10.1038@s41572 020-0184-y

Graves’ disease (GD), also known as von Basedow dis-
ease, is a syndrome characterized by an enlarged and
overactive thyroid gland (Graves’ hyperthyroidism),
ocular abnormalities (Graves’ orbitopathy; GO) and
localized dermopathy (pretibial myxoedema; PTM).
GD is the most common cause of hyperthyroidism
globally1,2
. Graves’ hyperthyroidism was originally
believed to be a result of excessive thyroid-stimulating
hormone (TSH) secretion by the pituitary gland, but
the discovery of TSH receptor (TSHR) autoantibodies
in 1956 established GD as an autoimmune disease3
.
These autoantibodies act as TSHR agonists and induce
thyroid cells to secrete excess thyroid hormones, with
which patients with GD most commonly present. GD
can manifest within two extremes — an asymptomatic
mild form, usually identified by decreased serum TSH
levels on routine thyroid function testing, or as a severe,
life-threatening ‘thyroid storm’, known as accelerated
hyperthyroidism, associated with tachycardia, increased
blood pressure, high fever, delirium and a high mortality.
Patients with Graves’ hyperthyroidism may develop
the ‘complete’ syndrome with extrathyroidal compli-
cations (that is, GO and PTM — the Graves’ Triad),
secondary to the action of TSHR autoantibodies
and TSHR-specific T cells on TSHR expressed in
non-thyroidal tissues, in particular fibroblasts and adi-
pocytes. GO is clinically apparent in ~5% of patients,
although detailed imaging suggests that GO is much
more common in a mild form in GD4
. GO is usually
characterized by retro-orbital inflammation leading to
extraocular muscle fibre disruption and the accumula-
tion of glycosaminoglycans, causing oedema. PTM is an
infiltrating dermopathy characterized by slowly advanc-
ing, non-pitting oedema that results from the accumu-
lation of glycosaminoglycans in the dermis5
. In some
patients with GD, PTM can advance to cause extra
ordinary disfigurement. The diverse clinical phenotypes
of GD suggest that multiple factors are involved in its
pathogenesis in different patients.
The treatment of GD has not changed considerably
in recent years but the application of conventional treat-
ments has become more sophisticated. Although most
patients try to avoid surgery, replacement of subtotal
thyroidectomy with total thyroidectomy has avoided the
distressing cases of recurrence post-surgery. Radioiodine
therapy has also decreased in popularity because of its
inherent nature and the potential exacerbation of GO
after treatment. However, popularity for the antithyroid
drug methimazole (or carbimazole)6
has surged, espe-
cially given the issues of liver toxicity associated with
the antithyroid drug propylthiouracil. However, in rare
cases, methimazole can also cause agranulocytosis and
birth defects. Therefore, the medical management of GD
remains an area ripe for improvement.
In this Primer, we discuss the epidemiology, patho-
genesis and diagnosis as well as the conventional
Graves’ disease
Terry F. Davies1,2,3 ✉, Stig Andersen4
, Rauf Latif1,2
, Yuji Nagayama5
, Giuseppe Barbesino6
,
Maria Brito3
, Anja K. Eckstein7
, Alex Stagnaro-Green8
and George J. Kahaly9
Abstract | Graves’ disease (GD) is an autoimmune disease that primarily affects the thyroid gland.
It is the most common cause of hyperthyroidism and occurs at all ages but especially in women of
reproductive age. Graves’ hyperthyroidism is caused by autoantibodies to the thyroid-stimulating
hormone receptor (TSHR) that act as agonists and induce excessive thyroid hormone secretion,
releasing the thyroid gland from pituitary control. TSHR autoantibodies also underlie Graves’
orbitopathy (GO) and pretibial myxoedema. Additionally, the pathophysiology of GO (and likely
pretibial myxoedema) involves the synergism of insulin-like growth factor 1 receptor (IGF1R) with
TSHR autoantibodies, causing retro-orbital tissue expansion and inflammation. Although the
aetiology of GD remains unknown, evidence indicates a strong genetic component combined
with random potential environmental insults in an immunologically susceptible individual.
The treatment of GD has not changed substantially for many years and remains a choice between
antithyroid drugs, radioiodine or surgery. However, antithyroid drug use can cause drug-induced
embryopathy in pregnancy, radioiodine therapy can exacerbate GO and surgery can result in
hypoparathyroidism or laryngeal nerve damage. Therefore, future studies should focus on
improved drug management, and a number of important advances are on the horizon.
✉e-mail: terry.davies@
mssm.edu
https://doi.org/10.1038/
s41572-020-0184-y
1
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treatment options for Graves’ hyperthyroidism, GO
andPTM.Furthermore,wealsodiscussthescreeningand
management of GD in pregnancy and the emerging
therapeutics from clinical trials that will hopefully help
to treat GD with minimal adverse effects in the future.
Epidemiology
Data on the incidence of GD are particularly sensitive
to the methods applied. In some regions, hospital regis-
tries are prone to under-recording patients with GD as
most are treated as outpatients. This under-estimation
is illustrated by the difference in epidemiological data
obtained using secondary referral centres or tertiary
referral centres versus hospital registries1,7
. However, the
Nordic regions in Europe have registries of almost all dis-
ease as no citizen can have a blood test without this being
recorded in nationwide registers. Hence, data from these
countries are the most reliable sources of information
on the epidemiology of GD.
Graves’ hyperthyroidism
GD is a common disorder that affects ~2% of women
and 0.2% of men globally (with a female to male ratio
of ~10:1)1,2,8
. Epidemiological studies indicate that the
incidence of GD is ~20–40 cases per 100,000 population
per year (Table 1). GD is most common in adults aged
between 20 and 50 years and the majority of patients
with hyperthyroidism who are <40 years of age might
be assumed to have GD9
. As discussed earlier, the inci-
dence of GD varies depending on the areas surveyed
and methods applied. For example, a study in Denmark
showed that the frequency of GD estimated at a referral
centre was lower than the incidence estimated by cases
recorded using a highly sensitive diagnostic algorithm10
.
Referral bias is a likely explanation for this difference,
which hampers referral centre-based and hospital-based
studies7
. However, individual prospective follow-up in
Denmark has allowed for a detailed diagnosis of new
cases of hyperthyroidism, which has helped to document
the actual incidence of GD11
.
A comparative study between Iceland (popula-
tion with abundant iodine intake) and East Jutland,
Denmark (an iodine-deficient population), reported
that, in Iceland, 84% of patients with newly diagnosed
hyperthyroidism had GD whereas the incidence was
only 39% in East Jutland12
. However, this difference was
due to additional cases of multinodular toxic goitre (also
associated with hyperthyroidism) in the iodine-deficient
population and not due to a decreased prevalence of GD.
Indeed, the lifetime risk of GD was similar between these
two populations. The age-standardized incidence did
not differ with iodine intake in Denmark but decreased
after nearly 20 years of iodine supplementation13
.
This finding was further validated by monitoring
antithyroid drug prescriptions, which is an alternative
approach to measuring the occurrence of GD, ignoring
the uncommon use of antithyroid drugs in multinod-
ular goitre14
. A Chinese survey analysed three popu-
lations with distinct iodine intake levels ranging from
mild iodine deficiency to excessive intake. The survey
included a 5-year follow-up and demonstrated that both
the prevalence (1.2%) and incidence (0.7%) of GD did
not differ between these populations15,16
. These data
support the contention that, unlike multinodular goitre,
the epidemiology of GD cannot be solely explained by
iodine levels. Instead, a genetic component to the auto-
immune background17
, shown by concordance rates18
and the familial trait19
, as well as recent findings of ethnic
differences in the occurrence of GD20,21
should be taken
into consideration.
Author addresses
1
Thyroid Research Laboratory, Icahn School of Medicine at Mount Sinai, New York,
NY, USA.
2
James J. Peters VA Medical Center, New York, NY, USA.
3
Mount Sinai Thyroid Center, Mount Sinai Downtown at Union Sq, New York, NY, USA.
4
Department of Geriatric and Internal Medicine and Arctic Health Research Center,
Aalborg University Hospital, Aalborg, Denmark.
5
Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University,
Nagasaki, Japan.
6
Thyroid Unit, Division of Endocrinology, Massachusetts General Hospital, Boston,
MA, USA.
7
Department of Ophthalmology, University Duisburg Essen, Essen, Germany.
8
Departments of Medicine, Obstetrics and Gynecology and Medical Education,
University of Illinois College of Medicine at Rockford, Rockford, IL, USA.
9
Department of Medicine I, Johannes Gutenberg University Medical Centre,
Mainz, Germany.
Table1|Reported incidence of Graves’ hyperthyroidism
Country Year Incidencea
Ref.
USA 1935–1967 19.8 245
1989–2001 38b 246
United Kingdom 1982 15 247
1983 15.9 248
1972–1993 50 249
Austria 1987– 1995 12.2–24.4 250
Iceland 1938–1967 9.7–13.8 251
1980–1982 19.3 252
Denmark 1987–1988 14.8 12
1997–2000 31.2 11
2014–2016 22.2 13
Sweden 1970–1974 17.7 253
1975–1984 16.6 254
1987–1989 12.7 255
1988–1990 22.3 256
2003–2005 21.0 257
Switzerland 1995–1996 20.6 258
Spain 1985–1989 2.6–6.4 259
1990–1992 22.2 260
Serbia 1971–1980 5.6 261
1981–1990 11.7 261
1996 45.3 261
New Zealand 1983–1985 23.5 262
China 1999–2004 120 15
a
Cases per 100,000 individuals per year. b
Women only.
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Graves’ orbitopathy and pretibial myxoedema
According to the European Group on Graves’ Orbito
pathy (EUGOGO), GO has a prevalence of 10 per 10,000
persons and 16 per 10,000 persons in Europe and Japan,
respectively4,22
. Hence, ~5% of patients with GD have
distinctive signs of GO, although many patients have less
identifiable disease. Furthermore, symptoms of GO
can appear before, during or after the manifestation
of hyperthyroidism. In addition, ~2% of such patients
develop severe GO with optic neuropathy, most com-
monly presenting with blurred vision and restricted
upward gaze23
, ~50% of whom eventually need decom-
pression surgery. The prevalence of PTM with GO has
been reported as 0.15 per 10,000 persons and is therefore
an even more rare complication of GD4
.
Risk factors
The development of GD depends on a combination of
environmental and genetic factors involving unique
susceptibility genes as well as environmental triggers,
including epigenetic pathways and the microbiota, all
of which then initiate an immunopathogenetic process.
Despite the high concordance shown in genetic studies,
GD most likely develops when the stochastic combi-
nation of these genetic and environmental influences
exceeds a certain threshold.
Genetic susceptibility. The aetiology of GD has a major
genetic component. Twin studies have provided strong
evidence of gene susceptibility and showed that identical
twins have a higher concordance rate (that is, the rate of
the probability that two individuals with shared genetics
will develop the same disease) than non-identical twins.
