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

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This approach is in line with the ATA and AACE guide Key points
lines on diagnosis of hyperthyroidism;16 thus, the finding
Diagnosis of Graves disease is now usually based on anti-TSH-receptor
of increased levels of free T4 and decreased levels of TSH
antibody assays and thyroid ultrasonography
is usually sufficient to confirm the diagnosis of Graves Options for management of Graves disease include antithyroid drugs,
disease. Serum levels of free T3 or total T3 are also com 131
I-radiotherapy and thyroidectomy; however, drug-treated patients have a high
monly increased in patients with hyperthyroidism, relapse rate, and ablative therapies induce lifelong hypothyroidism
but measurement of free T3 or total T3 levels was only In Europe and Japan, antithyroid drugs remain the preferred first-line therapy
requested by 40% of the endocrinologists in the above for Graves disease, whereas in North America 131I-radiotherapy is the preferred
survey (with no geographical differences in whether or option, despite increasing use of antithyroid drugs
not this additional test was requested).15 However, 24% Thyroidectomy is rarely used as a first-line treatment for Graves disease in any
geographical region
of patients with hyperthyroidism have normal serum
Methimazole or carbimazole are the preferred thionamide antithyroid drugs;
levels of free T4 and increased serum levels of free T3 use of propylthiouracil is restricted to patients who cannot tolerate other
or total T3 (so-called T3 thyrotoxicosis).8 Thus, in the thionamides and to women in the first trimester of pregnancy
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 a 100 b North America
isadvised. 90 Europe
Determination of the serum levels of TRAb is a useful Asia and Oceania
80
laboratory test to determine whether Graves disease is the Survey respondents (%)
70
cause of hyperthyroidism. Whereas antibodies against
thyroglobulin and thyroid peroxidase (TPO) are found 60

in patients with Hashimoto thyroiditis as well as in those 50


with Graves disease, modern immunoassays and bioassays 40
for TRAb with high sensitivity and specificity, enable the 30
precise aetiology of hyperthyoidism to be identified.1721 20
Whereas early TRAb assays were expensive and time-
10
consuming, automated TRAb assays developed over the
0
past 510years are comparable to anti-TPO antibody
1991 2011 1991 2011
assays in terms of ease of use and cost.22 A meta-analysis Year Year
published in 2012 indicated that the pooled sensitiv
Figure 1 | The use of diagnostic tests for Graves disease
ity and specificity values for third-generation TRAb in North America, Europe, and Asia and Oceania. Data on
assays are 98.3% and 99.2%, respectively.23 The likeli a | TSH-receptor antibody testing and b | isotope studies
hood that a patient has Graves disease is 1,3673,420- (thyroid uptake of 131I and/or thyroid scintigraphy) are
fold greater if they are TRAbpositive than if they are are derived from surveys from 199131 and 2011.15 Of note, in
TRAb-negative.23 the 1991 survey, all respondents from the Asia and
The ATA and AACE guidelines from 2011 suggest Oceania region were from Japan, whereas in the 2011
that measurement of serum TRAb levels should be util survey the respondents from this region were from Japan
and other countries in Asia and Oceania.
ized when measurement of radioactive iodine uptake or
thyroid scintigraphy is not available or contraindicated.16
However, other researchers disagree with this restric Isotope uptake measurements and imaging studies
tion on the diagnostic use of TRAb measurement.2426 According to the current ATA and AACE guidelines,
In the 2011 survey,15 the measurement of serum levels of thyroid uptake of radioactive iodine should be meas
TRAb for diagnostic purposes was practiced by 58.1% ured when the patients clinical presentation indicates
of respondents overall, with a significantly higher propor thyrotoxicosis, but is not diagnostic of Graves disease.16
tion in Europe (77.5%) than in North America (54.3%), These guidelines also recommend that thyroid scinti
and an intermediate number of respondents in Asia and graphy should be added to diagnose the disease if
Oceania (65.3%). Japanese experts confirmed that thyroid nodularity is present.16 In the survey of clinical
measurement of serum levels of TRAb is much more practice from 2011,15 uptake of radioactive iodine and/or
widely used in Japan than it is in the USA.27 Interestingly, thyroid scintigraphy were used as diagnostic tools by
international surveys carried out >20years ago show 70.9% of North American respondents, 54.2% of respon
similar usage patterns: the proportions of endocrinolo dents in Asia and Oceania and only 30.3% of European
gists who requested measurement of serum TRAb levels respondents. The use of isotope uptake tests has declined
were 9% in North America,28 38% in Europe29 and 28% in considerably over the past 20years; for example, around
Japan30 (Figure1a). In view of the greatly improved sen 66% of European respondents were using isotope-uptake
sitivity, specificity and cost of currently available TRAb tests to diagnose Graves disease in surveys done before
assays, I also support the opinion that TRAb testing 1991,31 more than twice as many as in the 2011 survey
should be included in the initial assessment of patients (Figure1b).15 Moreover, the results of a large retrospec
with suspected Graves disease, particularly if extra tive study from the UK show that in most patients with
thyroidal m anifestations, such as Graves ophthalmopathy, hyperthyroidism, the results of radioiodine uptake tests
are absent. or thyroid scintigraphy did not influence the aetiological

