Professional Documents
Culture Documents
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.
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
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
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.
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
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
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
1. Brent, G.A. Clinical practice. Graves 9. Bartalena, L. & Tanda, M.L. Clinical practice. themanagement of Graves disease. J. Clin.
disease.N.Engl. J. Med. 358, 25942605 (2008). Graves ophthalmopathy. N. Engl. J. Med. 360, Endocrinol. Metab. 97, 45494558 (2012).
2. Filipsson Nystrom, H., Jansson, S. & Berg, G. 9941001 (2009). 16. Bahn, R.S. etal. Hyperthyroidism and other
Incidence rate and clinical features of 10. Tanda, M.L. etal. Prevalence and natural history causes of thyrotoxicosis: management
hyperthyroidism in a long-term iodine sufficient of Graves orbitopathy in a large series of guidelines of the American Thyroid Association
area of Sweden (Gothenburg) 20032005. patients with newly diagnosed Graves and American Association of Clinical
Clin.Endocrinol. (Oxf.) 78, 768776 (2013). hyperthyroidism seen at a single center. J. Clin. Endocrinologists. Thyroid 21, 593646 (2011).
3. Weetman, A.P. Graves disease. N. Engl. J. Med. Endocrinol. Metab. 98, 14431449 (2013). 17. Yoshimura Noh, J. etal. Evaluation of a new
343, 12361248 (2000). 11. Piantanida, E., Tanda, M.L., Lai, A., Sassi, L. rapid and fully automated electroluminescence
4. Brix, T.H., Kyvik, K.O., Christensen, K. & &Bartalena, L. Prevalence and natural history immunoassay for thyrotropin receptor
Hegeds, L. Evidence for a major role of heredity ofGraves orbitopathy in the XXI century. autoantibodies. Thyroid 18, 11571164 (2008).
in Graves disease: a population-based study of J.Endocrinol. Invest. 36, 444449 (2013). 18. Schott, M. etal. Clinical value of the first
two Danish twin cohorts. J. Clin. Endocrinol. 12. Fatourechi, V. Thyroid dermopathy and acropachy. automated TSH receptor autoantibody assay
Metab. 86, 930934 (2001). Best Pract. Res. Clin. Endocrinol. Metab. 26, forthe diagnosis of Graves disease (GD): an
5. Brand, O.J. & Gough, S.C. L. Genetics of thyroid 553565 (2012). international multicentre trial. Clin. Endocrinol.
autoimmunity and the role of the TSHR. Mol. Cell. 13. Boelaert, K., Torlinska, B., Holder, R.L. (Oxf.) 71, 566573 (2009).
Endocrinol. 322, 135143 (2010). & Frannklyn, J.A. Older subjects with 19. Hermsen, D. etal. Technical evaluation of the
6. Morshed, S.A., Latif, R. & Davies, T.F. hyperthyroidism present with a paucity of first fully automated assay for the detection of
Delineating the autoimmune mechanisms in symptoms and signs: alarge cross-sectional TSH receptor autoantibodies. Clin. Chim. Acta
Graves disease. Immunol. Res. 54, 191203 study. J. Clin. Endocrinol. Metab. 95, 27152726 401, 8489 (2009).
(2012). (2010). 20. Lytton, S.D. etal. A novel thyroid-stimulating
7. Prabhakar, B.S., Bahn, R.S. & Smith, T.J. 14. Bartalena, L., Pinchera, A. & Marcocci, C. immunoglobulin bioassay is a functional indicator
Current perspective on the pathogenesis of Management of Graves ophthalmopathy: reality of activity and severity of Graves orbitopathy.
Graves disease and ophthalmopathy. Endocr. and perspectives. Endocr. Rev. 21, 168199 J.Clin. Endocrinol. Metab. 95, 21232131 (2010).
Rev. 24, 802835 (2003). (2000). 21. Kamijo, K., Murayama, H., Uzu, T., Togashi, K.