Additionally, family members of patients with GD show
a high sibling recurrence risk (λs = 11.6)24–26
. These
observations imply that, despite non-identical immune
repertoires in identical twins, non-variable region genes
must be involved in GD susceptibility as the rearrange-
ment of B cell and T cell variable region genes is random.
The association of increased susceptibility with certain
HLA genes, which encode the major histocompati-
bility complex (MHC) class of proteins in humans, is
long known and widely investigated. For example, the
frequency of the HLA*DR3 and DQA*10501 haplotypes
was increased in white people with GD27,28
compared
with controls. Nonetheless, the HLA region provides
only ~5% of the calculated genetic susceptibility to GD
and only gives a 2–4-fold increased risk29,30
.
A large number of associated genetic loci might
also contribute to GD susceptibility. These loci include
the immune-related genes CTLA4 (encoding a protein
involved in immune checkpoint), CD25 and CD40
(encoding proteins that regulate T cell activity), PTPN22
(encoding a protein involved in T cell signalling) and
FOXP3 (encoding a key transcription factor involved in
the development of regulatory T (Treg) cells that mod-
ulates the immune response). As individual genes,
they only seem to provide a small part of the calcu-
lated genetic risk (risk ratios usually <2.0)17
. However,
the interaction of the genes with each other and with
non-genetic factors might be important31
. Of particu-
lar importance, the search for thyroid-specific gene
susceptibility in autoimmune thyroid disease, such as
GD and Hashimoto thyroiditis, has shown associations
with polymorphisms in TG (which encodes thyroglob-
ulin, the substrate for thyroid hormone synthesis) and
TSHR, which was found to be associated only with GD,
underscoring its role in GD pathophysiology32
. In this
regard, data on the expression of TSHR and its variant
forms in the thymus (where deletion of autoreactive
T cells occurs) is important33
. TSHR expression in the
thymus might provide critical insight into the develop-
ment of tolerance or the failure of tolerance in patients
destined to develop GD34
. If the immune system is una-
ble to delete TSHR-specific T cells, then such cells will
be available for the development of GD.
Although the literature is full of conjectures, no data
confirming a distinct genetic risk that can be ascribed to
GO have been reported, suggesting that the strength of
the immune response and environmental or structural
factors lead to enhanced retro-orbital inflammation in
some patients35,36
(Box 1).
Sex. GD is 5–10 times more common in women than
in men. Although GD becomes more prevalent after
puberty, the incidence of GD is not decreased after
menopause. The predominance of female sex in GD that
persists even after menopause has suggested X chromo-
some involvement rather than sex steroids. However, the
association of FOXP3 (located at Xp11.23) with autoim-
mune thyroid disease has been inconsistent37,38
. The phe-
nomenon of inappropriate X chromosome inactivation
(that is, silencing of one X chromosome) has also been
Box 1 | Risk factors for GO and PTM
All the risk factors we describe may bring about the onset of Graves’ hyperthyroidism.
However, additional distinct risk factors appear to predispose individuals to developing
Graves’ orbitopathy (GO) and pretibial myxoedema (PTM) that deserve attention.
High TSHR autoantibody titres
Patients with the most severe GO (that is, patients with sight-threatening ocular
complications such as dysthyroid optic neuropathy and/or corneal breakdown) and
sometimes PTM have the highest titres of autoantibodies to the thyroid-stimulating
hormone receptor (TSHR) and, in general, their expression level often correlates with
the severity of GO264
. This correlation is most obvious in patients with the ‘Graves’ triad’
(that is, manifestation in thyroid, eye and skin).
Smoking
Many studies have reported an increased risk of ophthalmic involvement in Graves’
disease for smoking. Whether this is related to stress, tissue hypoxia or inflammation
is unclear265–267
.
Radioiodine
Radioiodine exacerbates GO69
, which can be transient and might be due to the surge
in autoimmunity observed after radioiodine therapy as reflected by elevated TSHR
autoantibody levels67
.
Trauma
Physical trauma to the orbit has been shown to play a role in the initiation and
exacerbation of GO-related retro-orbital inflammation35,268,269
and aggravation of PTM.
Indeed, surgical debridement of PTM has been shown to exacerbate the condition and
is the wrong approach to treatment.
Anatomy
Few data are available as to the role of the orbital structure in GO; small orbits may
be more likely to cause restrictive disease270
. The degree of proptosis might vary from
non-existent to severe. The success of orbital decompression surgery likely implies that
bone restriction is crucial.
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repeatedly described in GD, further emphasizing the
involvement of the X chromosome39–42
. This phenome-
non is a reflection of whether maternal or paternal chro-
mosomes are being used within a cell for transcription
and seems to be skewed in GD.
Pregnancy. Pregnancy, a time of major immune changes,
is also accompanied by marked fluctuations in the inci-
dence of Graves’ hyperthyroidism43
(Fig. 1). Graves’ hyper-
thyroidism might be aggravated in early pregnancy44
and in the year after delivery45–48
. However, hyper
thyroidism is considered an inhibitor of fertility49
; only
~0.5% of women becoming pregnant have GD, ~0.2%
are treated during pregnancy50
and the risk of develop-
ing GD during pregnancy is very low (~0.05%)51
. As
pregnancy progresses, GD tends to improve with the
influence of Treg cells becoming more prominent and
the mother’s immune tolerance being strengthened with
alterations in both T cell and B cell function52
. However,
immune rebound after delivery contributes to the devel-
opment of postpartum autoimmune thyroid disease53
.
In a retrospective Swedish study, 30% of women of
reproductive age reported a history of pregnancy within
12 months of a diagnosis of GD46
.
Stress. Major stress (for example, due to divorce, bereave
ment or job loss) has often been associated with an
increased risk of GD54
. Stress is well known to induce
excessive cortisol output via corticotropin-releasing
hormone, which can suppress the immune response54,55
.
Furthermore, cortisol levels fall in the post-partum
period56
; for example, an excessive immune response
follows the loss of immune tolerance when the stress of
pregnancy is relieved by birth, as revealed by increased
autoantibody titres56
. This increase can result in greater
immune reactivity and in the initiation or relapse of
autoimmune disease.
Infection. Structural or conformational similarity
(in sequence, structure or both) between different anti-
gens can lead to specificity crossover (also known as
molecular mimicry)57
. One study demonstrated that
4% of monoclonal antibodies raised against a variety of
viruses cross-reacted with antigens in tissues58
. Infectious
microorganisms, such as Yersinia enterocolitica and
Helicobacter pylori, have long been considered as
possible causative agents in the pathogenesis of GD,
although this association has not been proved59
. Viral
infections that affect the thyroid gland, such as sub
acute thyroiditis, congenital rubella and hepatitis C, are
associated with the presence of thyroid autoantibodies
but are not predictable initiators of GD60
. However,
the potential influence of various common infections
(such as Epstein–Barr virus and influenza virus) on the
epigenetic characteristics of a variety of susceptibility
genes remains a major hypothesis for the aetiology of
GD. Such common viral infections have the theoretical
potential to epigenetically modify genes associated with
GD susceptibility. In fact, using RNA-seq followed by
pathway analysis25
, we (R.L. and T.F.D.) found that the
gene expression pathways potentially associated with
viral infection were enhanced in thyroid tissue from
patients with GD compared with normal thyroid tissue25
.
In addition, another study showed that interferon-α
(IFNα) induced the lysosomal degradation of thyro
globulin, releasing pathogenetic peptides that might
trigger thyroid autoimmunity, thus supporting a role for
virus-associated cytokines in the pathogenesis of GD61
.
Iodine and related drugs. Iodine and iodine-containing
drugs,suchasamiodarone(whichisusedtotreatventricu-
lar fibrillation and tachycardia) and iodine-containing CT
scan contrast media, precipitate GD or its recurrence in
a genetically susceptible individual62,63
. During thyroid
hormone synthesis, the loading of thyroglobulin (one of
the autoantigens in GD) with iodine enhances thyroid
hormone production as well as its antigenicity and might
be a possible precipitating mechanism. In addition, iodine
might also damage thyroid cells directly, releasing thyroid
antigens to the immune system64
.
Radiation. In some patients with toxic multinodu-
lar goitre, radioiodine treatment precipitated GD65,66
.
Radioiodine causes a steep transient increase in TSHR
autoantibodies after being used for the treatment of
Graves’ hyperthyroidism, which might suggest that
such observations are a reflection of the patients hav-
ing a nodular form of GD rather than pure multinod-
ular goitre67
. Studies have reported that the levels of
TSHR autoantibodies are often considerably higher
even 5 years after radioiodine therapy than after
antithyroid drugs or surgery68
. In addition, the release
of thyroid antigens, including TSHR antigen from the
radioiodine-damaged thyroid, and the susceptibility of
Treg cells to radiation, leading to reduced immune sup-
pression and enhanced TSHR autoantibody and T cell
reactivity, could all be possible explanations for this
observation. This ‘flare’ in autoimmunity might also
be the cause of the onset or worsening of clinical GO
(symptomatic GO) observed in ~15% of patients with
GD treated with radioiodine69
.
Immune-modulating agents. GD has been reported
to develop after immune (or lymphocyte) reconsti-
tution following anti-CD52 monoclonal antibody
therapy, anti-retrovirus therapy or bone marrow trans
plantation, where the pathogenetic immune cells
propagate and become activated during the recovery
Cases
(100,000
per
year)
250
100
50
0
+2 years
Conception +1 year
–1 year
200
150
Birth
Time
Pregnancy
Fig. 1 | Incidence of hyperthyroidism in pregnancy. The graph illustrates the incidence
of maternal hyperthyroidism in 3-month intervals around pregnancy. Reprinted with
permission from ref.43
, Oxford University Press.
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from, for example, lymphopenia70
. According to a large
meta-analysis71
, endocrine glands, particularly the thy-
roid, are highly vulnerable to immune-related adverse
events of immune-checkpoint inhibitors. The majority
of thyroid-related adverse effects reported were destruc-
tive thyroiditis, and GD was only seen occasionally in
case reports71
.
Microbiota. Next-generation sequencing techniques
are being employed to investigate the role of micro
biota in autoimmune thyroid diseases. Dysbiosis, that
is, alterations in bacterial function and diversity, have
been shown to likely contribute to autoimmune diseases
such as type I diabetes mellitus, multiple sclerosis, rheu-
matoid arthritis and, now, GD72
. Data on gut micro-
biota have been accumulated from patients with GD,
with or without GO73–75
. In Europe, the Investigation
of Novel Biomarkers and Definition of the Role of the
Microbiome in Graves’ Orbitopathy (INDIGO) initia-
tive has launched extensive studies on gut microbiota
in GO76
. Studies in a mouse model of GD and findings
of retro-orbital adipocyte expansion and macrophage
accumulation reminiscent of GO have yielded positive
and negative results77,78
, which suggests that mutual
interactions between intestinal microflora and thy-
roid function might be at play79
. Careful investigations
are required in the future as such observations have
potential implications for treatment.