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Table 1 | Advantages and disadvantages of treatments for Graves disease


Treatment Advantages Disadvantages
Antithyroid drugs Conservative treatment High relapse rate
No hospitalization required Requires frequent clinic visits for monitoring
Low risk of subsequent hypothyroidism Poor adherence
No radiation exposure Adverse events (rarely major)
No adverse effect on Graves ophthalmopathy
Safe to use during pregnancy and breastfeeding
I-radiotherapy
131
Definitive treatment Lifelong hypothyroidism
Low cost Radiation exposure
No hospitalization required Slow control of hyperthyroidism
No need for surgery or anaesthetic Possible progression or denovo occurrence of Graves
ophthalmopathy
Thyroidectomy Definitive treatment Lifelong hypothyroidism
No radiation exposure Adverse events related to surgical procedure and anaesthetic
Prompt control of hyperthyroidism Hospitalization
High cost
Permanent scar

diagnosis based on clinical and immunological findings; differentiate between the two conditions. Thyroid glands
only 5.7% of such diagnoses were mismatched with those in patients with Graves disease show increased peak sys
based on isotope measurements or thyroid scintigraphy.32 tolic blood flow velocity compared with that in thyroid
Modern TRAb assays can be diagnostically used in glands from patients with Hashimoto thyroiditis.35,41,42
place of isotopic studies in most patients with diffuse The ATA and AACE guidelines state that ultra
goitre.33 Reduced use of isotope-based tests not only sonography does not generally contribute to the differen
avoids radiation exposure but also decreases costs as tial diagnosis of thyrotoxicosis, although its diagnostic
well as inconvenience to the patient.33 However, thyroid role is recognized in patients for whom isotopic studies
scintigraphy remains a useful tool to identify nodular are contraindicated (for example, during pregnancy) or
variants of Graves disease, although colour flow Doppler not informative, owing to iodine contamination from,
ultrasonography of the thyroid might replace it. for example, drugs such as amiodarone.16 By contrast,
Thyroid ultrasonography is noninvasive, sensitive the diagnostic accuracy of colour flow Doppler ultra
and inexpensive, and does not involve radiation expo sonography is widely recognized in Europe. 25 In an
sure. This technique can be used to rapidly diagnose international survey from 1991, thyroid ultrasonography
not only nodular thyroid disorders but also Graves was not even mentioned,31 whereas in a European survey
disease. 34 Typically, in patients with Graves disease, from 1987 ultrasonography was already selected by 21%
the thyroid gland appears diffusely enlarged and hypo of respondents.29 In the 2011 survey of clinical practice
echoic on conventional grey-scale ultrasonography. 35 patterns, thyroid ultrasonography was requested only
In a study of 426 patients with Graves disease, thyroid by 25.8% of endocrinologists overall, but this low pro
ultras onography led to a correct diagnosis in 406 portion probably reflects the preponderance of North
patients (95.2%), whereas thyroid scintigraphy led to a American respondents.15 Interestingly, the majority
correct diagnosis in 415 patients (97.4%).36 As expected, of respondents who used thyroid ultrasonography as
ultrasonography was significantly more sensitive than a diagnostic tool did not also request an isotope study
thyroid scintigraphy for detecting concomitant nodular suggesting that thyroid ultrasonography could replace
lesions (which were detected in 16% of patients by ultra isotope studies.15
sonography, compared with 2% of patients by thyroid
scintigraphy).36 An analysis of cost-effectiveness also Management of Graves disease
favoured ultrasonography over thyroid scintigraphy.36 The ideal treatment for Graves disease should restore
Colour flow Doppler ultrasonography is useful to normal thyroid function, avoid recurrence of hyper
distinguish nodular variants of Graves disease from thyroidism, prevent development of hypothyroidism
nonautoimmune toxic multinodular goitre.37 Nodules and prevent denovo occurrence or progression of Graves
in patients with Graves disease have normal vascularity ophthalmopathy. Unfortunately, no currently available
and increased extranodular vascularity, whereas those in treatment fulfils these criteria; the advantages and dis
patients with nonautoimmune toxic multinodular goitre advantages of each form of treatment (Table1) should,
have increased intranodular and perinodular vascular therefore, be clearly and objectively presented to patients.
ity but normal extranodular vascularity.37 Investigation Various pharmacological therapies for Graves disease
of the thyroid vascularity can also distinguish between that aim to target the disease process as well as its
Graves disease and destructive thyroiditis as the cause extrathyroidal manifestations are currently under inves
of thyrotoxicosis.3840 Although both Graves disease and tigation.43 However, for the time being, management
Hashimoto thyroiditis appear as a hypoechoic pattern on of Graves disease still relies on three approaches that
conventional grey-scale ultrasonography of the thyroid, have been used for several decades: pharmacological
colour flow Doppler ultrasonography can effectively treatment with antithyroid drugs, 131I-radiotherapy and

