diagnostic purposes was practiced by 58.1%
of respondents overall, with a significantly higher propor
tion in Europe (77.5%) than in North America (54.3%),
and an intermediate number of respondents in Asia and
Oceania (65.3%). Japanese experts confirmed that
measurement of serum levels of TRAb is much more
widely used in Japan than it is in the USA.27 Interestingly,
international surveys carried out >20years ago show
similar usage patterns: the proportions of endocrinolo
gists who requested measurement of serum TRAb levels
were 9% in North America,28 38% in Europe29 and 28% in
Japan30 (Figure1a). In view of the greatly improved sen
sitivity, specificity and cost of currently available TRAb
assays, I also support the opinion that TRAb testing
should be included in the initial assessment of patients
with suspected Graves disease, particularly if extra
thyroidal m anifestations, such as Graves ophthalmopathy,
are absent.
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Key points
Diagnosis of Graves disease is now usually based on anti-TSH-receptor
antibody assays and thyroid ultrasonography
Options for management of Graves disease include antithyroid drugs,
131
I-radiotherapy and thyroidectomy; however, drug-treated patients have a high
relapse rate, and ablative therapies induce lifelong hypothyroidism
In Europe and Japan, antithyroid drugs remain the preferred first-line therapy
for Graves disease, whereas in North America 131I-radiotherapy is the preferred
option, despite increasing use of antithyroid drugs
Thyroidectomy is rarely used as a first-line treatment for Graves disease in any
geographical region
Methimazole or carbimazole are the preferred thionamide antithyroid drugs;
use of propylthiouracil is restricted to patients who cannot tolerate other
thionamides and to women in the first trimester of pregnancy
a 100 b North America
90 Europe
Asia and Oceania
80
Survey respondents (%)
70
60
50
40
30
20
10
0
1991 2011 1991 2011
Year Year
Figure 1 | The use of diagnostic tests for Graves disease
in North America, Europe, and Asia and Oceania. Data on
a | TSH-receptor antibody testing and b | isotope studies
(thyroid uptake of 131I and/or thyroid scintigraphy) are
derived from surveys from 199131 and 2011.15 Of note, in
the 1991 survey, all respondents from the Asia and
Oceania region were from Japan, whereas in the 2011
survey the respondents from this region were from Japan
and other countries in Asia and Oceania.
Isotope uptake measurements and imaging studies
According to the current ATA and AACE guidelines,
thyroid uptake of radioactive iodine should be meas
ured when the patients clinical presentation indicates
thyrotoxicosis, but is not diagnostic of Graves disease.16
These guidelines also recommend that thyroid scinti
graphy should be added to diagnose the disease if
thyroid nodularity is present.16 In the survey of clinical
practice from 2011,15 uptake of radioactive iodine and/or
thyroid scintigraphy were used as diagnostic tools by
70.9% of North American respondents, 54.2% of respon
dents in Asia and Oceania and only 30.3% of European
respondents. The use of isotope uptake tests has declined
considerably over the past 20years; for example, around
66% of European respondents were using isotope-uptake
tests to diagnose Graves disease in surveys done before
1991,31 more than twice as many as in the 2011 survey
(Figure1b).15 Moreover, the results of a large retrospec
tive study from the UK show that in most patients with
hyperthyroidism, the results of radioiodine uptake tests
or thyroid scintigraphy did not influence the aetiological
REVIEWS
Table 1 | Advantages and disadvantages of treatments for Graves disease
Treatment Advantages
Antithyroid drugs Conservative treatment
No hospitalization required
Low risk of subsequent hypothyroidism
No radiation exposure
No adverse effect on Graves ophthalmopathy
Safe to use during pregnancy and breastfeeding
I-radiotherapy
131
Definitive treatment
Low cost
No hospitalization required
No need for surgery or anaesthetic
Thyroidectomy Definitive treatment
No radiation exposure
Prompt control of hyperthyroidism
diagnosis based on clinical and immunological findings;
only 5.7% of such diagnoses were mismatched with those
based on isotope measurements or thyroid scintigraphy.32
Modern TRAb assays can be diagnostically used in
place of isotopic studies in most patients with diffuse
goitre.33 Reduced use of isotope-based tests not only
avoids radiation exposure but also decreases costs as
well as inconvenience to the patient.33 However, thyroid
scintigraphy remains a useful tool to identify nodular
variants of Graves disease, although colour flow Doppler
ultrasonography of the thyroid might replace it.