Mechanisms/pathophysiology
Immune infiltration of thyroid glands
The thyroid glands in patients with GD show thickened,
hypertrophied follicular cells with active thyroglobulin
production and intracellular colloid droplets contain-
ing thyroglobulin. The gland exhibits classic lympho-
cytic infiltrates of T cells and B cells, although usually
less intense than observed in Hashimoto thyroiditis
(Fig. 2). The infiltrate tends to be heterogeneous, with
areas of varying intensity, as seen in surgical samples
from treated patients; the intensity and presentation of
the immune infiltrate in untreated patients is not well
documented. The infiltrate is suggested to be primarily
associated with TSHR autoantibody secretion as the fol-
licular cells seem to be most active where the infiltrate
is most dense80
. Histological examination also shows
the typical characteristics of thyroiditis, including occa-
sional apoptotic cells and a certain extent of follicular
destruction81
. Such observations fit well with the pres-
ence of autoantibodies to thyroglobulin and thyroid
peroxidase in most patients with GD.
T cells and B cells. Autoreactive T cells and B cells survive
central and peripheral deletion82,83
and TSHR-sensitized
B cells secrete TSHR autoantibodies (Fig. 3). T cells sen-
sitized to TSHR antigen are implicated in the manifes-
tation of symptoms in GD8
. T cells resident within the
thyroid gland might become activated via cytokine secre-
tion as demonstrated in animal models of bystander acti-
vation (that is, activation of T cells for a specific antigen),
including experimental autoimmune thyroiditis84
(Box 2).
Pro-inflammatory cytokines, such as IL-2 and IL-17, that
are released by infiltrating T cells and B cells activate
resident TSHR-reactive immune cells. This mechanism
could explain how different types of viral infections that
stimulate the secretion of pro-inflammatory cytokines
could lead to GD.
Antigen presentation by thyroid follicular cells. Normal
thyroid follicular cells express HLA class I but do not
express HLA class II antigens, which are generally
expressed by antigen-presenting cells, for example, den-
dritic cells or B cells. By contrast, thyroid glands from
patients with GD show increased levels of HLA class I
Fig. 2 | Histopathology of Graves’ disease. Periodic
acid-Schiff-stained thyroid section from a patient with
Graves’ disease showing the hypertrophied epithelial cells
and the mononuclear cell infiltrate around dilated blood
vessels (arrows; 50× magnification).
TH
17
cell
T cell
Treg
cell
TSHR
autoantibodies
APC
MHC
TCR
Thyroid cell
proliferation
↑ T3 and T4
TSHR
Follicular
cell
Colloid
IGF1R
Thyroid
gland
Blood vessel
IGF1
Plasma cell
TSHR
peptide MHC II
Fig. 3 | Pathogenesis of Graves’ hyperthyroidism.Thyroidcellsarestimulatedbythyroid-
stimulating hormone receptor (TSHR) autoantibodies to secrete thyroid hormones,
namely tri-iodothyronine (T3) and thyroxine (T4), causing the clinical manifestations
of hyperthyroidism. The autoantibodies are produced by local B cells and plasma cells
controlled by T cells and are aided by insulin-like growth factor 1 (IGF1), originating in
the liver. The T cells are activated by TSHR peptides on antigen-presenting cells (APCs),
which might be the thyroid cells themselves or B cells, macrophages or dendritic cells in
the vicinity. IGF1R, insulin-like growth factor 1 receptor; MHC, major histocompatibility
complex; TH cell, T helper cell; Treg cell, regulatory T cell; TCR, T cell receptor.
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as well as high levels of HLA class II, which enables the
thyroid cells to present antigen85–87
. This induction of
HLA class II antigens is mediated via interferons (such
as IFNγ), which might exert their effect during an
inflammatory response. As HLA class II antigens effi-
ciently present autoantigen to T cells, their expression by
follicular thyroid cells results in the activation of local,
that is, resident, autoreactive thyroid-specific T cells or
T cells that have infiltrated, and initiate proliferation of
antigen-specific T cells.
Defects in immune modulation. In general, inflamma-
tory responses involve a balance between IL-17-secreting
T helper (TH) cells and CD4+
CD25+
Treg cells. Treg cells
suppress the immune response by diminishing the activ-
ity of TH1 (cytotoxic leaning) and TH2 (antibody leaning)
cells. Treg cells express the transcription factor FOXP3, the
gene for which has been associated with GD (see above).
Some but not all studies have reported that the immune-
modulating function via CD4+
CD25+
Foxp3+
cells
might be diminished in GD88,89
. The immune response
in patients with GD might also be overreactive owing
to the failure of additional mechanisms usually con-
trolling the immune response, including peripheral
T cell deletion (a mechanism by which the immune
system deletes self-reactive T cells that escaped thymic
deletion) and anergy (inducing cell stasis), which
are known to contribute to normal antigen-specific
tolerance82,90
. Studies in mice have implicated a func-
tion for a checkpoint regulator called VISTA (T-type
immunoglobulin domain-containing suppressor of
T cell activation) in autoimmunity91
. VISTA enforces
quiescence in naive T cells, which is inhibited when anti-
gen stimulation occurs under inflammatory conditions.
This mechanism needs to be investigated in patients
with GD.
Autoimmunity to TSHR
In addition to TSHR autoantibodies, most patients also
exhibit variable titres of autoantibodies to thyroglobulin
and thyroid peroxidase, which are typically characteris-
tic of Hashimoto thyroiditis92,93
. The autoantibodies to
thyroglobulin and thyroid peroxidase are polyclonal, as
opposed to the restricted IgG type of TSHR autoanti-
bodies, and are therefore presumed to be secondary to
thyroid cell destruction94
. Thus, GD seems to develop on
a background of autoimmune thyroiditis. Hence, unsur-
prisingly, Hashimoto thyroiditis and Graves’ disease can
occur not only in the same family but in the same patient
at different times, so patients with hypothyroidism can
suddenly develop hyperthyroidism and vice versa.
StructureofTSHR.TSHR,amemberoftheclassAGPCR
superfamily, is a heavily glycosylated protein with a large
ectodomain consisting of a leucine-rich domain (LRD)
and a ‘hinge’ region, which connects the ectodomain
to the signal transducing transmembrane domain. The
hinge region includes a 50-amino acid region clea
ved by proteolysis, known as the cleaved or C-region
(Fig. 4). Furthermore, the ectodomain on the cell surface
is cleaved into α-subunits and β-subunits attached by
Box 2 | Animal models of GD
The thyroid-stimulating hormone receptor (TSHR) α-subunit transgenic NOD.H2h4
mouse is the only available spontaneous model of Graves’ hyperthyroidism228
. Other
models require active immunization with cells stably expressing TSHR and MHC class II
antigen or DNA vaccination using a recombinant adenovirus or plasmid coding for TSHR
with or without in vivo electroporation. Antigen-presenting dendritic cells expressing
TSHR have also been used to induce the disease271
. Amongst these techniques, DNA
vaccination is the most reliable as it offers a high reproducibility and a high disease
induction rate272,273
. A long-term hyperthyroid state can be obtained by repetitive
immunizations274
.
Insights from these animal models can be summarized as follows: first, successful
immunization can only be achieved with in vivo expression of TSHR, emphasizing
the crucial role for the receptor’s 3D structure in antigenicity. Second, the receptor
α-subunit is more efficient in disease induction than the full-length receptor97
,
confirming the α-subunit as the major autoantigen. Third, although Graves’ disease
(GD) is generally believed to be mediated by a T helper 2 (TH2) cell immune response,
a mixture of TH1 cell-mediated and TH2 cell-mediated immune responses were
observed in animal models. Furthermore, the importance of TH17 cells in the immune
response varies depending on the mouse strain used275
. Fourth, Graves’ orbitopathy
(GO) can be replicated in some of the models, although only incompletely276–278
,
proving the involvement of TSHR autoantibodies in the pathogenesis of GO. However,
the mouse models do not replicate all the symptoms or signs of the disease; for
example, no sex bias in disease incidence is present271
and no dermopathy develops.
Further efforts are necessary to establish better models that faithfully replicate the
diverse symptoms and signs of GD, including GO and Graves’ dermopathy.
Extracellular
ECD
TMD
Intracellular
Hinge
LRD
C-region
Fig. 4 | The structure of TSHR.Thethyroid-stimulating
hormonereceptor(TSHR)comprisesalargeectodomain
(ECD)consistingoftheleucine-richdomain(LRD)(grey)
withthehingeregion(orange)shownasaloopedstructure
thatconnectstheECDtothetransmembranedomain
(TMD).TheTMDisillustratedhereascylindricalstructures
connectedtooneanotherviaintracellularandextracellular
loops.Theshortcytoplasmictailofthereceptorisnot
visibleinthisrepresentation.TheLRDregiondetermines
thebindingofthyroid-stimulatinghormoneaswellas
stimulatingandblockingautoantibodies,whereasthe
TMDisthesignallingunitthatcouplestoGproteinsand
β-arrestins.C-region,cleavedregion.
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disulfide bonds95
. The disulfide bonds are reduced by a
protein isomerase, and a subset of α-subunits is thought
to be secreted in a soluble form96
. Seminal studies have
clearly established that the α-subunit of TSHR is involved
in the initiation and/or amplification of the autoimmune
response to the full-length receptor97–99
. In addition to
standard post-translational modifications, the recep-
tor also exists as high-order complexes or multimers100
bound at the ectodomain and the transducing trans-
membrane domain101,102
. These high-order complexes
have a role in the negative cooperativity of TSH with
its own or other bound TSHRs as well as in differential
signalling103
and regulation of receptor cleavage104
, and
might drive autoantibody affinity maturation105
, result-
ing in the formation of receptor-stimulating autoanti-
bodies. In addition, important cross-talk between TSHR
and insulin-like growth factor 1 receptor (IGF1R) has
been described but the importance of the different con-
formational forms of TSHR in this cross-talk has not yet
been defined106
.
TSHR autoantibodies. TSHR autoantibodies were dis-
covered in the sera of patients with GD107
and were orig-
inally called long-acting thyroid stimulators owing to
their prolonged action in stimulating radioiodine release
from the thyroid of rodents93,108,109
. Studies, including
epitope analysis, trying to delineate and characterize
the binding properties of these autoantibodies isolated
from the sera of patients or from rodent models of GD,
have identified three types of TSHR autoantibody —
stimulating, blocking and neutral (Fig. 5). Studies have
demonstrated the presence of all three types of TSHR
autoantibody in patients with GD but stimulating anti-
bodies are the hallmark of Graves’ hyperthyroidism.
When present, blocking and neutral antibodies most
likely modify the potency of stimulating antibodies.