8. Franklyn, J.A. & Boelaert, K. Thyrotoxicosis. 15. Burch, H.B., Burman, K.D. & Cooper, D.S. &Kahaly, G.J. A novel bioreporter assay for
Lancet 379, 11551166 (2012). A2011 survey of clinical practice patterns in thyrotropin receptor antibodies using a chimeric
thyrotropin receptor (mc4) is more useful in 37. Boi, F., Loy, M., Piga, M., Serra, A. & Mariotti, S. hyperthyroidism. N. Engl. J. Med. 324, 947953
differentiation of Graves disease from painless The usefulness of conventional and echo colour (1991).
thyroiditis than conventional thyrotropin- Doppler sonography in the differential diagnosis 57. Abraham, P., Avell, A., Park, C.M., Watson, W.A.
stimulating antibody assay using porcine thyroid of toxic multinodular goitres. Eur. J. Endocrinol. & Bevan, J.S. A systematic review of drug
cells. Thyroid 20, 851856 (2010). 143, 339346 (2000). therapy for Graves hyperthyroidism. Eur. J.
22. Ajjan, R.A. & Weetman, A.P. Techniques to 38. Kurita, S. etal. Measurement of thyroid blood Endocrinol. 153, 489498 (2005).
quantify TSH receptor antibodies. Nat. Clin. Pract. flow area is useful for diagnosing the cause of 58. Weetman, A.P., Pickerill, A.P., Watson, P.,
Endocrinol. Metab. 4, 461468 (2008). thyrotoxicosis. Thyroid 15, 12491252 (2005). Chatterjee, V.K. & Edwards, O.M. Treatment of
23. Tozzoli, R., Bagnasco, M., Giavarina, D. 39. Ota, H. etal. Quantitative measurement of Graves disease with the block-replace regimen
&Bizzaro, N. TSH receptor autoantibody thyroid blood flow for differentiation of painless of antithyroid drugs: the effect of treatment
immunoassay in patients with Graves disease: thyroiditis from Graves disease. Clin. Endocrinol. duration and immunogenetic susceptibility on
improvement of diagnostic accuracy over (Oxf.) 67, 4145 (2007). relapse. Q. J. Med. 87, 337341 (1994).
different generations of methods. Systematic 40. Hari Kumar, K.V. etal. Role of thyroid Doppler in 59. Azizi, F., Atale, L., Hedayati, M., Mehrabi, Y.
review and meta-analysis. Autoimmun. Rev. 12, differential diagnosis of thyrotoxicosis. Endocr. &Sheikholeslami, F. Effect of long-term
107113 (2012). Pract. 15, 69 (2009). continuous methimazole treatment of
24. Dasgupta, S. & Savage, M.W. Evaluation of 41. Bogazzi, F. etal. Thyroid vascularity and blood hyperthyroidism: comparison with radioiodine.
management of Graves disease in district flow are not dependent on serum thyroid Eur. J. Endocrinol. 152, 695701 (2005).
general hospital: achievement of consensus hormone levels: studies invivo by color flow 60. Laurberg, P. Remission of Graves disease
guidelines. Int. J. Clin. Pract. 59, 10971100 Doppler sonography. Eur. J. Endocrinol. 140, during anti-thyroid drug therapy. Time to
(2005). 452456 (1999). reconsider the mechanism? Eur. J. Endocrinol.
25. Kahaly, G.J., Bartalena, L. & Hegeds, L. 42. Erdogan, M.F., Anil, C., Cesur, M., Baskal, N. 155, 783786 (2006).
TheAmerican Association/American &Erdogan, G. Color flow Doppler sonography 61. Mazza, E. etal. Long-term follow-up of patients
Associationof Clinical Endocrinologists forthe etiologic diagnosis of hyperthyroidism. with hyperthyroidism due to Graves disease
guidelines for hyperthyroidism and other causes Thyroid 17, 223228 (2007). treated with methimazole. Comparison of usual
of thyrotoxicosis: a European perspective. 43. Bahn, R.S. Emerging pharmacotherapy for treatment schedule with drug discontinuation vs
Thyroid 21, 585591 (2011). treatment of Graves disease. Expert Rev. Clin. continuous treatment with low methimazole
26. Pearce, E.N., Hennessey, J.V. & McDermott,M.T. Pharmacol. 5, 605607 (2012). doses: a retrospective study. J. Endocrinol.