Thyroid ultrasonography is noninvasive, sensitive
and inexpensive, and does not involve radiation expo
sure. This technique can be used to rapidly diagnose
not only nodular thyroid disorders but also Graves
disease. 34 Typically, in patients with Graves disease,
the thyroid gland appears diffusely enlarged and hypo
echoic on conventional grey-scale ultrasonography. 35
In a study of 426 patients with Graves disease, thyroid
ultras onography led to a correct diagnosis in 406
patients (95.2%), whereas thyroid scintigraphy led to a
correct diagnosis in 415 patients (97.4%).36 As expected,
ultrasonography was significantly more sensitive than
thyroid scintigraphy for detecting concomitant nodular
lesions (which were detected in 16% of patients by ultra
sonography, compared with 2% of patients by thyroid
scintigraphy).36 An analysis of cost-effectiveness also
favoured ultrasonography over thyroid scintigraphy.36
Colour flow Doppler ultrasonography is useful to
distinguish nodular variants of Graves disease from
nonautoimmune toxic multinodular goitre.37 Nodules
in patients with Graves disease have normal vascularity
and increased extranodular vascularity, whereas those in
patients with nonautoimmune toxic multinodular goitre
have increased intranodular and perinodular vascular
ity but normal extranodular vascularity.37 Investigation
of the thyroid vascularity can also distinguish between
Graves disease and destructive thyroiditis as the cause
of thyrotoxicosis.3840 Although both Graves disease and
Hashimoto thyroiditis appear as a hypoechoic pattern on
conventional grey-scale ultrasonography of the thyroid,
colour flow Doppler ultrasonography can effectively
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Disadvantages
High relapse rate
Requires frequent clinic visits for monitoring
Poor adherence
Adverse events (rarely major)
Lifelong hypothyroidism
Radiation exposure
Slow control of hyperthyroidism
Possible progression or denovo occurrence of Graves
ophthalmopathy
Lifelong hypothyroidism
Adverse events related to surgical procedure and anaesthetic
Hospitalization
High cost
Permanent scar
differentiate between the two conditions. Thyroid glands
in patients with Graves disease show increased peak sys
tolic blood flow velocity compared with that in thyroid
glands from patients with Hashimoto thyroiditis.35,41,42
The ATA and AACE guidelines state that ultra
sonography does not generally contribute to the differen
tial diagnosis of thyrotoxicosis, although its diagnostic
role is recognized in patients for whom isotopic studies
are contraindicated (for example, during pregnancy) or
not informative, owing to iodine contamination from,
for example, drugs such as amiodarone.16 By contrast,
the diagnostic accuracy of colour flow Doppler ultra
sonography is widely recognized in Europe. 25 In an
international survey from 1991, thyroid ultrasonography
was not even mentioned,31 whereas in a European survey
from 1987 ultrasonography was already selected by 21%
of respondents.29 In the 2011 survey of clinical practice
patterns, thyroid ultrasonography was requested only
by 25.8% of endocrinologists overall, but this low pro
portion probably reflects the preponderance of North
American respondents.15 Interestingly, the majority
of respondents who used thyroid ultrasonography as
a diagnostic tool did not also request an isotope study
suggesting that thyroid ultrasonography could replace
isotope studies.15
Management of Graves disease
The ideal treatment for Graves disease should restore
normal thyroid function, avoid recurrence of hyper
thyroidism, prevent development of hypothyroidism
and prevent denovo occurrence or progression of Graves
ophthalmopathy. Unfortunately, no currently available
treatment fulfils these criteria; the advantages and dis
advantages of each form of treatment (Table1) should,
therefore, be clearly and objectively presented to patients.
Various pharmacological therapies for Graves disease
that aim to target the disease process as well as its
extrathyroidal manifestations are currently under inves
tigation.43 However, for the time being, management
of Graves disease still relies on three approaches that
have been used for several decades: pharmacological
treatment with antithyroid drugs, 131I-radiotherapy and

thyroidectomy.44 Several criteria can influence the choice
of treatment (Box1).