Stimulating TSHR autoantibodies are conforma
tional110
and bind mostly to the LRD of TSHR. These
autoantibodies activate Gαs and induce cAMP genera-
tion, which is the primary signalling pathway involved
in thyroid cell proliferation and thyroid hormone syn-
thesis and secretion. Structural studies have mapped
the C terminus of the LRD as the predominant binding
site of these stimulating antibodies111
, implying that this
binding can induce a TSHR conformation that initiates
the most efficient activating signal.
Blocking TSHR autoantibodies are usually confor-
mational and effectively prevent the binding of both
TSH and low-affinity stimulating TSHR autoantibod-
ies to TSHR. This blocking might modulate the degree
of receptor activation or totally block all downstream
signalling. This modulation might cause swings from
thyroid overactivity to underactivity (referred to as
Graves’ Alternans)112
. The blocking antibodies also bind
to the LRD towards the N terminus of the ectodomain113
.
Although the blockers are oriented differently from
stimulating antibodies, how the two autoantibodies
directed to the same TSHR ectodomain lead to different
conformational changes with opposite actions remains
unclear. A mechanistic explanation (reviewed elsewhere)
exists for this agonist and antagonist activity based on
TSHR structural models114,115
.
Neutral TSHR autoantibodies are present in up to
60% of patients with GD and are TSH non-competing,
linear antibodies that recognize epitopes in the hinge
region (H-antibodies), including the C-region
(C-antibodies) of the TSHR ectodomain. These hinge
region antibodies neither block TSH binding nor trigger
traditional TSHR signalling but harbour non-canonical
biological effects on thyroid and extrathyroid cells116
.
Furthermore, immunization models have indicated
that the hinge region is a hot spot against which many
of these linear TSHR autoantibodies develop117
.
Signalling by TSHR autoantibodies. TSHR can induce
a complex signalling cascade owing to its ability to
couple to all four major classes of G proteins as well
as β-arrestins (which are negative regulators of GPCR
signalling)118,119
(Fig. 6). Primarily, TSHR couples to Gαs,
leading to initiation of the PKA pathway via cAMP pro-
duction, which mediates cell proliferation and thyroid
hormone synthesis. At high concentrations of TSH,
TSHR also couples to Gαq/11, thereby activating PLC-β,
which leads to increased levels of intracellular Ca2+
via
the DAG–IP3 pathway and in turn activates NF-кB,
leading to gene transcription. After ligand binding,
phosphorylated TSHR recruits β-arrestin, which is fol-
lowed by receptor internalization and signal dampen-
ing. The engagement of β-arrestin to the receptor can
also activate the MAPK pathway120
, leading to protein
synthesis and cell differentiation. Thus, stimulating or
blocking antibodies influence thyroid cell activation
and proliferation by modulating these major signalling
cascades. Studies involving neutral TSHR autoanti-
bodies have demonstrated that these antibodies induce
thyroid cell stress by causing the failure of endosomal
maturation121
. The resultant increase in reactive oxygen
species by their misdirected routing leads to cellular
Stimulating TSHR
autoantibody
Blocking TSHR
autoantibody
‘Neutral’ TSHR
autoantibody
G protein
signal
G protein
blockade
No G protein signal and/or
no TSH blockade
Non-canonical signalling
Fig. 5 | TSHR autoantibodies. The thyroid-stimulating hormone (TSH) binding pocket
represented by the leucine-rich domain (LRD), comprising the α-helices and the
β-pleated sheet (grey), show the binding sites of stimulating and blocking antibodies.
The neutral antibodies bind to the unique cleaved region (316–366aa) of the receptor,
which is illustrated by a broken line, and also to the other parts of the hinge region
(orange). Stimulating antibodies that bind to the LRD lead to signalling of the receptor.
A blocking antibody would be effective in sterically hindering TSH binding. Neutral
antibodies neither block TSH binding nor stimulate GPCR signalling but activate
non-canonical signal transduction. TSHR, TSH receptor.
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stress and the apoptosis of thyroid cells both in vitro
and in vivo81,121
.
Extrathyroidal manifestations of GD
TSHR is found in a variety of extrathyroidal sites, some
of which take part in the autoimmune response, in par-
ticular the retro-orbit and the pretibial dermis122,123
. The
extrathyroidal distribution of TSHR includes lympho-
cytes, thymus, pituitary glands, testes, kidney, heart,
brain, adipose tissue, fibroblasts and bone. Although
why more tissues are not involved in the autoimmune
response is unclear, data suggest that TSHR expression
is higher in retro-orbital tissue than in other extrathy-
roidal sites. Furthermore, the risk of developing GO is
associated with the levels of TSHR autoantibodies124
,
and TSHR autoantibody titres are correlated with the
severity of GO in patients, suggesting a role for antibody
signalling in its aetiology. Nevertheless, TSHR autoanti
bodies alone have not been shown to transfer GO to
mice, although careful studies are lacking.
TSHR and IGF1R are closely intertwined and TSHR
autoantibodies can generate signals from both receptors.
The importance of the synergy between TSHR autoanti
bodies and IGF1R125,126
has been further emphasized
by the successful clinical use of an IGF1R monoclo-
nal antibody in patients with moderate to severe GO127
(see below) (Fig. 7).
In GO, retro-orbital adipocyte accumulation is
enhanced by the binding of circulating TSHR autoanti-
bodies to TSHR expressed on pre-adipocytes as well as
on fibroblasts, which is thought to induce IGF1R cross-
talk, resulting in increased hyaluronic acid production128
.
Cytoplasm
Nucleus
TSHR
TSH
TSHR autoantibody
Cross-talk
IGF1R
β α
Gαq/11
p90RSK
Elk1
Gαs
DAG
Raf
MEK1/2
PLCβ
PI3K
PDK1
AKT
mTOR
S6K
S6K
Rho
IRS1
IRS2
Gα12/13
p90RSK
β-arrestins
NF-κB
PKC
NF-κB
ERK1/2
AC Gαi/o
MEK1/2
cAMP
RAP1
PKA
EPAC
CREB
CREB
Thyroid cell proliferation
Thyroid hormone synthesis
Fig. 6 | Signalling cascade by TSHR autoantibodies. The figure illustrates the major signalling pathways from the
thyroid-stimulating hormone receptor (TSHR) due to the engagement of various G proteins by thyroid-stimulating
hormone (TSH) or TSHR autoantibodies, which bind to the leucine-rich domain of the receptor. The cAMP/PKA pathway
is the major pathway activated by Gαs, which leads to key physiological outcomes such as thyroid hormone synthesis or
secretion and thyroid growth. However, high TSH concentrations enable the receptor to also engage Gαq/11, leading to
activation of the PLCβ/PKC pathway, which is thought to play a role in thyroid hormone iodination262
. Additionally, in some
cases, TSH can activate Gα12/13, which leads to MAPK signalling via Rho-GTPase activation263
. In addition to its classical role
of inhibition of cAMP, Gαi/o has been recently implicated in biphasic responses to TSH264
. Although this complex signalling
cascade is a generic signalling pathway from TSHR in thyrocytes, its downstream signalling varies based on cell types265
.
The literature has shown that TSHR can also cross-talk with the insulin-like growth factor 1 receptor (IGF1R) in orbital
fibroblasts and fibrocytes and this may be mediated by β-arrestins106
. Molecules such as PKA and PKC are the essential
signalling pathways for thyrocyte proliferation, growth and hormone secretion. Furthermore, scaffolding proteins such as
theβ-arrestins bind to the activated TSHR for internalization and lead to activation of the MAPK pathway. AKT, RAC-alpha
serine/threonine-proteinkinase;cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-bindingprotein;
Elk1, ETS domain-containing protein; EPAC, exchange protein activated by cAMP; MEK, mitogen-activated protein kinase
kinase; mTOR, mammalian target of rapamycin; NF-кB, nuclear factor-кB; PLC, phospholipase C; Raf, RAF proto-oncogene
serine/threonine protein kinase; RAP1, Ras-related protein 1; PKA, protein kinase A; PKC, protein kinase C; S6K, ribosomal
protein S6 kinase 1.
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The extraocular muscles become osmotically swollen
and are disrupted by the excess accumulation of glycos-
aminoglycans in the extracellular matrix. Glycosamino
glycans are produced by the local fibroblasts, which are
stimulated by TSHR autoantibodies and by cytokines,
such as IFNγ, resulting from the local inflammatory
response. The damaged eye muscles subsequently
become fibrosed and show a patchy lymphocytic infil-
trate and express HLA class II antigen. The retro-orbital
fibrocytes (mesenchymal cells that arise from monocyte
precursors) can be derived from the circulation after
originating in the bone marrow and might be involved
in retro-orbital tissue expansion due to their high TSHR
expression129
.
A clear understanding of the pathophysiology of
PTM is currently lacking, although molecular pathways
similar to those involved in GO are almost certainly
involved and revolve around TSHR expression in der-
mal fibroblasts. Hence, future studies that provide more
insights into how accumulation of glycosaminoglycans
leads to elephantiasis are needed.
Diagnosis, screening and prevention
GD is the most common but not the only cause of
hyperthyroidism2
. Other common causes include toxic
multinodular goitre, active thyroid adenoma and suba-
cute destructive thyroiditis (caused by viral infections,
autoimmunity or drugs). In destructive thyroiditis of
any cause, self-limited leakage of previously stored thy-
roid hormone causes transient hyperthyroidism. Rare
causes include factitious hyperthyroidism, struma ovarii
and amiodarone-induced hyperthyroidism (Table 2).
As treatment options vary considerably according to
the origin of hyperthyroidism, an accurate aetiological
diagnosis is of paramount importance.
Presentation
The presenting symptoms of hyperthyroidism vary
widely,independentlyofthecause.Clinicalhyperthyroid-
ism can present in a mild (or subclinical) form defined
as the presence of subnormal TSH levels with normal
thyroid hormone levels or an overt form with increa
sed thyroid hormone levels and a variety of symptoms,
including anxiety, weight loss, palpitations and insom-
nia. Elderly patients tend to present with cardiovascu-
lar symptoms ranging from sinus tachycardia to atrial
fibrillation and heart failure130
. In younger patients
(<50 years of age), neurogenic symptoms, such as tremor
and anxiety, predominate; in some cases, overt psychosis
can occur130
. A distinct feature of GD may be the sudden
onset of symptoms compared with the slow and indolent
course of toxic multinodular goitre. In GD, the presence
of extrathyroidal manifestations, such as GO, is often
associated with a more severe degree of hyperthyroidism
and a larger goitre.