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thyroidectomy.44 Several criteria can influence the choice Box 1 | Factors influencing the choice of treatment for Graves disease
of treatment (Box1).
First episode of hyperthyroidism
Antithyroid drugs, 131I-radiotherapy, (thyroidectomy)
Treatment with antithyroid drugs
Relapse of hyperthyroidism
The thionamide-derived antithyroid drugs approved for
Small goitre: 131I-radiotherapy, thyroidectomy*, (antithyroid drugs)
use in patients with Graves disease include methimazole, Large goitre: thyroidectomy, 131I-radiotherapy
carbimazole (which after absorption is converted into the Pregnancy
active form methimazole) and propylthiouracil. These Antithyroid drugs, (thyroidectomy)
drugs can have either direct or indirect (through normal Breastfeeding
ization of thyroid status) immunosuppressive effects,45,46 Antithyroid drugs
but their main mode of action is to decrease excess Cytologically suspicious nodules
thyroid hormone synthesis by inhibiting TPO, thereby Thyroidectomy
reducing the production of T3 and T4. Antithyroid drugs, Intolerance of or major adverse events using antithyroid drugs
such as potassium perchlorate for amiodarone-induced
131
I-radiotherapy, thyroidectomy*
thyrotoxicosis, which are not thionamide-based, have Graves ophthalmopathy
limited applications.46,47 Mild: antithyroid drugs, 131I-radiotherapy, thyroidectomy
The current ATA and AACE guidelines indicate that Moderate to severe: antithyroid drugs, 131I-radiotherapy, thyroidectomy
methimazole should be used in all patients selected for Sight-threatening: antithyroid drugs||
treatment with antithyroid drugs, except women during *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
their first trimester of pregnancy.16 Propylthiouracil is intolerance to or major adverse events of antithyroid drug treatment; can be performed during
still the advised treatment option for pregnant women, the second trimester. Steroid prophylaxis should also be administered: low-dose oral
owing to the risk of embryopathy associated with prednisone to patients with mild Graves ophthalmopathy; high-dose intravenous
glucocorticoids to patients with moderate to severe Graves ophthalmopathy. ||The use of
carbimazole and methimazole.4850 antithyroid drugs rather than definitive treatment is controversial in patients with moderate to
Propylthiouracil was for many years the first-choice severe Graves ophthalmopathy. Treatments within parenthesis are not the ideal choice of
antithyroid drug in both the USA and South America.51 treatment under these circumstances, but they can be used.