Treatment with antithyroid drugs
The thionamide-derived antithyroid drugs approved for
use in patients with Graves disease include methimazole,
carbimazole (which after absorption is converted into the
active form methimazole) and propylthiouracil. These
drugs can have either direct or indirect (through normal
ization of thyroid status) immunosuppressive effects,45,46
but their main mode of action is to decrease excess
thyroid hormone synthesis by inhibiting TPO, thereby
reducing the production of T3 and T4. Antithyroid drugs,
such as potassium perchlorate for amiodarone-induced
thyrotoxicosis, which are not thionamide-based, have
limited applications.46,47
The current ATA and AACE guidelines indicate that
methimazole should be used in all patients selected for
treatment with antithyroid drugs, except women during
their first trimester of pregnancy.16 Propylthiouracil is
still the advised treatment option for pregnant women,
owing to the risk of embryopathy associated with
carbimazole and methimazole.4850
Propylthiouracil was for many years the first-choice
antithyroid drug in both the USA and South America.51
However, propylthiouracyl can cause severe hepatotoxic
effects, which might be lethal or require liver transplanta
tion.5254 Methimazole is used in most European coun
tries and Japan, whereas carbimazole is mainly used in
the UK. A study published in 2010 showed that during
19912008 the annual prescriptions of methimazole
in the USA increased by ninefold, and this agent has been
the most commonly prescribed antithyroid drug in this
region since 1996.51
Treatment regimens
Antithyroid drug therapy can be administered according
to two different approaches: the titration method, and
the blockreplace method.55 In the titration method,
a variable starting daily dose of an antithyroid drug
(1540mg of methimazole or equivalent doses of other
agents) is used, and the drug is then gradually decreased
to the lowest dose that maintains serum levels of T4 in the
euthyroid range. In the blockreplace method, a standard
dose of an antithyroid drug (for example, 2030mg of
methimazole) is administered together with a replace
ment dose of levothyroxine, to avoid hypothyroidism.55
The rationale for using the blockreplace approach rather
than titration is that the higher dose of antithyroid drugs
used might abate the process of autoimmune disease
and lead to permanent remission of hyperthyroidism.
One study showed that the addition of levothyroxine
during and after low-dose methimazole treatment was
associated with a markedly increased remission rate,56
but subsequent randomized clinical trials could not
replicate this finding.57 A systematic review published
in 2010 also failed to show any significant difference
between the two dosing methods in terms of long-term
efficacy. 55 Antithyroid drug therapy using the titra
tion method should be continued for 1824months,55
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Box 1 | Factors influencing the choice of treatment for Graves disease
First episode of hyperthyroidism
Antithyroid drugs, 131I-radiotherapy, (thyroidectomy)
Relapse of hyperthyroidism
Small goitre: 131I-radiotherapy, thyroidectomy*, (antithyroid drugs)
Large goitre: thyroidectomy, 131I-radiotherapy
Pregnancy
Antithyroid drugs, (thyroidectomy)
Breastfeeding
Antithyroid drugs
Cytologically suspicious nodules
Thyroidectomy
Intolerance of or major adverse events using antithyroid drugs
131
I-radiotherapy, thyroidectomy*
Graves ophthalmopathy
Mild: antithyroid drugs, 131I-radiotherapy, thyroidectomy
Moderate to severe: antithyroid drugs, 131I-radiotherapy, thyroidectomy
Sight-threatening: antithyroid drugs||
*Options for definitive treatment should be discussed with the patient, after informing them
about the advantages and disadvantages of each therapy. Only in exceptional cases, such as
intolerance to or major adverse events of antithyroid drug treatment; can be performed during
the second trimester. Steroid prophylaxis should also be administered: low-dose oral
prednisone to patients with mild Graves ophthalmopathy; high-dose intravenous
glucocorticoids to patients with moderate to severe Graves ophthalmopathy. ||The use of
antithyroid drugs rather than definitive treatment is controversial in patients with moderate to
severe Graves ophthalmopathy. Treatments within parenthesis are not the ideal choice of
treatment under these circumstances, but they can be used.
whereas prolonging blockreplace antithyroid drug treat
ment beyond 6months does not increase the remission
rate.58 However, some researchers contend that prolonged
treatment, for 510 years or more, with low doses of
antithyroid drugs could improve the permanent remis
sion rate.5961 Patient adherence to blockreplace regi
mens might be reduced owing to the need to take high
numbers of tablets per day, unless, as in some countries,
2030mg methimazole tablets are available.