Diagnosis
A reliable diagnosis of GD can often be established
quickly on clinical grounds. A history of symptoms
lasting for several months in a patient with any sign of
GO and a diffuse goitre (swelling of the entire thyroid
gland) firmly establishes the diagnosis. If ultrasonogra-
phy is available, one can quickly dismiss the presence of
nodules. However, in many cases, the diagnosis is not
B cell
TSHR
autoantibodies
Adipocytes
Myoﬁbroblast
Autoreactive
T cell
IGF1R
CD20
Adipogenesis
Orbital
ﬁbroblast
Fibrocyte
Bone marrow
Expanded
orbital
tissues
Hyaluronan
Cytokines
CD154
CD40
T cell chemoattractants
(CCL5 and IL-16)
MHC
Cross-talk
TSHR PGE2
S1P
Fibrosis
TSHR
TSHR
peptide
Fig. 7 | Pathogenesis of Graves’ orbitopathy. Fibroblasts can differentiate into adipocytes and myofibroblasts to
contribute to tissue expansion and secrete hyaluronic acid, which leads to the disruption of the extraocular muscles.
The fibroblasts and adipocytes are activated by the thyroid-stimulating hormone receptor (TSHR) and induce a cross-talk
with insulin-like growth factor 1 receptor (IGF1R). T cells bind to CD40 on orbital fibroblasts and induce further T cell
infiltration via sphingosine 1-phosphate (S1P). Activation of orbital fibroblasts by CD40 ligation induces the production
of pro-inflammatory cytokines and PGE2. The B cells produce TSHR autoantibodies and interact with CD4+
T cells. MHC,
major histocompatibility complex; PGE2, prostaglandin E2.
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immediately evident on a clinical basis, for example, in
patients who present only with hyperthyroidism without
any of the other distinctive signs131
. Thyroid overactivity
is usually diagnosed by measuring serum TSH levels and
free thyroxine levels. When a diagnosis cannot be estab-
lished on clinical grounds alone, in addition to TSH and
free thyroxine levels, the detection of TSHR autoantibod-
ies in the serum can confirm a GD diagnosis (Fig. 8). If a
diagnosis is established, appropriate management deci-
sions can be made. If the autoantibody test is negative,
then a radioiodine uptake and thyroid scan should be
performed to establish the diagnosis. In GD, radioiodine
uptake is characterized by a normal or increased percent-
age uptake; a very low or absent uptake is representative
of thyroiditis, unless an iodine-related cause suppresses
the uptake or there is direct damage to the thyroid cells.
TSHR autoantibody tests. The presence of stimulating
TSHR autoantibodies in the serum of a patient with
hyperthyroidism definitively establishes the diagnosis
of GD. As the patient is already diagnosed with hyper-
thyroidism, laborious and expensive bioassays employ-
ing TSHR-transfected cells are not indicated as first-line
tests. Instead, third-generation receptor binding assays
for TSHR autoantibodies now display excellent analyt-
ical and clinical performance in most laboratories132
and are strongly recommended as first-line tests for
the diagnosis of GD133
. Automated testing of TSHR
autoantibodies for a fraction of the cost of a thyroid scan
is now possible134
. Modern assays display both sensiti
vity and specificity of >95% when used to diagnose GD
in patients with overt hyperthyroidism135
. However,
the performance of these tests in patients with mild
(subclinical) hyperthyroidism has not been well studied
in separate cohorts. In such patients, bioassays with a
slightly increased sensitivity might be superior to bind-
ing assays when the receptor assay is negative. A radio
iodine uptake and thyroid scan will be needed for the few
patients with negative receptor antibody tests although,
in most cases, these patients prove to have thyroiditis.
Thyroid ultrasonography. Thyroid ultrasonography,
which was pioneered by two researchers in the late
1960s, was initially widely used to differentiate solid
nodules from cystic nodules136,137
. Currently, the advent
of high-quality and affordable portable ultrasonography
instruments has changed the face of clinical thyroidol-
ogy, with nodules being instantly excluded in each new
patient with GD. The drawback of this approach can
be the overdiagnosis of small thyroid cancers, which
are generally clinically dormant138
. Nevertheless, ultra-
sonography has become an important and practical tool
for the thyroidologist; the clinician can immediately dis-
tinguish toxic multinodular goitre from GD often on a
patient’s first visit at low cost and without the need for
radiological imaging (Fig. 9). While CT and MRI scans
can detect thyroid nodules, they are less precise and do
not add more information to the ultrasonographical
examination except when searching for enlarged lymph
nodes in thyroid cancer.
Radioiodine uptake and thyroid scan. Radioiodine
uptake by the thyroid gland and a thyroid scan can offer
an accurate study of thyroid function. A radioactive
iodine (123
I) tracer dose is administered orally and images
that give a measurement of iodine uptake by the thyroid
gland are obtained after 24 hours (Fig. 10). In the setting
of low TSH levels, high or normal iodine uptake indicates
TSH-independent activation of thyroid hormone synthe-
sis and release, indicating GD (via TSHR autoantibodies)
or toxic multinodular goitre (via activating mutations).
A low or <1% iodine uptake can indicate destructive thy-
rotoxicosis (with no new thyroid hormone synthesis),
factitious thyrotoxicosis (with an extrathyroidal source
of thyroid hormone) or struma ovarii (in which TSH
is suppressed, thereby inhibiting radioiodine uptake).
A diffuse pattern of iodine uptake confirms the diagnosis
of GD, whereas a patchy pattern indicates multinodular
or uninodular toxic goitre (Fig. 10). A radioiodine scan
used to be the gold standard for diagnosis but, given its
high cost and the advances in TSHR binding assays as
Table 2 | Causes of hyperthyroidism and their diagnosis
Cause TSHR
autoantibodies
Radioiodine uptake
and thyroid scan
pattern
Thyroid ultrasonography
and Doppler flow
Thyroglobulin
levels
Graves’ disease Positive Normal or high;
diffuse uptake
Normal or hyperechoic
signals; high or normal flow
High
Toxic multinodular goitre Negative Normal or high;
patchy uptake
Multiple nodules; high or
normal flow
High
Destructive thyrotoxicosis Negative None or very low
uptake
Hypoechoic signals; low
flow
High
Toxic adenoma Negative Normal or high;
unifocal uptake
Single nodule; high or
normal flow
High
Factitious thyrotoxicosis Negative No uptake Normal signals Undetectable
Struma ovarii Negative No uptake Normal signals High
Amiodarone induced, type I Negative Minimal or no uptake Variable signals High
Amiodarone induced, type II Negative No uptake Normal signals; low flow High
Biotina
Negative Normal uptake Normal signals Low
TSHR, thyroid-stimulating hormone receptor. a
Excessive doses of biotin can cause interference in thyroid function tests
mimicking GD263
.
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well as the widespread availability of ultrasonography,
this is no longer the case139
.
Graves’ orbitopathy. Patients with GD may present
with varying degrees of orbitopathy and usually pres-
ent with irritation, tearing, inflammation and pain
behind the eye. In severe cases, exophthalmos (proptosis,
that is, protrusion of the eyes forward) occurs as a result
of retro-orbital inflammation and extraocular muscle
oedema owing to tissue expansion and the accumulation
of glycosaminoglycans. The resulting ocular muscle
damage causes double vision and can endanger sight
itself. Sight-threatening manifestations are associated
with muscle thickening, which induces pressure at the
orbital apex (called apical crowding). Dysthyroid optic
neuropathy from apical crowding140
, corneal ulceration
due to lagophthalmos (inability to close one’s eyelids)
and increased intraocular pressure are all possible
consequences.
GO is clinically staged according to international
guidelines and the EUGOGO classifies GO into mild,
moderate and severe (Box 3). Additionally, patients are
divided into two groups — active disease and inac-
tive disease — using the clinical activity score or the
International Thyroid Eye Disease Society (ITEDS)
classification. Both the clinical activity score and the
ITEDS classification systems take into consideration
patients’ individual pressure sensation, pain associ-
ated with eye movement, five key inflammatory signs
(namely conjunctival redness, conjunctival oedema,
caruncular oedema, lid redness and lid oedema) and
disease dynamics (that is, progression versus improve-
ment or stable disease), which include proptosis, motility
and visual acuity (Fig. 11). Furthermore, GO can also be
scored using the ITEDS classification with a maximum
of 20 points141,142
(Box 3). The natural history of the dis-
ease is to progress from the initial active stage with vari-
able degrees of inflammation through to a stable inactive
state, which might involve considerable residual damage.
Graves’ dermopathy. GD-associated dermopathy is most
commonly observed in the lower extremities (namely,
PTM). However, dermopathy can also manifest on the
elbows, feet and toes; in severe cases, the entire lower
leg might be affected (Fig. 12). The most common pres-
entation of PTM can be described as an erythematous,
non-pitting thickening of the dermis in the pretibial
region with a characteristic palpable edge where the
Graves’ disease
Destructive thyrotoxicosis
Factitious thyrotoxicosis
Struma ovarii
Low TSH and high free thyroxine
Present
Diﬀuse
uptake
Absent
Low or
no uptake
Radioiodine uptake and thryoid scan
Measure TSHR autoantibodies
Hyperthyroidism
Measure TSH and free thyroxine levels
Suspect hyperthyroidism
Exclude nodules with ultrasonography exam
Fig. 8 | Diagnosis of Graves’ disease.Aschematicofanapproachtothediagnosisof
Graves’disease(GD).Whenthepatienthasclearclinicalsigns,suchasGraves’orbitopathy,
physiciansoftenrecommendnofurtherdiagnostictestsorassessments.However,the
measurementofthyroid-stimulatinghormonereceptor(TSHR)autoantibodiesremains
ausefuladjunctforclinicalmanagementandprovidesadefinitivediagnosisofGD.TSH,
thyroid-stimulatinghormone.
a c
d e
b
Fig. 9 | Ultrasonographic examination of the thyroid. An example of an enlarged thyroid with a normal appearance
very typical of Graves’ disease. Ultrasonography is useful to exclude the presence of thyroid nodules in all new patients.
Images from Doppler ultrasonography showing thyroid lobes (left lobe (parts c and d) and right lobe (parts a and e))
with and without the colour views, which show the vascularity of the Graves’ thyroid and the thick isthmus (indicated
by an arrow) is seen clearly in the middle section (part b).
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inflammatory reaction ends. In mild cases, the skin
might be micronodular on palpation, with a character-
istic appearance similar to an ‘orange peel’. More severe
cases display larger fleshy nodules and, in extreme cases,
elephantiasis myxoedema — gigantic deformities of the
pretibial region and the toes ensue (Fig. 12). The diag-
nosis is usually clinical and a biopsy to detect dermal
deposition of glycosaminoglycans is rarely needed and
might precipitate worsening of the lesions. Therefore,
PTM can be mild or may steadily progress to cause
marked damage from its fibrous invasion. Although not
malignant, PTM is often difficult to treat. Why PTM pre-
sents most often in the lower legs is uncertain, although
poor circulation and frequent damage are often blamed
as contributing factors.
Thyroid acropachy. A rare form of nail clubbing
and swelling of fingers and toes known as acropachy
occurs exclusively in some patients with GO and PTM.
Acropachy is seen on X-ray radiographs as periosteal
new bone formation143
. Acropachy is hypothesized to be
a consequence of the increased cardiac output in severe
hyperthyroidism inducing peripheral bone changes.