However, propylthiouracyl can cause severe hepatotoxic


effects, which might be lethal or require liver transplanta whereas prolonging blockreplace antithyroid drug treat
tion.5254 Methimazole is used in most European coun ment beyond 6months does not increase the remission
tries and Japan, whereas carbimazole is mainly used in rate.58 However, some researchers contend that prolonged
the UK. A study published in 2010 showed that during treatment, for 510 years or more, with low doses of
19912008 the annual prescriptions of methimazole antithyroid drugs could improve the permanent remis
in the USA increased by ninefold, and this agent has been sion rate.5961 Patient adherence to blockreplace regi
the most commonly prescribed antithyroid drug in this mens might be reduced owing to the need to take high
region since 1996.51 numbers of tablets per day, unless, as in some countries,
2030mg methimazole tablets are available.
Treatment regimens
Antithyroid drug therapy can be administered according Adjunctive therapies
to two different approaches: the titration method, and -blockers can be used during the initial phases of
the blockreplace method.55 In the titration method, antithyroid drug treatment to reduce hyperthyroid
a variable starting daily dose of an antithyroid drug symptoms such as tachycardia,7,46 and administration of
(1540mg of methimazole or equivalent doses of other cholestyramine together with propylthiouracil acceler
agents) is used, and the drug is then gradually decreased ates the decline in serum levels of thyroid hormones.62,63
to the lowest dose that maintains serum levels of T4 in the A Japanese study reported that 2weeks of combined
euthyroid range. In the blockreplace method, a standard treatment with antithyroid drugs and iodide supplemen
dose of an antithyroid drug (for example, 2030mg of tation shortened the time to achieve control of Graves
methimazole) is administered together with a replace hyperthyroidism, although the long-term remission rate
ment dose of levothyroxine, to avoid hypothyroidism.55 was not increased.64 Several hospitals and institutions in
The rationale for using the blockreplace approach rather Japan use this combined treatment for Graves disease
than titration is that the higher dose of antithyroid drugs (S.Nagataki, personal communication).
used might abate the process of autoimmune disease
and lead to permanent remission of hyperthyroidism. Adverse effects
One study showed that the addition of levothyroxine Antithyroid drugs cause (usually minor and transient)
during and after low-dose methimazole treatment was adverse effects in a minority of patients.46,65 Adverse
associated with a markedly increased remission rate,56 effects are more commonly observed during the initial
but subsequent randomized clinical trials could not phases of methimazole treatment, when high doses might
replicate this finding.57 A systematic review published be needed, although the doseresponse relationship is less
in 2010 also failed to show any significant difference clear than it is with propylthiouracil therapy.46,65 The most
between the two dosing methods in terms of long-term serious adverse event is agranulocytosis (agranulocyte
efficacy. 55 Antithyroid drug therapy using the titra count <500 cells/cm3); however, this phenomenon is seen
tion method should be continued for 1824months,55 in only 0.10.5% of treated patients.46,65 In a retrospective