Adjunctive therapies
-blockers can be used during the initial phases of
antithyroid drug treatment to reduce hyperthyroid
symptoms such as tachycardia,7,46 and administration of
cholestyramine together with propylthiouracil acceler
ates the decline in serum levels of thyroid hormones.62,63
A Japanese study reported that 2weeks of combined
treatment with antithyroid drugs and iodide supplemen
tation shortened the time to achieve control of Graves
hyperthyroidism, although the long-term remission rate
was not increased.64 Several hospitals and institutions in
Japan use this combined treatment for Graves disease
(S.Nagataki, personal communication).
Adverse effects
Antithyroid drugs cause (usually minor and transient)
adverse effects in a minority of patients.46,65 Adverse
effects are more commonly observed during the initial
phases of methimazole treatment, when high doses might
be needed, although the doseresponse relationship is less
clear than it is with propylthiouracil therapy.46,65 The most
serious adverse event is agranulocytosis (agranulocyte
count <500 cells/cm3); however, this phenomenon is seen
in only 0.10.5% of treated patients.46,65 In a retrospective
REVIEWS
Box 2 | Relapse after antithyroid drug treatment
Factors associated with a high rate of relapse after
antithyroid drug treatment:
Positive TSH receptor antibody tests69,70
Large goitre67,70
Young age67,68
Male sex68
Severe hyperthyroidism68
Cigarette smoking69
Postpartum period71
Japanese study, agranulocytosis was more common
in patients given an initial dose of 30mg methimazole
(0.81%) than in those given an initial dose of 15mg
methimazole (0.22%).66 However, routine monitoring of
granulocyte levels during treatment is not beneficial, as
the onset of agranulocytosis is abrupt.16
The major drawback of antithyroid drug therapy is
the high rate of recurrence, which varies across studies
from 30% to 70%.55,67,68 Patients who are still positive for
TRAb at the end of treatment have an increased risk of
relapse,69,70 but relapse can also occur in patients who
became negative for TRAb during antithyroid drug treat
ment.67,70 Women in the postpartum period are also at
risk of recurrence of Graves disease, even if they had pre
viously been in prolonged remission after treatment.71
Other factors have also been associated with increased
recurrence rate (Box2).
131
I-radiotherapy
131
I is an effective therapy for patients with Graves
disease,72 as it causes gradual necrosis of thyroid cells.
The loss of functional thyroid tissue eventually results
in hypothyroidism in most patients who receive this
therapy.73 Indeed, hypothyroidism is a desired goal of
131
I-radiotherapy because the use of low doses of this
isotope, aimed at restoring euthyroidism, is associated
with a high rate of recurrence of hyperthyroidism. 16
131
I-radiotherapy can be administered in fixed amounts
or as calculated doses based on the estimated size of the
thyroid and uptake of 131I 24h after administration, as
measured by thyroid scintigraphy.72 No consensus has yet
been reached on whether fixed doses or calculated doses
should be employed. One of the arguments supporting the
use of fixed doses is that this approach requires neither
an additional clinic visit nor local expertise in the use of
thyroid scintigraphy to calculate 131I uptake.44 A survey
of UK specialists showed that fixed doses were used by
70% of respondents.73 Use of high doses (0.78GBq)
of 131I is associated with a higher treatment success rate
and earlier achievement of cure than are low doses of
131
I (0.56GBq).74 The practice recommendations pub
lished by the ATA in 201175 should be carefully followed
to maintain radiation safety for the patients close family
after 131I-radiotherapy.