Once regularly seen in patients with GD, acropachy
is now a rare symptom owing to early GD diagnosis
and treatment.
Pregnancy
The diagnosis of GD in pregnancy can be extremely
difficult if TSHR autoantibody tests are negative. The
symptoms of pregnancy, which include, for example,
palpitations and perspiration, together with high serum
total thyroxine levels due to increased oestrogen pro-
duction, can confound inexperienced practitioners.
Furthermore, many women have low TSH in early
pregnancy because of the influence of human chorionic
gonadotropin on the thyroid, adding to the confusion.
However, as pregnancy progresses, increased immune
tolerance usually results in the disease becoming
inactive and it rarely needs treatment. Those women
with persistent disease have high levels of stimulating
TSHR autoantibodies, which is useful in establishing a
diagnosis.
The decision to screen all pregnant women for thy-
roid disease has been a topic of ongoing debate since the
early 2000s. Interestingly, the impact of the deleterious
effects of overt thyroid disease in pregnancy has received
scant attention in the debate on universal screening (that
is, the screening of all pregnant women). This omission is
critical as treating overt hyperthyroidism and overt
hypothyroidism has been shown to decrease maternal
and fetal adverse events (such as maternal heart failure,
pre-eclampsia, stillbirth and preterm delivery).
In 1968, the WHO published criteria according to
which new screening tools are evaluated144
. The most
important of the criteria for evaluating the screening of
overt hyperthyroidism in pregnancy include address-
ing whether overt hyperthyroidism causes adverse
maternal or fetal outcomes, whether a cheap screen-
ing test and well-accepted treatments are commonly
available, and whether the treatment of overt hyper-
thyroidism is cost-effective. In fact, screening for overt
hyperthyroidism meets all of the criteria except, pos-
sibly, cost-effectiveness as no such analyses have been
performed so far. A recent meta-analysis revealed a
prevalence of 0.64% of overt hyperthyroidism during
pregnancy, that is, >1 in every 200 pregnant women145
.
Increasingly, most pregnant women are indeed screened
for thyroid dysfunction in many countries using serum
TSH levels and we continue to recommend that all
pregnant women should be screened for thyroid disease.
Management
The main goal in the management of GD is con-
trolling hyperthyroidism by establishing normal thy-
roid hormone levels. In addition, the presence of goitre
and/or GO will influence the choice of therapy. Treat
ments that address symptoms as well as providing a
definitive‘cure’forGDareincludedintheAmerican Thy
roid Association guidelines133
and the European
Thyroid Association guidelines146
.
Antithyroid drugs
Thionamides are a class of antithyroid drugs that inhibit
thyroid hormone synthesis147
. In GD, thionamides can
be used both acutely and chronically to reduce thyroid
a
c d
b
Fig. 10 | Radioiodine uptake and scan.Examplesofradioiodine(123
I)thyroidscintigraphy
images in various forms of hyperthyroidism. a| Typical findings in Graves’ disease include
diffuse and intense accumulation of the isotope in a bilaterally enlarged gland.b| A case
of destructive thyrotoxicosis from painless thyroiditis where glandular uptake of iodine
is absent and the thyroid is not visualized.c| A case of toxic adenoma: the autonomously
functioning nodule accumulates the isotope avidly. As thyroid-stimulating hormone is
suppressed owing to excessive thyroid hormone production from the nodule, no uptake
is observed in the extranodular thyroid tissue. d| A case of toxic multinodular goitre
in which the isotope concentrates in several nodular regions throughout the gland
(G.B., personal observation).
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hormone levels as well as to induce remission. Currently,
methimazole and propylthiouracil are the commonly
available thionamides in the USA, whereas carbima-
zole (a carbethoxy derivative of methimazole) is used
in other parts of the world. Methimazole (or carbima-
zole) is the drug of choice in most people owing to its
longer duration of action (9 hours versus 1–2 hours
for propylthiouracil) and reduced incidence of adverse
events compared with propylthiouracil. However, pro-
pylthiouracil is preferred during the first trimester of
pregnancy because of the greater teratogenic effects
associated with methimazole148
. The most common
adverse effect of thionamides is a rash (usually transient
and responsive to diphenhydramine)149
. Furthermore, all
thionamides have risks of hepatotoxicity149–151
, pancreati-
tis and bone marrow toxicity (granulocytopenia)148,152,153
and, therefore, are contraindicated in patients with an
absolute neutrophil count of <1,000 cells/µl or elevated
liver transaminases (>5-fold the upper limit of normal).
Hence, a review of complete blood count and liver func-
tion tests is needed before commencing these drugs
as hyperthyroidism itself can cause aberrations in the
complete blood count and liver enzymes. In addition,
patients on an antithyroid drug should be instructed to
contact their physician in case of fever or pharyngitis.
Treatment is usually recommended for at least
12 months and studies have shown a greater remission
(>1 year without active disease) rate with a longer treat-
ment course154,155
. Predictors of a low remission rate
before starting treatment include a large goitre, GO,
PTM, high thyroglobulin levels and high TSHR autoan-
tibody titres. During treatment, predictors of poor
responsiveness include persistently low TSH levels and
persistent and high TSHR autoantibody levels154,155
. The
duration of elevated TSHR autoantibodies varies from
patient to patient. Although the ideal treatment length
is >1 year, persistently high TSHR autoantibody levels
beyond this period is the most useful predictor of a low
remission rate.
Patients with Graves’ Alternans, who fluctuate from
hyperthyroidism to hypothyroidism and vice versa, may
express TSHR blocking autoantibodies, which wax and
wane with time and can be difficult to manage clin-
ically. In such patients, a ‘block and replace’ approach
can sometimes be helpful, providing both antithyroid
drug and levothyroxine (used to treat the induced
hypothyroidism) at the same time.
The prevalence of GD in children is less common
than in adults and GD in children is best managed
with methimazole156
. If the disease persists, a more
definitive therapy can be provided after puberty.
When there are contraindications to antithyroid drugs,
thyroid-destructive therapy may be recommended
earlier than usual in the management course.
Radioiodine. Radioiodine is often considered the defin-
itive treatment of choice in many countries, especially
in patients with small goitres (<50 g), in patients who
are difficult to manage with thionamides or in patients
for whom thionamides are contraindicated. Treatment
can be given as soon as the diagnosis is made, without
pretreatment with thionamides if symptoms of hyper-
thyroidism are mild and in the absence of a previous
history of heart disease. However, in many patients,
achieving a euthyroid state (that is, having normal thy-
roid hormone levels) beforehand is recommended to
avoid radiation-associated thyroiditis, which can further
increase thyroid hormone levels.
Radioactive sodium iodide (Na131
I) is given orally
and rapidly concentrates in the thyroid gland. After
causing extensive tissue damage, ablation of the thyroid
gland with a reduction in thyroid hormone levels occurs
within 6–18 weeks157
. Once hypothyroidism is achieved,
thyroid hormone replacement is initiated. When treated
appropriately with potentially ablative doses, <15% of
patients require >1 round of radioiodine to ablate their
thyroid gland158
. Radioiodine is not recommended dur-
ing pregnancy and lactation and in patients with GO
owing to its inherent risk of worsening the disease.
Radioiodine treatment is also discouraged in smokers,
who are more prone to GO than non-smokers. Some
studies have reported an increased long-term risk of can-
cer in patients receiving radioiodine but this risk is small
or negligible in the doses used in GD159,160
.
Surgery. Thyroidectomy (partial or total) was the orig-
inal treatment for GD throughout the world and is still
the preferred definitive therapy in patients with large
goitres (>80 g) and in patients with moderate to severe
GO. Surgery is also considered in patients in whom
thionamides are unsuitable, in women planning a preg-
nancy within 6 months, when thyroid malignancy is
documented or suspected, when large thyroid nodules
(>4 cm) are present, and in the rare patients with coexis
ting hyperparathyroidism133
. Thyroidectomy is avoided
in the first trimester of pregnancy because of the tera-
togenic effects and increased fetal loss associated with
anaesthesia and in the third trimester owing to an
increased risk for preterm labour161
.
Box 3 | GO grading schemes
European Group on Graves’ Orbitopathy
• Mild: patients whose features of Graves’ orbitopathy (GO) have only a minor
effect on daily life insufficient to justify immunosuppressive or surgical treatment.
Patients usually have one or more of the following: minor lid retraction (<2 mm),
mild soft-tissue involvement, exophthalmos <3 mm above normal for ethnicity
and sex, no or intermittent diplopia, and corneal exposure responsive to lubricants.
• Moderate: patients without sight-threatening GO whose eye disease has sufficient
effect on daily life to justify the risks of immunosuppression (if active) or surgical
intervention (if inactive). Patients usually have two or more of the following: lid
retraction ≥2 mm, moderate or severe soft-tissue involvement, exophthalmos ≥3 mm
above normal for ethnicity and sex, and/or inconstant or constant diplopia.
• Severe: patients with sight-threatening ocular complications such as dysthyroid optic
neuropathy and/or corneal breakdown.
International Thyroid Eye Disease Society scoring
• Visual acuity: optic neuropathy (yes (1 point), no (0 points))
• Inflammation: caruncular oedema (0–1 points), chemosis (0–2 points), conjunctival
redness (0–1 points), lid redness (0–1 points), lid oedema (0–2 points), retrobulbar ache
(0–2 points), diurnal variation (0–1 points)
• Strabismus: diplopia (none (0 points), with gaze (1 point), intermittent (2 points)
constant (3 points)), restriction (>45° (0 points), 30–45° (1 point), 15–30° (2 points),
<15° (3 points))
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A high-volume thyroid surgeon is usually preferred
in order to avoid postoperative complications162–164
.
Thyroid surgery for GD might be particularly associ-
ated with hypocalcaemia from parathyroid injury and
laryngeal nerve damage at a significantly higher rate
than in thyroid surgery for other benign conditions,
such as simple or multinodular goitre, perhaps owing
to the high vascularity or inflammatory features of the
disorder.
Ideally, patients should be treated with thionamides
and β-blockers (see below) preoperatively to achieve a
euthyroid state and cardiac rate control. Vitamin D and
calcium are given preoperatively to prevent postopera-
tive hypocalcaemia in patients with a high risk of para-
thyroid injury165
. In rare circumstances, when achieving
a euthyroid state is not possible prior to surgery because
of an urgent need for thyroidectomy or when thio-
namides are contraindicated, the patient should be
treated with a combination of β-blockers, potassium
iodide, glucocorticoids and, possibly, cholestyramine
in the immediate preoperative period (7 days before
surgery) to decrease thyroid hormone levels149,151–153
.
After thyroidectomy, thyroid hormone replacement is
initiated in the patient to manage the hypothyroid state
and serum TSH levels are measured every 4–6 weeks
postoperatively to adjust the dosing.