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Box 2 | Relapse after antithyroid drug treatment that increase the risk associated with exacerbation of
hyperthyroidism (resulting from transient destructive
Factors associated with a high rate of relapse after
antithyroid drug treatment:
thyroiditis) that can occur after 131I-radiotherapy. In
Positive TSH receptor antibody tests69,70 several European countries, antithyroid drugs are com
Large goitre67,70 monly administered for a few months before 131I treat
Young age67,68 ment to induce euthyroidism, and withdrawn 57days
Male sex68 before 131I-radiotherapy.8 Pretreatment with antithyroid
Severe hyperthyroidism68 drugs could reduce the time needed to achieve control of
Cigarette smoking69 the disease symptoms, as the effect of 131I-radiotherapy
Postpartum period71
alone is slow, and might also prevent possible worsen
ing of the patients clinical symptoms resulting from
Japanese study, agranulocytosis was more common 131
I-radiotherapy. However, pretreatment with propyl
in patients given an initial dose of 30mg methimazole thiouracil seems to be associated with a degree of thyroid
(0.81%) than in those given an initial dose of 15mg resistance to 131I-radiotherapy, which is less evident with
methimazole (0.22%).66 However, routine monitoring of methimazole. 76 This resistance can be overcome by
granulocyte levels during treatment is not beneficial, as increasing the dose of 131I.77
the onset of agranulocytosis is abrupt.16 The effect of 131 I-radiotherapy is not immedi
The major drawback of antithyroid drug therapy is ate, and temporary reinstatement of treatment with
the high rate of recurrence, which varies across studies antithyroid drugs after 131I-radiotherapy is advisable
from 30% to 70%.55,67,68 Patients who are still positive for in elderly individuals or patients with relevant comor
TRAb at the end of treatment have an increased risk of bid conditions, particularly cardiovascular disorders,
relapse,69,70 but relapse can also occur in patients who as this treatment does not affect the effectiveness of
became negative for TRAb during antithyroid drug treat 131
I-radiotherapy.78 Lithium carbonate, given concomi
ment.67,70 Women in the postpartum period are also at tantly with 131I-radiotherapy, enables prompt control of
risk of recurrence of Graves disease, even if they had pre thyrotoxicosis, which might also be important in these
viously been in prolonged remission after treatment.71 two groups.79 However, lithium carbonate treatment
Other factors have also been associated with increased does not improve the long-term cure rate achieved by
recurrence rate (Box2). 131
I-radiotherapy.80,81 A few studies have shown increased
all-cause and cardiovascular-related mortality following
131
I-radiotherapy 131
I-radiotherapy,82,83 which is probably attributable to
131
I is an effective therapy for patients with Graves previous hyperthyroidism perse rather than to the effects
disease,72 as it causes gradual necrosis of thyroid cells. of this treatment.84,85 Notably, a study published in 2013
The loss of functional thyroid tissue eventually results showed no increased mortality in patients >40years of
in hypothyroidism in most patients who receive this age who became hypothyroid after 131I-radiotherapy.85
therapy.73 Indeed, hypothyroidism is a desired goal of Although most studies have failed to demonstrate an
131
I-radiotherapy because the use of low doses of this association between 131I-radiotherapy and cancer,72,8688
isotope, aimed at restoring euthyroidism, is associated one study from Finland showed dose-related increases in
with a high rate of recurrence of hyperthyroidism. 16 the incidence of several cancers (particularly those of the
131
I-radiotherapy can be administered in fixed amounts stomach, kidney and breast).89 By contrast, a large UK
or as calculated doses based on the estimated size of the study demonstrated an overall decrease in the incidence
thyroid and uptake of 131I 24h after administration, as of (and mortality from) cancer in patients treated with
measured by thyroid scintigraphy.72 No consensus has yet 131
I, although increase in incidence were reported for
been reached on whether fixed doses or calculated doses thyroid cancers and small-bowel cancers.90 Furthermore,
should be employed. One of the arguments supporting the no increased incidence of cancer, including thyroid
use of fixed doses is that this approach requires neither cancer, has been observed in adults who were treated
an additional clinic visit nor local expertise in the use of with 131I-radiotherapy in childhood or adolescence.91
thyroid scintigraphy to calculate 131I uptake.44 A survey 131
I-radiotherapy causes denovo occurrence or exacer
of UK specialists showed that fixed doses were used by bation of pre-existing mild Graves ophthalmopathy 9294
70% of respondents.73 Use of high doses (0.78GBq) in about 1520% of patients,95 the majority of whom are
of 131I is associated with a higher treatment success rate smokers.94 Progression of mild Graves ophthalmopathy
and earlier achievement of cure than are low doses of after 131I-radiotherapy is often transient, although not
131
I (0.56GBq).74 The practice recommendations pub negligible from the patients standpoint; immuno
lished by the ATA in 201175 should be carefully followed suppressive treatment for active, moderate to severe
to maintain radiation safety for the patients close family Graves ophthalmopathy is needed in 5% of patients.93
after 131I-radiotherapy. This complication can usually be preventedin
Whether 131I-radiotherapy should be given after a patients with mild or absent Graves ophthalmopathy,
course of antithyroid drug treatment is a matter of but with risk factors, such as smoking or high TRAb
debate. The ATA and AACE guidelines 16 recommend levels, associated with progression of this complication
drug pretreatment in patients with severe hyperthyroid after 131I-radiotherapyby steroid prophylaxis, using
ism, cardiovascular complications and other conditions low doses of oral prednisone.93,96,97 Early and prompt