Whether 131I-radiotherapy should be given after a
course of antithyroid drug treatment is a matter of
debate. The ATA and AACE guidelines 16 recommend
drug pretreatment in patients with severe hyperthyroid
ism, cardiovascular complications and other conditions
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that increase the risk associated with exacerbation of
hyperthyroidism (resulting from transient destructive
thyroiditis) that can occur after 131I-radiotherapy. In
several European countries, antithyroid drugs are com
monly administered for a few months before 131I treat
ment to induce euthyroidism, and withdrawn 57days
before 131I-radiotherapy.8 Pretreatment with antithyroid
drugs could reduce the time needed to achieve control of
the disease symptoms, as the effect of 131I-radiotherapy
alone is slow, and might also prevent possible worsen
ing of the patients clinical symptoms resulting from
131
I-radiotherapy. However, pretreatment with propyl
thiouracil seems to be associated with a degree of thyroid
resistance to 131I-radiotherapy, which is less evident with
methimazole. 76 This resistance can be overcome by
increasing the dose of 131I.77
The effect of 131 I-radiotherapy is not immedi
ate, and temporary reinstatement of treatment with
antithyroid drugs after 131I-radiotherapy is advisable
in elderly individuals or patients with relevant comor
bid conditions, particularly cardiovascular disorders,
as this treatment does not affect the effectiveness of
131
I-radiotherapy.78 Lithium carbonate, given concomi
tantly with 131I-radiotherapy, enables prompt control of
thyrotoxicosis, which might also be important in these
two groups.79 However, lithium carbonate treatment
does not improve the long-term cure rate achieved by
131
I-radiotherapy.80,81 A few studies have shown increased
all-cause and cardiovascular-related mortality following
131
I-radiotherapy,82,83 which is probably attributable to
previous hyperthyroidism perse rather than to the effects
of this treatment.84,85 Notably, a study published in 2013
showed no increased mortality in patients >40years of
age who became hypothyroid after 131I-radiotherapy.85
Although most studies have failed to demonstrate an
association between 131I-radiotherapy and cancer,72,8688
one study from Finland showed dose-related increases in
the incidence of several cancers (particularly those of the
stomach, kidney and breast).89 By contrast, a large UK
study demonstrated an overall decrease in the incidence
of (and mortality from) cancer in patients treated with
131
I, although increase in incidence were reported for
thyroid cancers and small-bowel cancers.90 Furthermore,
no increased incidence of cancer, including thyroid
cancer, has been observed in adults who were treated
with 131I-radiotherapy in childhood or adolescence.91
131
I-radiotherapy causes denovo occurrence or exacer
bation of pre-existing mild Graves ophthalmopathy 9294
in about 1520% of patients,95 the majority of whom are
smokers.94 Progression of mild Graves ophthalmopathy
after 131I-radiotherapy is often transient, although not
negligible from the patients standpoint; immuno
suppressive treatment for active, moderate to severe
Graves ophthalmopathy is needed in 5% of patients.93
This complication can usually be preventedin
patients with mild or absent Graves ophthalmopathy,
but with risk factors, such as smoking or high TRAb
levels, associated with progression of this complication
after 131I-radiotherapyby steroid prophylaxis, using
low doses of oral prednisone.93,96,97 Early and prompt

correction of hypothyroidism after 131I-radiotherapy is
also necessary to prevent the possible progression of
Gravesophthalmopathy.98101
Thyroidectomy
Surgery is a valid and definitive treatment for Graves
disease102106 but is used less often than 131I-radiotherapy.
Patient preferences have a major role in the choice of
surgery or 131I-radiotherapy.107 Thyroidectomy is clearly
indicated in patients with relapse of hyperthyroidism
after antithyroid drug treatment and in those with large
goitres, or when associated malignancy is suspected
(Box1). In exceptional circumstances, such as in preg
nant women who cannot tolerate antithyroid drugs,
thyroidectomy might be performed during the second
trimester. Thyroidectomy might also be offered to
patients who refuse 131I-radiotherapy, which is a common
occurrence in some Asian countries. 24 In selected
patients, such as those with small goiter or no suspicion
of malignancy, minimally invasive video-assisted thy
roidectomy,108 endoscopic subtotal thyroidectomy by the
breast 109 or robot-assisted transaxillary thyroidectomy 110
might represent valid surgical approaches.
The rates of complications of thyroid surgery, includ
ing hypoparathyroidism, palsy of the recurrent laryngeal
nerve and wound infections, are inversely correlated with
surgeon experience and annual volume of thyroidecto
mies.111 Near-total or total thyroidectomy is the preferred
procedure,16 because subtotal thyroidectomy bears an
increased risk of relapse of hyperthyroidism. 102,103
Moreover, near-total or total thyroidectomy does not
increase the complication rate102,103 and has no delete
rious effect on postoperative quality of life, compared
with subtotal thyroidectomy based on the short form
36 questionnaire.104 A systematic review also showed
that surgery is more successful than 131I-radiotherapy
as definitive treatment for Graves disease, and that
total thyroidectomy should be the preferred surgical
approach.106 A cost-effectiveness analysis of treatment
options for Graves disease in the USA showed that total
thyroidectomy is more cost-effective than either lifelong
treatment with antithyroid drugs or 131I-radiotherapy,
for patients who are not in remission after an 18-month
course of antithyroid drugs. 105 However, whether
the results ofthis analysis can be generalized to other
populations of patients is not yet settled.