New American Thyroid Association and American 44. Abraham, P. & Acharya, S. Current and emerging Invest. 31, 866872 (2008).
Association of Clinical Endocrinologists treatment options for Graves hyperthyroidism. 62. Solomon, B.L., Wartofsky, L. & Burman, K.D.
guidelines for thyrotoxicosis and other forms of Ther. Clin. Risk Manag. 6, 2940 (2010). Adjunctive cholestyramine therapy for
hyperthyroidism: significant progress for the 45. Weetman, A.P. How antithyroid drugs work in thyrotoxicosis. Clin. Endocrinol. (Oxf.) 38, 3943
clinician and a guide to future research. Thyroid Graves disease. Clin. Endocrinol. (Oxf.) 37, (1993).
21, 573576 (2011). 317318 (1992). 63. Tsai, W.C. etal. The effect of combination
27. Yamashita, S., Amino, N. & Shong, Y.S. The 46. Cooper, D.S. Antithyroid drugs. N. Engl. J. Med. therapy with propylthiouracil and cholestyramine
American Thyroid Association and American 352, 905917 (2005). in the treatment of Graves hyperthyroidism. Clin.
Association of Clinical Endocrinologists 47. Bogazzi, F., Tomisti, L., Bartalena, L., Endocrinol. (Oxf.) 62, 521524 (2005).
hyperthyroidism and other causes of AghiniLombardi, F. & Martino, E. Amiodarone 64. Takata, K. etal. Benefit of short-term iodide
thyrotoxicosis guidelines: viewpoints from Japan and the thyroid: a 2012 update. J. Endocrinol. supplementation to antithyroid drug treatment
and Korea. Thyroid 21, 577580 (2011). Invest. 35, 340348 (2012). ofthyrotoxicosis due to Graves disase. Clin.
28. Solomon, B., Glinoer, D., Lagasse, R. & 48. Karlsson, F.A., Axelsson, O. & Melhus, H. Severe Endocrinol. (Oxf.) 72, 845850 (2010).
Wartofsky, L. Current trends in the management embriopathy and exposure to methimazole in 65. Bartalena, L., Bogazzi, F. & Martino, E. Adverse
of Graves disease. J. Clin. Endocrinol. Metab. 70, early pregnancy. J.Clin. Endocrinol. Metab. 87, effects of thyroid hormone preparations and
15181524 (1990). 947948 (2001). antithyroid drugs. Drug Saf. 15, 5363 (1996).
29. Glinoer, D., Hesch, D., Lagasse, R. & 49. Foulds, N., Walpole, I., Elmslie, F. & Mansour, S. 66. Takata, K. etal. Methimazole-induced
Laurberg,P. The management of Carbimazole embryopathy: an emerging agranulocytosis in patients with Graves disease
hyperthyroidism due to Graves disease in phenotype. Am. J. Med. Genet. A 132A, 130135 is more frequent with an initial dose of 30mg
Europe in 1986. Results of an international (2005). daily than with 15mg daily. Thyroid 19, 559563
survey. Acta Endocrinol. Suppl. (Copenh.) 285, 50. Clementi, M. etal. Treatment of hyperthyroidism (2009).
323 (1987). in pregnancy and birth defects. J. Clin. 67. Vitti, P. etal. Clinical features of patients with
30. Nagayama, Y., Izumi, M. & Nagataki, S. The Endocrinol. Metab. 95, E337E341 (2010). Graves disease undergoing remission after
management of hyperthyroidism due to Graves 51. Emiliano, A.B., Governale, L., Parks, M. antithyroid drug treatment. Thyroid 7, 369375
disease in Japan in 1988. Endocrinol. Jpn 36, &Cooper,D.S. Shifts in propylthiouracil and (1997).