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correction of hypothyroidism after 131I-radiotherapy is Geographical differences in therapies


also necessary to prevent the possible progression of The choice of treatment for patients with Graves disease
Gravesophthalmopathy.98101 could be influenced by local availability of expertise and
suitable facilities, as well as socioeconomic conditions.
Thyroidectomy A retrospective study from an urban county hospital
Surgery is a valid and definitive treatment for Graves in OH, USA showed a disproportionately high number
disease102106 but is used less often than 131I-radiotherapy. of thyroidectomies (16% in this study versus 2% in the
Patient preferences have a major role in the choice of literature) among patients who were uninsured or had
surgery or 131I-radiotherapy.107 Thyroidectomy is clearly Medicaid health insurance (a government-subsidized
indicated in patients with relapse of hyperthyroidism programme for low-income individuals and families); by
after antithyroid drug treatment and in those with large contrast, only one of the 44 patients (2%) who elected to
goitres, or when associated malignancy is suspected undergo surgery had commercial (non-Medicaid) health
(Box1). In exceptional circumstances, such as in preg insurance.116 Selection of surgery by the patient might be
nant women who cannot tolerate antithyroid drugs, related to the fact that the hypothyroidism that inevitably
thyroidectomy might be performed during the second follows thyroidectomy requires less surveillance, in terms
trimester. Thyroidectomy might also be offered to of both hospital visits and hormone assays (one TSH assay
patients who refuse 131I-radiotherapy, which is a common per year), than that during antithyroid drug therapy.116
occurrence in some Asian countries. 24 In selected Moreover, in other areas, such as sub-Saharan Africa, the
patients, such as those with small goiter or no suspicion number of thyroidectomies for Graves disease has tripled
of malignancy, minimally invasive video-assisted thy over the past 510years, owing to the paucity of special
roidectomy,108 endoscopic subtotal thyroidectomy by the ized endocrinology and nuclear medicine centres.117 In
breast 109 or robot-assisted transaxillary thyroidectomy 110 India, where a report from 1993 indicated that antithyroid
might represent valid surgical approaches. drugs were the preferred first-line treatment for Graves
The rates of complications of thyroid surgery, includ disease,118 an increase in the number of thyroidectomies
ing hypoparathyroidism, palsy of the recurrent laryngeal was reported in 2007, because many patients cannot
nerve and wound infections, are inversely correlated with afford the costs of long-term treatment with antithyroid
surgeon experience and annual volume of thyroidecto drugs, including the necessary hormone assays and
mies.111 Near-total or total thyroidectomy is the preferred follow-up visits, and consequent loss of working hours.119
procedure,16 because subtotal thyroidectomy bears an Howe ver, in a tertiary referral centre in North India,
increased risk of relapse of hyperthyroidism. 102,103 131
I-radiotherapy has gained widespread acceptance.120
Moreover, near-total or total thyroidectomy does not When antithyroid drug availability is limited or patient
increase the complication rate102,103 and has no delete adherence is low, thyroid surgery might be advisable, as
rious effect on postoperative quality of life, compared indicated in a study from Khartoum, Sudan.121 A report
with subtotal thyroidectomy based on the short form from sub-Saharan Africa suggests that rates of loss to
36 questionnaire.104 A systematic review also showed follow-up are very high in developing countries and
that surgery is more successful than 131I-radiotherapy that the lack of diagnostic and therapeutic tools can
as definitive treatment for Graves disease, and that also impede the delivery of appropriate treatment. 122
total thyroidectomy should be the preferred surgical An editorial from Japan and Korea published in 2011
approach.106 A cost-effectiveness analysis of treatment pointed out that many patients in Asia have an extreme
options for Graves disease in the USA showed that total fear of radiation and are, therefore, reluctant to receive
thyroidectomy is more cost-effective than either lifelong 131
I-radiotherapy unless they have progression of thyroid
treatment with antithyroid drugs or 131I-radiotherapy, cancer. 24 In a survey of endocrinologists carried out
for patients who are not in remission after an 18-month >20years ago, 131I-radiotherapy was the preferred first-
course of antithyroid drugs. 105 However, whether line treatment according to 69% of North American
the results ofthis analysis can be generalized to other respondents, but only 22% of the Japanese respon
populations of patients is not yet settled. dents and 11% of European respondents (Figure2). 31
Preparation for thyroid surgery usually involves, Conversely, antithyroid drugs were the preferred treat
in addition to restoration of euthyroidism using anti ment option for a first episode of hyperthyroidism
thyroid drugs, administration of saturated potassium according to the majority of European and Japanese
iodide solutions for 1014days to decrease intra respondents, 77% and 88%, respectively, but only 30%
thyroidal blood flow and limit perioperative blood of NorthAmericans.31 Thyroidectomy is rarely recom
loss. 112 Thyroidectomy does not seem to affect the mended by endocrinologists as the first-line treatment
natural course of Graves ophthalmopathy.113 However, in any region.31
a beneficial (indirect) effect of surgery cannot be ruled During the same time period, the results of a differ
out, owing to the decline in serum TRAb levels that ent study showed that antithyroid drugs were the pre
occurs following thyroidectomy.114 Although, in a ran ferred treatment option in Australia (81%)123 and, to a
domized prospective study, the decrease in serum TRAb lesser extent, in New Zealand (59%).124 The increasing
levels did not prevent progression of eye disease in 16 number of prescriptions of antithyroid drugs observed in
of 191 patients with mild Graves ophthalmopathy who the USA during 19912008could reflect a trend towards
were followed up for 5years.115 wider use of such agents, particularly methimazole, as the