Preparation for thyroid surgery usually involves,
in addition to restoration of euthyroidism using anti
thyroid drugs, administration of saturated potassium
iodide solutions for 1014days to decrease intra
thyroidal blood flow and limit perioperative blood
loss. 112 Thyroidectomy does not seem to affect the
natural course of Graves ophthalmopathy.113 However,
a beneficial (indirect) effect of surgery cannot be ruled
out, owing to the decline in serum TRAb levels that
occurs following thyroidectomy.114 Although, in a ran
domized prospective study, the decrease in serum TRAb
levels did not prevent progression of eye disease in 16
of 191 patients with mild Graves ophthalmopathy who
were followed up for 5years.115
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Geographical differences in therapies
The choice of treatment for patients with Graves disease
could be influenced by local availability of expertise and
suitable facilities, as well as socioeconomic conditions.
A retrospective study from an urban county hospital
in OH, USA showed a disproportionately high number
of thyroidectomies (16% in this study versus 2% in the
literature) among patients who were uninsured or had
Medicaid health insurance (a government-subsidized
programme for low-income individuals and families); by
contrast, only one of the 44 patients (2%) who elected to
undergo surgery had commercial (non-Medicaid) health
insurance.116 Selection of surgery by the patient might be
related to the fact that the hypothyroidism that inevitably
follows thyroidectomy requires less surveillance, in terms
of both hospital visits and hormone assays (one TSH assay
per year), than that during antithyroid drug therapy.116
Moreover, in other areas, such as sub-Saharan Africa, the
number of thyroidectomies for Graves disease has tripled
over the past 510years, owing to the paucity of special
ized endocrinology and nuclear medicine centres.117 In
India, where a report from 1993 indicated that antithyroid
drugs were the preferred first-line treatment for Graves
disease,118 an increase in the number of thyroidectomies
was reported in 2007, because many patients cannot
afford the costs of long-term treatment with antithyroid
drugs, including the necessary hormone assays and
follow-up visits, and consequent loss of working hours.119
Howe ver, in a tertiary referral centre in North India,
131
I-radiotherapy has gained widespread acceptance.120
When antithyroid drug availability is limited or patient
adherence is low, thyroid surgery might be advisable, as
indicated in a study from Khartoum, Sudan.121 A report
from sub-Saharan Africa suggests that rates of loss to
follow-up are very high in developing countries and
that the lack of diagnostic and therapeutic tools can
also impede the delivery of appropriate treatment. 122
An editorial from Japan and Korea published in 2011
pointed out that many patients in Asia have an extreme
fear of radiation and are, therefore, reluctant to receive
131
I-radiotherapy unless they have progression of thyroid
cancer. 24 In a survey of endocrinologists carried out
>20years ago, 131I-radiotherapy was the preferred first-
line treatment according to 69% of North American
respondents, but only 22% of the Japanese respon
dents and 11% of European respondents (Figure2). 31
Conversely, antithyroid drugs were the preferred treat
ment option for a first episode of hyperthyroidism
according to the majority of European and Japanese
respondents, 77% and 88%, respectively, but only 30%
of NorthAmericans.31 Thyroidectomy is rarely recom
mended by endocrinologists as the first-line treatment
in any region.31
During the same time period, the results of a differ
ent study showed that antithyroid drugs were the pre
ferred treatment option in Australia (81%)123 and, to a
lesser extent, in New Zealand (59%).124 The increasing
number of prescriptions of antithyroid drugs observed in
the USA during 19912008could reflect a trend towards
wider use of such agents, particularly methimazole, as the
REVIEWS
a 100 b
North America
90 Europe
80
Asia and Oceania
Survey respondents (%)
70
60
50
40
30
20
10
0
Antithyroid drugs Radiolabelled Antithyroid drugs Radiolabelled
iodine therapy iodine therapy
Treatment Treatment
Figure 2 | Changes over time in the use of antithyroid drugs and 131I-radiotherapy
as first-line treatments for Graves disease in North America, Europe, and Asia
and Oceania. Data are derived from two separate surveys, published in a | 199131
andb | 2011.15 Of note, in the 1991 survey all respondents from the Asia and
Oceania region were from Japan, whereas in the 2011 survey the respondents
from this region were from Japan and other countries in Asia and Oceania.