299314 (1989). methimazole prescribing practices: antithyroid 68. Allahabadia, A., Daykin, J., Holder, R.L.,
31. Wartofsky, L. etal. Differences and similarities in drug use in the United States from 1991 to Sheppard,M.C. & Franklyn, J.A. Age and gender
the diagnosis and treatment of Graves disease 2008. J.Clin. Endocrinol. Metab. 95, 22272233 predict the outcome of treatment for Graves
in Europe, Japan, and the United States. Thyroid (2010). hyperthyroidism. J. Clin. Endocrinol. Metab. 85,
1, 129135 (1991). 52. Ruiz, J.K. etal. Fulminant hepatic failure 10381042 (2000).
32. Okosieme, O.E., Chan, D., Price, S.A. & associated with propylthiouracil. Ann. 69. Nedrebo, B.G. etal. Predictors of outcome and
Lazarus,J.H. The utility of radioiodine uptake Pharmacother. 37, 224228 (2003). comparison of different drug regimens for the
and thyroid scintigraphy in the diagnosis and 53. Bahn, R.S. etal. The role of propylthiouracil in prevention of relapse in patients with Graves
management of hyperthyroidism. Clin. the management of Graves disease in adults: disease. Eur. J. Endocrinol. 147, 583589
Endocrinol. (Oxf.) 72, 122127 (2010). report of a meeting jointly sponsored by the (2002).
33. Franklyn, J.A. What is the role of radioiodine American Thyroid Association and the Food and 70. Kashiwai, T. etal. Practical treatment with
uptake measurement and thyroid scintigraphy Drug Administration. Thyroid 19, 673674 minimum maintenance dose of antithyroid drugs
inthe diagnosis and management of (2009). for prediction of remission in Graves disease.
hyperthyroidism? Clin. Endocrinol. (Oxf.) 72, 54. Cooper, D.S. & Rivkees, S.A. Putting Endocr. J. 50, 4549 (2003).
1112 (2010). propylthiouracil in perspective. J. Clin. Endocrinol. 71. Rotondi, M. etal. The effects of pregnancy on
34. Bogazzi, F. & Vitti, P. Could improved ultrasound Metab. 94, 18811882 (2009). subsequent relapse from Graves disease after
and power Doppler replace thyroidal radioiodine 55. Abraham, P., Avenell, A., McGeoch, S.C., a successful course of antithyroid drug therapy.
uptake to assess thyroid disease? Nat. Clin. Clark,L.F. & Bevan, J.S. Antithyroid drug J.Clin. Endocrinol. Metab. 93, 39853988 (2008).
Pract. Endocrinol. Metab. 4, 7071 (2008). regimen for treating Graves hyperthyroidism. 72. Ross, D.S. Radioiodine therapy for
35. Vitti, P. etal. Thyroid blood flow evaluation by Cochrane Database of Systematic Reviews, hyperthyroidism. N. Engl. J. Med. 364, 542550
color-flow Doppler sonography distinguishes Issue1, Art no.: CD003420. http://dx.doi.org/ (2011).
Graves disease from Hashimotos thyroiditis. 10.1002/14651858.CD003420.pub4. 73. Vaidya, B., Williams, G.R., Abraham, P.
J.Endocrinol. Invest. 18, 857861 (1995). 56. Hashizume, K. etal. Administration of thyroxine &Pearce,S.H. S. Radioiodine treatment for
36. Cappelli, C. etal. The role of imaging in Graves in treated Graves disease. Effects on the level benign thyroid disorders: results of a nationwide
disease: a cost-effectiveness analysis. Eur. J. of antibodies to thyroid-stimulating hormone survey of UK endocrinologists. Clin. Endocrinol.
Radiol. 65, 99103 (2008). receptors and on the risk of recurrence of (Oxf.) 68, 814820 (2008).