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a 100 b
North America
Management of Graves ophthalmopathy
90 Europe Graves ophthalmopathy, the main extrathyroidal
80
Asia and Oceania expression of Graves disease, is fortunately rare, at least
Survey respondents (%)

70
in its severe form. In fact, in a nontertiary centre, 26%
of newly diagnosed patients with Graves disease had
60
ocular involvement, but only 5% had moderate to severe
50
Graves ophthalmopathy, and an additional 1% had sight-
40 threatening Graves ophthalmopathy.11,12 Nevertheless,
30 even mild Graves ophthalmopathy impairs patient
20 quality of life, owing to its disfiguring appearance and
10 the associated visual impairment (such as exophthalmos
and diplopia).9 Two important questions are whether
0
treatments for hyperthyroidism influence the course of
Antithyroid drugs Radiolabelled Antithyroid drugs Radiolabelled
iodine therapy iodine therapy Graves ophthalmopathy, and which is the preferred treat
Treatment Treatment ment for hyperthyroidism in patients with moderate to
Figure 2 | Changes over time in the use of antithyroid drugs and 131I-radiotherapy severe Graves ophthalmopathy.125
as first-line treatments for Graves disease in North America, Europe, and Asia In general, neither antithyroid drugs nor thyroid
and Oceania. Data are derived from two separate surveys, published in a | 199131 ectomy are considered to be disease-modifying treat
andb | 2011.15 Of note, in the 1991 survey all respondents from the Asia and ments with regard to Graves ophthalmopathy, although
Oceania region were from Japan, whereas in the 2011 survey the respondents reversal of hyperthyroidism with antithyroid drugs is
from this region were from Japan and other countries in Asia and Oceania.
associated with amelioration of Graves ophthalmo
pathy.126,127 131I-radiotherapy can cause denovo occur
primary treatment for Graves disease in the USA.51 This rence or progression of mild Graves ophthalmopathy,
trend is confirmed by the findings ofthe 2011 survey of particularly in smokers,9295 but this exacerbation can
clinical practice patterns; overall, antithyroid drugs were usually be prevented by a concomitant short course
selected as the first-line treatment for Graves disease by of oral prednisone. 93,96,97 Steroid prophylaxis is only
383 of 711 respondents (53.9%), 131I-radiotherapy required if 131I-radiotherapy is used (particularly in
by 320 (45%) and thyroidectomy by only 5 respondents smokers).125 Thus, if Graves ophthalmopathy is absent
(0.7%). 15 When the analysis was restricted to North or mild, hyperthyroidism can be managed by any treat
American respondents, 131I-radiotherapy was the pre ment. A European questionnaire-based survey indicated
ferred treatment for 58.9%. Although still the most that antithyroid drugs were the preferred treatment in
popular option, first-line use of 131I-radiotherapy seems patients with sight-threatening Graves ophthalmopathy
to be declining in North America, in line with a concom due to dysthyroid optic neuropathy. 128 However, in
itant increasein the use of antithyroid drugs to 40.5% patients with active, moderate to severe (but not sight-
(Figure2).15 Interestingly, the proportion of respondents threatening) Graves ophthalmopathy, management of
whose preferred first-line therapy was antithyroid drugs the eye disease should be prioritized over addressing
was higher in Canada (56.7%) than in the USA (39.4%).15 other symptoms, because the effectiveness of treat
Compared with similar surveys carried out in the 1990s, ment (usually high-dose glucocorticoids 129,130 with