primary treatment for Graves disease in the USA.51 This
trend is confirmed by the findings ofthe 2011 survey of
clinical practice patterns; overall, antithyroid drugs were
selected as the first-line treatment for Graves disease by
383 of 711 respondents (53.9%), 131I-radiotherapy
by 320 (45%) and thyroidectomy by only 5 respondents
(0.7%). 15 When the analysis was restricted to North
American respondents, 131I-radiotherapy was the pre
ferred treatment for 58.9%. Although still the most
popular option, first-line use of 131I-radiotherapy seems
to be declining in North America, in line with a concom
itant increasein the use of antithyroid drugs to 40.5%
(Figure2).15 Interestingly, the proportion of respondents
whose preferred first-line therapy was antithyroid drugs
was higher in Canada (56.7%) than in the USA (39.4%).15
Compared with similar surveys carried out in the 1990s,
the survey from 2011 showed that the preference for
131
I-radiotherapy as first-line treatment had decreased
further in Europe, to 13.3%, and had increased in
theAsia and Oceaniagroup, to 29.4%. However, the data
for Asia and Oceania should be interpreted with caution,
as the 1990s survey included only Japanese respondents
in this category, whereas the corresponding group in the
survey from 2011 also included respondents from other
countries in Asia and Oceania. Furthermore, the total
number of respondents in Asia and Oceania groups was
small, as was the number of European respondents.
Thus, although geographical differences remain, a
trend is evident towards increasing use of antithyroid
drugs as the first-line treatment for Graves disease, par
ticularly in patients with a first episode of hyperthyroid
ism, and in those whose goitre is not large and/or those
have mild or absent ocular involvement. The role of thy
roidectomy as first-line treatment currently remains as
modest as it was 20years ago, but surgery might main
tain a relevant role as primary treatment in countries
where facilities for administration of (and isotopes used
in) 131I-radiotherapy are not readily available.
730 | DECEMBER 2013 | VOLUME 9  www.nature.com/nrendo
2013 Macmillan Publishers Limited. All rights reserved
Management of Graves ophthalmopathy
Graves ophthalmopathy, the main extrathyroidal
expression of Graves disease, is fortunately rare, at least
in its severe form. In fact, in a nontertiary centre, 26%
of newly diagnosed patients with Graves disease had
ocular involvement, but only 5% had moderate to severe
Graves ophthalmopathy, and an additional 1% had sight-
threatening Graves ophthalmopathy.11,12 Nevertheless,
even mild Graves ophthalmopathy impairs patient
quality of life, owing to its disfiguring appearance and
the associated visual impairment (such as exophthalmos
and diplopia).9 Two important questions are whether
treatments for hyperthyroidism influence the course of
Graves ophthalmopathy, and which is the preferred treat
ment for hyperthyroidism in patients with moderate to
severe Graves ophthalmopathy.125
In general, neither antithyroid drugs nor thyroid
ectomy are considered to be disease-modifying treat
ments with regard to Graves ophthalmopathy, although
reversal of hyperthyroidism with antithyroid drugs is
associated with amelioration of Graves ophthalmo
pathy.126,127 131I-radiotherapy can cause denovo occur
rence or progression of mild Graves ophthalmopathy,
particularly in smokers,9295 but this exacerbation can
usually be prevented by a concomitant short course
of oral prednisone. 93,96,97 Steroid prophylaxis is only
required if 131I-radiotherapy is used (particularly in
smokers).125 Thus, if Graves ophthalmopathy is absent
or mild, hyperthyroidism can be managed by any treat
ment. A European questionnaire-based survey indicated
that antithyroid drugs were the preferred treatment in
patients with sight-threatening Graves ophthalmopathy
due to dysthyroid optic neuropathy. 128 However, in
patients with active, moderate to severe (but not sight-
threatening) Graves ophthalmopathy, management of
the eye disease should be prioritized over addressing
other symptoms, because the effectiveness of treat
ment (usually high-dose glucocorticoids 129,130 with
or without orbital 131I-radiotherapy 131) is higher if the
Graves ophthalmopathy is of recent onset.101 Some
researchers suggest that this group of patients should be
treated with long-term antithyroid drug treatment.132,133
Other researchers believe that the orbital and thyroid
disease should be treated concomitantly using ablative
approaches: thyroidectomy, 131I-radiotherapy or both
(total thyroid ablation).134137 Interestingly, in the 2011
US survey, 1 63% of respondents selected long-term
antithyroid drug treatment, 18.5% selected thyroid
ectomy, 16.9% opted for 131I-radiotherapy with steroid
prophyla xis, and only 1.9% chose 131I-radiotherapy
alone for patients with Graves opthalmopathy. In the
absence of robust randomized clinical trials, the optimal
treatment for hyperthyroidism in patients with Graves
ophthalmopathy remainsundetermined.125
Conclusions
No perfect treatment exists for Graves disease (Table1).