74. Sztal-Mazer, S. etal. Evidence for higher 93. Bartalena, L. etal. Relation between therapy aging Americans: at what cost? J. Am. Coll. Surg.
successrates and successful treatment earlier forhyperthyroidism and the course of Graves 206, 10971105 (2008).
in Graves disease with higher radioactive iodine ophthalmopathy. N. Engl. J. Med. 338, 7378 112. Erbil, Y. etal. Effect of lugol solution on thyroid
doses. Thyroid 22, 991995 (2012). (1998). gland blood flow microvessel density in the
75. Sisson, J.C. etal. Radiation safety in the 94. Trisk, F. etal. Thyroid-associated ophthalmopathy patients with Graves disease. J. Clin. Endocrinol.
treatment of patients with thyroid diseases by after treatment for hyperthyroidism with Metab. 92, 21822189 (2007).
radioiodine 131I: practice recommendations of antithyroid drugs or iodine131. J. Clin. Endocrinol. 113. Marcocci, C. etal. The course of Graves
the American Thyroid Association. Thyroid 21, Metab. 94, 37003707 (2009). ophthalmopathy is not influenced by near total
335346 (2011). 95. Acharya, S.H. etal. Radioiodine therapy (RAI) thyroidectomy: a casecontrol study. Clin.
76. Walter, M.A. etal. Effects of antithyroid drugs forGraves disease (GD) and the effect on Endocrinol. (Oxf.) 51, 503508 (1999).
onradioiodine treatment: systematic review and ophthalmopathy: a systematic review. Clin. 114. Laurberg, P. etal. TSH-receptor autoimmunity in
meta-analysis of randomized controlled trials. Endocrinol. (Oxf.) 69, 943950 (2008). Graves disease after therapy with anti-thyroid
BMJ 334, 514 (2007). 96. Bartalena, L. etal. Use of corticosteroids to drugs, surgery, or radioiodine: a 5year
77. Alexander, E.K. & Larsen, P.R. High dose of prevent progression of Graves ophthalmopathy prospective randomized study. Eur. J. Endocrinol.
131
Itherapy for the treatment of hyperthyroidism after radioiodine treatment for hyperthyroidism. 158, 6975 (2008).
caused by Graves disease. J. Clin. Endocrinol. N. Engl. J. Med. 321, 13491352 (1989). 115. Barczinsky, M., Konturek, A.,
Metab. 87, 10731077 (2002). 97. Lai, A. etal. Lower dose prednisone prevents HubalewskaDydejczyk, A., Golkowski, F. &
78. Bonnema, S.J. etal. Resumption of radioiodine-associated exacerbation of initially Nowak, W. Randomized clinical trial of bilateral
methimazole after 131I therapy of hyperthyroid mild or absent Graves orbitopathy: a subtotal thyroidectomy versus total thyroidectomy
diseases: effect on thyroid function and volume retrospective cohort study. J. Clin. Endocrinol. for Graves disease with a 5year follow-up. Br. J.
evaluated by a randomized clinical trial. Eur. J. Metab. 95, 13331337 (2010). Surg. 99, 515522 (2012).
Endocrinol. 149, 485492 (2003). 98. Tallstedt, L., Lundell, G., Blomgren, H. & Bring, J. 116. Jin, J., Sandoval, V., Lawless, M.E., Sehgal, A.R.
79. Bogazzi, F. etal. Comparison of radioiodine with Does early administration of thyroxine reduce & McHenry, C.R. Disparity in the management of
radioiodine plus lithium in the treatment of the development of Graves ophthalmopathy Graves disease observed at an urban county
Graves hyperthyroidism. J. Clin. Endocrinol. after radioiodine treatment? Eur. J. Endocrinol. hospital: a decade-long experience. Am. J. Surg.
Metab. 84, 499503 (1999). 130, 494497 (1994). 204, 199202 (2012).
80. Bogazzi, F. etal. Impact of lithium on efficacy of 99. Perros, P., Kendall-Taylor, P., Neoh, C., Frewin, S. 117. Sidib, E.H. Thyropathies en Afrique
radioactive iodine therapy for Graves disease: & Dickinson, J. A prospective study of the effects subsaharienne [French]. Cahiers Sant 17,
acohort study on cure rate, time to cure, and of radioiodine therapy for hyperthyroidism in 3339 (2007).