β-blockers. β-blockade is used in patients with moder-
ate to severe hyperthyroidism who require immediate
relief as other treatments take effect in reducing thyroid
hormone levels. Currently, selective β1 receptor blockers
such as atenolol and metoprolol (extended release) are
preferred. Propranolol is often the preferred β-blocker in
severe hyperthyroidism requiring hospitalization owing
to its reported effect in reducing the rate of deiodina-
tion of thyroxine (T4) to tri-iodothyronine (T3) (steps
involved in thyroid hormone synthesis)166
. Once thyroid
hormone levels are reduced considerably and symptoms
improve, β-blockers can be tapered off.
Graves’ orbitopathy
The basis for the successful management of GO is a
close collaboration between thyroid specialists and
ophthalamologists167
. The treatment is stage dependent
(Fig. 13) and should consider the dynamics, duration of
the disease and risk factors for disease progression168
.
Anti-inflammatory treatment is recommended for active
progressive disease stages and rehabilitative surgery is
performed only in the stable inactive phase, when func-
tional and appearance sequelae persist. Rehabilitative
orbital169
, squint170
and lid surgery171
are customized for
the patient needs and are performed step by step and
depend on the experience of the local experts. However,
current available therapies do not lead to complete
remission of GO symptoms in many patients and leave
them with an impaired quality of life.
First-line therapies. A euthyroid state is mandatory for
successful treatment and radioiodine therapy should
be avoided in active progressive GO68
. All patients
should be strongly advised to quit smoking owing to its
deleteriouseffectsindiseaseprogressionandtreatment172
.
A ‘wait and watch’ strategy can be followed for
patients with mild GO. Selenium supplementation can
be recommended to prevent further deterioration owing
to its anti-inflammatory effects173
. Depending on disease
progression (continued redness and tearing), patients
can be offered intravenous glucocorticoid treatment.
Alternatively, oral steroids can be used but the onset of
treatment effect is slower and sometimes associated with
burdensome adverse effects174
.
Several randomized clinical trials (RCTs) suggest
intravenous glucocorticoids as the first-line treatment
for patients with active moderate to severe GO174–176
.
The treatment effects of intravenous glucocorticoids
are apparent as early as after 1 week of treatment177
.
According to a meta-analysis, RCTs showed a decrease
of 1.14 mm of proptosis and a 33% reduction of diplo-
pia (double vision), whereas non-randomized studies
a b g
c d
e f
Fig. 11 | Clinical features of Graves’ orbitopathy. Classification of the severity of Graves’ orbitopathy according to
the European Group on Graves’ Orbitopathy consists of three grades: mild (part a), moderate to severe (part c) and sight
threatening (part e)141,142
. The corresponding orbital CT scans illustrating the muscle enlargement are shown in parts b,d
and f and the resulting retinal changes of optic neuropathy from severe crowding of the nerve are shown in part g.
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showed a decrease of 1.58 mm of proptosis and a 25%
reduction of diplopia in patients treated with intrave-
nous glucocorticoids178
. Activity and severity status
should be carefully re-evaluated at 6 weeks. Patients
who deteriorate at 6 weeks after intravenous glucocor-
ticoids are less likely to benefit from continued treat-
ment. Approximately only one-third of nonresponsive
patients improve by further continuing the treatment179
and therefore, at 6 weeks, treatment should be supple-
mented with or replaced by second-line treatments.
In patients with severe GO, emergency orbital decom-
pression has to be performed, especially in patients with
optic disc oedema, marked inflammation and marked
function loss169,180
.
The adverse effects of glucocorticoids are dose
dependent175,181
and, therefore, cumulative doses of
>8 g should be avoided because of hepatic toxicity.
Contraindications to high doses of glucocorticoids
include recent viral hepatitis, significant hepatic dys-
function, severe cardiovascular morbidity, uncontrolled
hypertension and psychiatric disorders. Alternatively,
oral corticosteroids can be used but the onset of a
treatment effect is slower and adverse effects may be
more common and more severe than with intravenous
glucocorticoids.
Patients also benefit from local treatments and these
are appropriate at all stages of disease. Diplopia in the
primary gaze position can be compensated with prisms
(either Fresnel prisms or prism glasses) or occlusion,
usually of the non-leading eye (the exception being if the
leading eye is more severely restricted). Botulinum toxin
can be injected into fibrosed, retracted upper eyelid mus-
cles or orbital muscles. The paresis caused by botulinum
toxin alleviates the restricted movement of the affected
muscles. Lid retraction and elevation deficits associ-
ated with low tear production, which causes dry-eye
symptoms, will need tear replacement solutions and/or
ointments and even local anti-inflammatory therapy.
Second-line therapies. RCTs have expanded the options
for second-line therapies for the treatment of GO. For
example, teprotumumab, a monoclonal antibody to
IGF1R, markedly decreased proptosis (–2.82 mm versus
–0.54 mm with placebo), diplopia (one class reduction
of 68% versus 29% with placebo) and disease activity
scores <2 (59% versus 21% with placebo) in patients with
moderate to severe and active GO127
. Teprotumumab is
a newly available therapy and its long-term outcome
remains uncertain. Similarly, in RCTs, although cyclo-
sporine was ineffective compared with steroids182,183
,
the widely available drug mycophenolate mofetil was
more effective in combination with intravenous glu-
cocorticoids (71%) than intravenous glucocorticoids
alone (53%)184
. Similarly, azathioprine was more effec-
tive in combination with oral steroids than oral steroids
alone or irradiation alone185
. Additionally, rituximab, a
humanized B cell-depleting monoclonal antibody, was
more effective (100%) than intravenous glucocorticoids
(69%) if given early in disease onset186
and also improved
PTM187
but was not effective if administered ≥12 months
after onset188
. Similarly, tocilizumab, a humanized
recombinant IL-6R monoclonal antibody, was more
effective than intravenous glucocorticoids189
. A reduc-
tion in proptosis of ≥2 mm was observed in 33.3% of the
patients who received rituximab compared with 6.35%
in the intravenous glucocorticoid group186
.
For patients with motility impairment, orbital irra-
diation can be initiated, which might help suppress
the downstream consequences of fibroblast activation
and the secretion of pro-inflammatory cytokines from
activated lymphocytes190,191
. Irradiation can improve
the effect of oral glucocorticoids192
or intravenous
glucocorticoids193
; for example, proptosis was reduced
and motility was significantly improved (62% in com-
bination therapy versus 45% in intravenous glucocor-
ticoids alone) but did not add to the anti-inflammatory
effect (65% versus 64%193
). However, orbital irradiation
is not widely used, requires an expert radiotherapist
and has been associated with rare retinopathy. The cost
of these therapies must be clarified with the insurance
companies and payers.
Optic neuropathy has been reported in RCTs with
steroids and all of the immunosuppressants described
above and seems to be a reflection of disease progression
in the reported patients rather than a side effect of the
treatment regimen.
Graves’ dermopathy
The treatment of PTM remains difficult and unsat-
isfactory. The most common approach remains the
application of powerful corticosteroid creams such as
fluocinolone or mometasone under plastic wrapping
or direct injection of corticosteroids into the lesions194
.
Usually, these patients have very high TSHR autoanti-
body levels that do not often disappear after a thyroid-
ectomy but might decrease considerably. However, this
reduction in autoantibody levels rarely produces a clini-
cal response. Studies involving patients being treated with
systemic steroids, rituximab, mycophenolate mofetil and
other immunosuppressive agents have reported a marked
improvement, although the results are inconsistent.
Women of reproductive age
Management of GD in pregnancy is one of the complex
clinical challenges facing endocrinologists. Multiple
factors need to be considered simultaneously — the
health of the mother, the impact of hyperthyroidism on
a c
b
Fig. 12 | Graves’ dermopathy. Three phases of pretibial myxoedema are shown, from
early small nodule formation with inflammation (part a) to a typical firm non-pitting
plaque with a distinct edge on examination (part b), and progressing in rare cases to
almost a malignant fibrous explosion with gross deformity (part c).
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the developing fetus, the potential teratogenic effects of
thionamides, the danger of overtreatment causing fetal
hypothyroidism, fetal thyroid development that com-
mences at the end of the first trimester and the thyroid
status of the neonate at birth. In addition, TSHR auto
antibody titres decrease throughout pregnancy, becom-
ing non-detectable in the third trimester. The delicate
balance of these issues makes care of the pregnant
patient with GD both a science and an art.
Preconception. Optimal care of a woman with GD
in pregnancy should ideally begin in the preconcep-
tion period. The 2017 American Thyroid Association
GuidelinesfortheDiagnosisandManagementofThyroid
Disease During Pregnancy and the Postpartum195
recom-
mend that, prior to conception, thyroid function tests
be euthyroid for a minimum of two tests performed
1 month apart with no change in therapeutic interven-
tion. Hence, women should be counselled to postpone
pregnancy until a euthyroid state is achieved. Women
treated with thionamides should be given the lowest
possible dose necessary to achieve a euthyroid state.
Similarly, women undergoing thyroidectomy should
ensure a stable euthyroid state on levothyroxine ther-
apy prior to attempting conception. Women undergo-
ing radioiodine ablation should avoid pregnancy for at
least 6 months after treatment to allow the clearance of
radioiodine from the body and to provide sufficient time
to achieve a euthyroid state with levothyroxine196
. The
radioiodine-induced increase in TSHR autoantibody
titres can place the fetus at greater risk of fetal or neona-
tal thyrotoxicosis and is therefore generally discouraged
before conception. Finally, women in remission follow-
ing successful treatment with antithyroid drugs while not
pregnant have an 84% chance of recurrence of GD in the
postpartum compared with a 56% relapse rate in women
in remission who do not have a subsequent pregnancy197
.
Pregnancy. Mild hyperthyroidism does not usually
require treatment in early pregnancy. However, thio-
namides remain the treatment of choice in pregnant
women with moderate to severe GD. Radioiodine is
Wait and watch
Selenium
administration
Text
Active disease
Poor QOL
IV or oral GCs
Irradiation for diplopia
is used in some centres
Text
Rehabilitative surgery
Text
If stable and inactive disease
Insufficient improvement
after 6 weeks
Progression
Ineffective or
progression
Text
IV GCs within 2 weeks
Text
Rapid decompression
Mild Moderate Text
Sight threatening
• Restore euthyroidism
• Cease smoking
• Refer to ophthalmologist
• Local treatments (artificial tears, prisms and/or botulinum toxin)
GO
Development of
sight-threatening GO
Inactive disease
Immunosuppression
or biologics
• Teprotumumab
• Mycophenolate
• Azathioprine
• Rituximab
• Tocilizumab
Fig. 13 | Management of GO. Management of patients with Graves’ orbitopathy (GO) is based on the decision of whether
the patient has mild, moderate or severe, sight-threatening, disease. Usually, a wait and watch approach is sufficient in mild
stages. Moderate to severe, active GO stages require anti-inflammatory treatment. Glucocorticoids (GCs) remain as the
first-line treatment but, in cases where an insufficient treatment response is obtained after 6 weeks, second-line therapy,
such as an immunosuppressants or biologics, should be considered. Teprotumumab is likely to be a first-line therapy in the
near future owing to its excellent treatment effect and good side-effect profile. Sight-threatening GO requires immediate
high-doseintravenous(IV)steroids,andinnon-responders,rapidorbitaldecompressionmaybeindicated.QOL,qualityoflife.