the survey from 2011 showed that the preference for or without orbital 131I-radiotherapy 131) is higher if the
131
I-radiotherapy as first-line treatment had decreased Graves ophthalmopathy is of recent onset.101 Some
further in Europe, to 13.3%, and had increased in researchers suggest that this group of patients should be
theAsia and Oceaniagroup, to 29.4%. However, the data treated with long-term antithyroid drug treatment.132,133
for Asia and Oceania should be interpreted with caution, Other researchers believe that the orbital and thyroid
as the 1990s survey included only Japanese respondents disease should be treated concomitantly using ablative
in this category, whereas the corresponding group in the approaches: thyroidectomy, 131I-radiotherapy or both
survey from 2011 also included respondents from other (total thyroid ablation).134137 Interestingly, in the 2011
countries in Asia and Oceania. Furthermore, the total US survey, 1 63% of respondents selected long-term
number of respondents in Asia and Oceania groups was antithyroid drug treatment, 18.5% selected thyroid
small, as was the number of European respondents. ectomy, 16.9% opted for 131I-radiotherapy with steroid
Thus, although geographical differences remain, a prophyla xis, and only 1.9% chose 131I-radiotherapy
trend is evident towards increasing use of antithyroid alone for patients with Graves opthalmopathy. In the
drugs as the first-line treatment for Graves disease, par absence of robust randomized clinical trials, the optimal
ticularly in patients with a first episode of hyperthyroid treatment for hyperthyroidism in patients with Graves
ism, and in those whose goitre is not large and/or those ophthalmopathy remainsundetermined.125
have mild or absent ocular involvement. The role of thy
roidectomy as first-line treatment currently remains as Conclusions
modest as it was 20years ago, but surgery might main No perfect treatment exists for Graves disease (Table1).
tain a relevant role as primary treatment in countries Moreover, one major limitation shared by all existing
where facilities for administration of (and isotopes used therapies for this condition is that they do not target
in) 131I-radiotherapy are not readily available. its underlying pathogenic mechanisms. The various

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2013 Macmillan Publishers Limited. All rights reserved
REVIEWS

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

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of very long-term treatment with antithyroid tomoderate Graves orbitopathy treated with (19342012), the authors mentor and an outstanding
drugs in Graves hyperthyroidism associated intravenous glucocorticoids. J. Clin. Endocrinol. scientist in the field of endocrinology. The author also
with Graves orbitopathy. Thyroid 21, 279283 Metab. 92, 16531658 (2007). thanks Prof. Stefano Mariotti, University of Cagliari,
(2011). 136. Leo, M. etal. Outcome of Graves orbitopathy Italy, for critically reviewing the manuscript.
133. Laurberg, P., Berman, D.C., Andersen, S. after total thyroid ablation and glucocorticoid L.Bartalenas research is partly supported by grants
&Blow Pedersen, I. Sustained control of treatment: follow-up of a randomized clinical from the Ministero della Istruzione, Universit e
Graves hyperthyroidism during long-term low- trial. J. Clin. Endocrinol. Metab. 97, E44E48 Ricerca (MIUR) Rome, and the University of Insubria
dose antithyroid drug therapy of patients with (2012). at Varese.

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