frequency of increased serum thyroxine after patients with minimally active Graves 118. Mithal, A., Shah, A. & Kumar, S. The
antithyroid drug withdrawal. J. Clin. Endocrinol. ophthalmopathy. J. Clin. Endocrinol. Metab. 90, management of Graves disease by Indian
Metab. 95, 201208 (2010). 53215323 (2005). thyroidologists. Natl Med. J. India 6, 163166
81. Martin, N.M. etal. Adjuvant lithium improves 100. Bartalena, L. Glucocorticoids for Graves (1993).
theefficacy of radioactive iodine treatment in orbitopathy: how and when. J. Clin. Endocrinol. 119. Pradeep, V.P. etal. Safety and efficacy of
Graves and toxic nodular disease. Clin. Metab. 90, 54975499 (2005). surgical management of hyperthyroidism:
Endocrinol. (Oxf.) 77, 621627 (2012). 101. Bartalena, L. etal. Consensus statement of 15-year experience from a tertiary care center in
82. Franklyn, J.A., Maisonneuve, P., Sheppard, M.C., theEuropean Group on Graves orbitopathy a developing country. World J. Surg. 31, 306312
Betteridge, J. & Boyle, P. Mortality after the (EUGOGO) on management of GO. Eur. J. (2007).
treatment of hyperthyroidism with radioactive Endocrinol. 158, 273285 (2008). 120. Sankar, R., Sekhri, T., Sripathy, G., Walia, R.P.
iodine. N. Engl. J. Med. 338, 712718 (1998). 102. Palit, T.K., Miller, C.C. 3rd & Miltenburg, D.M. &Jain, S.K. Radioactive iodine therapy in
83. Metso, S. etal. Increased cardiovascular and The efficacy of thyroidectomy for Graves Graves hyperthyroidism: a prospective study
cancer mortality after radioiodine treatment for disease: a meta-analysis. J. Surg. Res. 90, from a tertiary referral centre in north India.
hyperthyroidism. J. Clin. Endocrinol. Metab. 92, 161165 (2000). J.Assoc. Physicians India 53, 603606 (2005).
21902196 (2007). 103. Annerbo, M., Stlberg, P. & Hellman, P. 121. Ahmed, M.E., ElWasila, A.A., Sanhouri, M.
84. Vanderpump, M. Cardiovascular and cancer Management of Graves disease is improved by &Yagi, K. Surgical management of toxic goiter
mortality after radioiodine treatment of total thyroidectomy. World J. Surg. 36, 19431946 inKhartoum. Trop. Geogr. Med. 45, 124125
hyperthyroidism. J.Clin. Endocrinol. Metab. 92, (2012). (1993).
20332035 (2007). 104. Al-Adhami, A., Craig, W. & Krukowski, Z.H. 122. Akossou, S.Y. etal. Problems in the
85. Boelaert, K., Maisonneuve, P., Torlinska, B. Quality of life after surgery for Graves disease: management of thyrotoxicosis in Black Africa:
&Franklyn, J.A. Comparison of mortality in comparison of those having surgery intended to the Tongolese experience [French]. Ann.
hyperthyroidism during the periods of treatment preserve thyroid function with those having Endocrinol. (Paris) 62, 516520 (2001).
with thionamides and after radioiodine. J. Clin. ablative surgery. Thyroid 22, 494500 (2012). 123. Walsh, J.P. Management of Graves disease in
Endocrinol. Metab. 98, 18691882 (2013). 105. In, H. etal. Treatment options for Graves Australia. Aust. NZ J. Med. 30, 559566 (2000).
86. Holm, L.E. etal. Cancer risk after iodine131 disease: a cost-effectiveness analysis. J. Am. 124. Ford, H.C., Delahunt, J.W. & Feek, C.M.
therapy for hyperthyroidism. J. Natl Cancer Inst. Coll. Surg. 209, 170179 (2009). Themanagement of Graves disease in New
83, 10721077 (1991). 106. Genovese, B.M., Noureldine, S.I., Zealand: results of national survey. NZ Med. J.
87. Ron, E. etal. Cancer mortality following Gleeson,E.M., Tufano, R.P. & Kandil, E. What 104, 251252 (1991).
treatment for adult hyperthyroidism. JAMA 280, isthe best definitive treatment for Graves 125. Bartalena, L. The dilemma of how to manage
347355 (1998). disease? A systematic review of the existing Graves hyperthyroidism in patients with
88. Read, C.H. Jr, Tansey, M.J. & Menda, Y. literature. Ann. Surg. Oncol. 20, 660667 (2013). associated orbitopathy. J. Clin. Endocrinol. Metab.