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obviously contraindicated in pregnancy and surgery is
typically reserved for cases of severe reaction or resistance
to thionamides and, if required, surgery is recommended
only during the second trimester. The goal of thionamide
therapy, as defined by maternal thyroid function tests, has
evolved over time. Conventionally, the thionamide dose
was titrated to achieve a normal maternal TSH level and
a normal total or free thyroxine level. A large prospec-
tive observational trial showed that untreated subclinical
hyperthyroidism during pregnancy, defined as a low TSH
level (<2 μU/ml) with a normal free thyroxine level, has
no untoward impact on either the mother or the devel-
oping fetus198
. Additionally, over-treatment with thion-
amides was shown to result in fetal goitre and/or fetal
hypothyroidism199
. Accordingly, the goal of treatment is
now to achieve a maternal normal free thyroxine level at
or just above the upper limit of normal200
. Therapy should
not try to achieve a normal TSH level as this might result
in over-treatment of the fetus (Box 4).
Only in rare cases do significant levels of TSHR
autoantibodies persist throughout pregnancy. In such
women, the transfer of the autoantibody to the baby can
induce transient neonatal hyperthyroidism201
. The levels
of TSHR autoantibodies should therefore be monitored
until they become undetectable, usually after the first
trimester.
Quality of life
Quality of life might be severely affected by GD, in par-
ticular by GO. Health-related quality of life is defined
as a subjective and multidimensional construct of
health and wellbeing. The concepts of general health
and physical, psychological, and social functioning are
fundamental determinants of health-related quality of
life202
, which are markedly affected in patients with GD
and GO203–208
. Disfiguring proptosis and diplopia impair
patients’ quality of life both at home and at work.
Several studies have described the relevance of
physical and psychosocial factors for the quality of life
of patients with GD and GO206,209
. A total of 72% of
all patients described experiences of stress in their life
6 months prior to the outbreak of GD and GO, empha-
sizing the presence of extraordinary psychosocial strain
and the necessity of parallel psychological treatment.
The Medical Outcomes Study in patients with GD
and GO observed significant differences, especially in
vitality, social functioning, mental health, health per-
ceptions and body pain, compared with the control
group174
. Furthermore, 33% of patients with GO and
PTM reported diminished social contact owing to
the disease, 68% had occupational problems and 94%
reported psychological changes during the beginning of
illness210
. Almost 91% considered their quality of life as
bad prior to specific treatment and women were more
affected than men. In a controlled study encompassing
a large collective of patients with GD and GO206
, emo-
tional distress, diplopia, stressful events and depressive
coping had a major negative impact on the quality of
life. Hence, accompanying psychosomatic treatment is
indicated in ~50% of all patients with GO. Another study
that prospectively followed 250 patients with GD and
GO reported that 45% of patients complained of restric-
tions in their daily activities, 38% reported impaired
self-perception, 36% were on sick leave because of GO,
28% were disabled, 21% underwent psychotherapy,
5% retired early and 3% lost their jobs211
. Patients with
severe GO and motility disorders were on sick leave for
longer times and were more likely to be disabled. These
data indicate that patients with GD and GO experience
considerable emotional stress and occupational impair-
ment and point to the need for preventive care and rapid
rehabilitation. Finally, work impairment as well as direct
and indirect costs of GO significantly correlated with the
scores of the internationally standardized and specific
Graves’ Ophthalmopathy Quality of Life (GO-QOL)
questionnaire211
. Productivity loss and prolonged
therapy for GO incur great direct and indirect costs.
The 84-item thyroid-specific patient-reported out-
come measure, called ThyPRO, and the 16-item specific
GO-QOL instrument are the most extensively evaluated
instruments in patients with GD212–214
. Examples of the
domains in the quality of life questionnaires are the sub-
scales of visual functioning and appearance. ThyPRO,
GO-QOL and a less tested 11-item Thyroid Treatment
Satisfaction Questionnaire have reported a high num-
ber of positive ratings in such psychometric testing215–217
.
ThyPRO demonstrated strong evidence for internal
consistency, giving the test content, structural and
cross-cultural validity, but only 5 out of 9 measurements
produced reliable evaluations, reflecting a less than com-
prehensive assessment in GD218–220
. In comparison, the
GO-QOL has been well validated, widely used and is
available in eight languages211,221,222
. The GO-QOL has
been successfully tested in the routine assessment of GO
in daily clinical practice and as an independent primary
Box 4 | Thionamide use in pregnancy
Both propylthiouracil and methimazole are effective in the treatment of Graves’
hyperthyroidism in pregnancy, but both are associated with a small incidence of allergic
reactions, rashes and rare instances of agranulocytosis and liver dysfunction as well as
teratogenic effects.
First described in 1972, methimazole has been linked to a distinct scalp defect called
aplasia cutis congenita279
. Subsequently, a constellation of teratogenic birth defects
have been linked to methimazole, including choanal atresia, omphalomesenteric duct
anomalies, dysmorphic facies and trachea-oesophageal fistulas, collectively classified
as methimazole embryopathy280
.
In 2009, a joint conference between the American Thyroid Association and the FDA281
reported 22 cases of serious liver toxicities associated with propylthiouracil over 20
years, with five patients requiring transplantation and nine deaths. Accordingly,
propylthiouracil was recommended only as first-line therapy in the first trimester to
avoid methimazole embryopathy; if further intervention is needed, the patient should
be switched to methimazole282
. The report recommended that treatment with
radioiodine or surgery before conception should be considered for those who desire
a future pregnancy.
However, a 2014 review of 817,093 Danish births observed a significant increase in
birth defects in women treated with propylthiouracil283
. Although less severe than
methimazole-associated teratogenicity, most cases still required surgery. The largest
study to date, which reviewed 2,210,253 live births in Korea284
, reported a significant
increase in birth defects with both methimazole and propylthiouracil. Furthermore,
switching to methimazole after first-trimester use of propylthiouracil did not decrease
the incidence of birth defects.
Thus, the optimal treatment consists of switching to propylthiouracil upon a woman’s
intent to conceive, with propylthiouracil maintained throughout the first trimester.
Data are insufficient to conclude whether switching to methimazole in the second
trimester is worthwhile.
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outcome measure in several RCTs146,184,223–225
. Sixteen
questions pertaining to visual function and appearance
are included in the GO-QOL. The answers to these ques-
tions are transformed into scores and improvements in
scores are associated with clinically relevant changes
in daily functioning226,227
. Indeed, the quality of life scores
have been used to monitor treatment responses in
clinical randomized trials184
.
Outlook
Mechanistic questions
Despite >60 years having elapsed since the first descrip-
tions of autoimmunity in GD, the mechanisms at play are
not fully understood and, therefore, the aetiology of GD
remains to be elucidated. The combination hypothesis of
genetic and environmental factors remains weak for GD
as the genetic associations are relatively minor and the
contribution of environmental insults is unclear in many
patients. In the immediate future, examining the role of
the environment is likely to be more instructive until sig-
nificant advances in genetic technologies are achieved.
The importance of viral infection-induced epigenetic
changes of key gene response elements and the influence
of the microbiome in the pathogenesis of GD require
greater attention and further investigation. Progress has
beenslowintheseareasowingtothelackofaspontaneous
animal model of GD that truly replicates all disease fea-
tures. Current immunization models produce only weak
retro-orbital changes and the single spontaneous model
of breaking tolerance to TSHR has not been explored for
GO228
. A robust and spontaneous model would allow fur-
ther exploration of the disease mechanisms and serve for
the study of new therapeutic approaches.
Emerging drugs
The treatment of patients with GD has not changed sub-
stantially for many years, but great changes are on the
horizon.Avarietyofnewtreatmentsarecurrentlyinclini-
cal trials that will, hopefully, not have the same drawbacks
as the current approaches (Fig. 14). Indeed, the novel and
disease-specific treatments for thyroidal and extrathyroi-
dal GD aim to primarily target the main autoantigens of
the disease and/or molecules playing an important part
within the immunological response.
Future causally directed treatment of GD will most
likely involve monoclonal antibodies or small mole-
cules that block TSHR or block the stimulatory effect
of TSHR autoantibodies. In this respect, a human
anti-TSHR monoclonal antibody (K1-70) is being tested
in a phase I trial113,229
in patients with GD and GO. An
important concern is that this antibody has the potential
for non-traditional signalling unrelated to TSH action.
In addition, studies have reported TSHR-selective
small-molecule antagonists, although they require
much further development at this time230,231
. A small
controlled trial demonstrated that a combination of dif-
ferent TSHR peptides232
that can generate Treg cells and
suppress the immune response against TSHR in patients
with untreated GD generated a short-term response233
.
Furthermore, teprotumumab has now received FDA
approval in the USA.
Small uncontrolled studies of patients with GO using
two TNF blockers, etanercept234
and adalimumab235
,
reported no consistent benefit. By contrast, two RCTs
(n >300) have demonstrated beneficial effects for myco-
phenolate mofetil on orbital inflammation, diplopia,
eye muscle motility, proptosis and GO-QOL, with a
highly favourable risk to benefit ratio and reassuring
safety profile184,236,237
. Tocilizumab led to impressive
results on disease activity, disease severity and extra
ocular motility in patients with steroid-resistant disease
in an open-label study238
. However, a subsequent RCT
raised doubts about the reproducibility of these results189
.
Rituximab was evaluated in two RCTs that generated
conflicting results186,188
, which might be explained by
different TSHR autoantibody levels, shorter duration
of orbitopathy and different patient ages. Despite these
challenges, the high rate of drug-related adverse effects
B cell
T cell
BAFF
IGF1R
Fibroblast
Adipocyte
TSHR
Blocking TSHR antibody (K1-70)
SMANTAGs
Teprotumumab
Macrophage
CD154 CD40
CD20
Plasma cell
Mycophenolate mofetil?
Antigen
presentation
B cell activation
Iscalimab
Tocilizumab
Etanercept
Adalimumab
TNF
IL-6 and
IL-6R Cytokines
Rituximab Belimumab
TSHR
autoantibody
Fig. 14 | Emerging therapies for Graves’ Disease.SeveraldrugsarebeingassessedforthetreatmentofGraves’diseaseand
Graves’orbitopathythattargetmajorplayersintheaetiology,includingT cells,Bcells,fibroblastsandadipocytes.IGF1R,
insulin-likegrowthfactor1receptor;SMANTAGs,small-moleculeantagonists;TSHR,thyroid-stimulatinghormonereceptor.
Primer
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