Moreover, one major limitation shared by all existing
therapies for this condition is that they do not target
its underlying pathogenic mechanisms. The various
 REVIEWS

therapeutic options and general planning of treat
ment should, therefore, be thoroughly discussed at the
patients first visit to a specialist, because, unless one
treatment is strongly indicated (for example, thyroid
ectomy in a patient with suspected thyroid carcinoma),
the preference of the patient has an important role.107
Antithyroid drugs offer a conservative treatment
option, in which thyroid tissue is not eliminated. Anti
thyroid drugs are essentially safesome can be given to
children and pregnant womenand treatment can be
continued for 510 years or more.5961 The main draw
back of these drugs is the unacceptably high relapse
rate, which is independent of the different agents and
regimens used. By contrast, 131I-radiotherapy and thy
roidectomy are definitive treatments that act by ablat
ing the thyroid tissue. Thus, cure of hyperthyroidism
is ensured, albeit at the expense of permanent hypo
thyroidism requiring lifelong levothyroxine replace
ment. 131I-radiotherapy might also cause occurrence or
progression of Graves ophthalmopathy in a subset of
patients, particularly in smokers.9294 In addition, the
effect of 131I-radiotherapy is not immediate, and some
treated individuals, particularly elderly patients or
those with relevant comorbid conditions, might need
to resume antithyroid drugs after 131I-radiotherapy
for several weeks. Thyroidectomy allows an immedi
ate cure of hyperthyroidism, and does not worsen or
cause Graves ophthalmopathy. However, the procedure
requires anaesthesia and, even in the hands of skilled
thyroid surgeons, is associated with major complica
tions, including permanent hypoparathyroidism and
recurrent laryngeal nerve palsy. 100 Thyroidectomy
is preferable to 131I-radiotherapy if the goitre is large.
Management of Graves ophthalmopathy, the main
extrathyroidal manifestation of Graves disease, remains
a therapeutic challenge.
Geographical differences persist in the use of the three
available treatments for Graves disease. This variation
could be related to the availability of local facilities and
skilled thyroid surgeons, and the presence or absence of
nuclear medicine units in which 131I-radiotherapy can
be administered. In the USA, the proportion of patients
who undergo first-line 131I-radiotherapy is decreas
ing, and antithyroid drugs are consequently expected
to become the first-line treatment for Graves disease
worldwide. Furthermore, the indications for use of
the antithyroid drug propylthiouracil have changed.
Propylthiouracil was formerly the preferred antithyroid
drug in the USA and South America, but its use is now
restricted to women in the first trimester of pregnancy
and to patients who cannot tolerate methimazole
and/or carbimazole.
Ongoing preclinical and clinical studies are assess
ing the effectiveness of novel drugs or substances that
could intervene in the disease process. These therapeu
tic agents include rituximab, a monoclonal antibody
depleting CD20-positive Bcells, and other monoclonal
antibodies or small molecules that can block the thyroid-
stimulating effect of TRAb and, therefore, act as TRAb
antagonists.43 However, for the time being the data are
too preliminary to predict whether these drugs and com
pounds will become available for use in clinical practice
in the near future.
Review criteria
A search for original and review articles from 1993 until
2013 that focus on Graves disease was performed in
MEDLINE. The search terms used were Graves disease,
hyperthyroidism, antithyroid drugs, thionamides,
methimazole, carbimazole, propylthiouracil,
radioiodine, and thyroidectomy. Other relevant
sources, such as guidelines and textbook chapters, were
also consulted. The authors personal archive of papers
the reference lists of key articles were also searched to
identify additional relevant information.

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Acknowledgements
This paper is dedicated to Prof. Aldo Pinchera
(19342012), the authors mentor and an outstanding
scientist in the field of endocrinology. The author also
thanks Prof. Stefano Mariotti, University of Cagliari,
Italy, for critically reviewing the manuscript.
L.Bartalenas research is partly supported by grants
from the Ministero della Istruzione, Universit e
Ricerca (MIUR) Rome, and the University of Insubria
at Varese.