A36year retrospective analysis of the efficacy 107. Grodski, S., Stlberg, P., Robinson, B.G. 96, 592599 (2011).
and safety of radioiodine in treating young &Delbridge, L.W. Surgery versus radioiodine 126. Prummel, M.F. etal. Amelioration of eye
Graves patients. J. Clin. Endocrinol. Metab. 89, therapy as definitive management for Graves changes of Graves ophthalmopathy by achieving
42294233 (2004). disease: the role of patient preference. Thyroid euthyroidism. Acta Endocrinol. (Copenh.) 121
89. Metso, S. etal. Increased cancer incidence after 17, 157160 (2007). (Suppl. 2), 185189 (1989).
radioiodine treatment for hyperthyroidism. 108. Miccoli, P. etal. Minimally invasive video- 127. Prummel, M.F. etal. Effect of abnormal
Cancer 109, 19721979 (2007). assisted thyroidectomy for benign thyroid thyroidfunction on the severity of Graves
90. Franklyn, J.A., Maisonneuve, P., Sheppard, M., disease: an evidence-based review. World J. ophthalmopathy. Arch. Intern. Med. 150,
Betteridge, J. & Boyle, P. Cancer incidence and Surg. 32, 13331340 (2008). 10981101 (1990).
mortality after radioiodine treatment for 109. Sasaki, A. etal. Endoscopic thyroidectomy 128. Perros, P. etal. A questionnaire survey on the
hyperthyroidism: a population-based cohort bythebreast approach: a single institutions management of Graves orbitopathy in Europe.
study. Lancet 353, 21112115 (1999). 9yearexperience. World J. Surg. 32, 381385 Eur. J. Endocrinol. 155, 207211 (2006).
91. Rivkees, S.A. & Dinauer, C. An optimal treatment (2008). 129. Zang, S., Ponto, K.A., Pitz, S. & Kahaly, G.J.
for pediatric Graves disease is radioiodine. 110. Lee, J. & Chung, W.Y. Robotic surgery for thyroid Dose of intravenous steroids and therapy
J.Clin. Endocrinol. Metab. 92, 797800 (2007). disease. Eur. Thyroid J. 2, 93101 (2013). outcome in Graves orbitopathy. J. Endocrinol.
92. Tallstedt, L. etal. Occurrence of ophthalmopathy 111. Sosa, J.A., Mehta, P.J., Wang, T.S., Invest. 34, 876880 (2011).
after treatment for hyperthyroidism. N. Engl. J. Boudourakis, L. & Roman, S.A. A population- 130. Bartalena, L. etal. Efficacy and safety of three
Med. 326, 17331738 (1992). based study of outcomes from thyroidectomy in different cumulative doses of intravenous
methylprednisolone for moderate to severe severe Graves orbitopathy. Thyroid 21, 137. De Bellis, A. etal. Time course of Graves
andactive Graves orbitopathy. J. Clin. Endocrinol. 951956 (2011). ophthalmopathy after total thyroidectomy alone
Metab. 97, 44544463 (2012). 134. Moleti, M. etal. Effects of thyroidectomy alone or followed by radioiodine therapy: a 2year
131. Tanda, M.L. & Bartalena, L. Efficacy and safety orfollowed by radioiodine ablation of thyroid longitudinal study. Endocrine 41, 320326
of orbital radiotherapy for Graves orbitopathy. remnants on the outcome of Graves (2012).
J.Clin. Endocrinol. Metab. 97, 38573865 ophthalmopathy. Thyroid 13, 653658 (2003).
(2012). 135. Menconi, F. etal. Effects of total thyroid ablation Acknowledgements
132. Elbers, L., Mourits, M. & Wiersinga, W. Outcome versus near-total thyroidectomy alone on mild This paper is dedicated to Prof. Aldo Pinchera
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.