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Smith 2016
Smith 2016
Review Article
Graves’ Disease
Terry J. Smith, M.D., and Laszlo Hegedüs, M.D., D.M.Sc.
G
From the Department of Ophthalmology raves’ disease was first recognized in the 19th century as a
and Visual Sciences, Kellogg Eye Center, syndrome comprising an enlarged and overactive thyroid gland, an accel-
and the Department of Internal Medicine,
University of Michigan Medical School — erated heart rate, and ocular abnormalities (Fig. 1). Critical for our current
both in Ann Arbor (T.J.S.); and the De- understanding of this disease was the discovery of its autoimmune basis, which
partments of Endocrinology and Metab- results from complex interactions between genetic and environmental factors.1,2
olism (L.H.) and Ophthalmology (T.J.S.),
Odense University Hospital, University Graves’ disease has adverse effects on quality of life,3 as a consequence of so-
of Southern Denmark, Odense. Address matic4 and psychiatric5 symptoms and an inability to work,6 and is associated with
reprint requests to Dr. Smith at the De- an increased risk of death.7 Activating thyrotropin-receptor antibodies induce thyroid
partment of Ophthalmology and Visual
Sciences, University of Michigan Medical hormone overproduction. Many characteristic signs and symptoms of Graves’ dis-
School, Brehm Tower, 1000 Wall St., Ann ease result from elevated thyroid hormone levels. Debate persists concerning the
Arbor, MI 48105, or at terrysmi@
med diagnosis of hyperthyroidism and adequate clinical care of affected patients.8,9
.umich.edu.
Thyroid-associated ophthalmopathy (Fig. 1B), the most common and serious ex-
N Engl J Med 2016;375:1552-65. trathyroidal manifestation, results from underlying autoimmunity, but insights
DOI: 10.1056/NEJMra1510030
Copyright © 2016 Massachusetts Medical Society. into its pathogenesis and care remain elusive.
Epidemiol o gy
Graves’ disease is the most common cause of hyperthyroidism, with an annual
incidence of 20 to 50 cases per 100,000 persons.10 The incidence peaks between 30
and 50 years of age, but people can be affected at any age. The lifetime risk is 3%
for women and 0.5% for men. Long-term variations in iodine intake do not influ-
ence the risk of disease, but rapid repletion can transiently increase the incidence.
The annual incidence of Graves’ disease–associated ophthalmopathy is 16 cases
per 100,000 women and 3 cases per 100,000 men. It is more common in whites
than in Asians.11 Severe ophthalmopathy is more likely to develop in older men
than in younger persons.12 Orbital imaging reveals subtle abnormalities in 70% of
patients with Graves’ disease.13 In specialized centers, clinically consequential
ophthalmopathy is detected in up to 50% of patients with Graves’ disease, and it
threatens sight as a consequence of corneal breakdown or optic neuropathy in 3 to
5% of such patients.14 Hyperthyroidism and ophthalmopathy typically occur within
1 year of each other but can be separated by decades. In 10% of persons with
ophthalmopathy, either thyroid levels remain normal or autoimmune hypothyroid-
ism develops.12,14
A B
C D
intolerance, tremor, and palpitations are the most 10% of patients who are 60 years of age or older.
common symptoms, occurring in more than 50% Palpable goiter develops in most patients with
of patients. Weight loss, decreased appetite, and hyperthyroidism who are younger than 60 years
cardiac manifestations are more common in elder- of age (Fig. 1A), as compared with less than 50%
ly persons with hyperthyroidism than in those of older patients.16 Diffuse thyroid enlargement is
who are younger. Atrial fibrillation due to hyper- most frequent, but many patients with Graves’
thyroidism is rare in patients who are younger disease who live in iodine-deficient regions have
than 60 years of age but occurs in more than coexisting nodular goiter.17
Interleukin-1β CD40
Interleukin-6 TNF-α
Dendritic cell
Interleukin-12 TGF-β
(antigen-presenting) Interleukin-16 Interferon-γ Altered cell
Interleukin-17 RANTES behavior
B cell
T-cell
receptor
Inflammation
Thyroid CD40
antigen
Thyroid-stimulating
CD40 antibodies
T cell
ligand
Infiltration of
lymphocytes, Overactive
dendritic cells, and Activation thyrotropin Other Hypertrophy
macrophages receptor and hyperplasia
pathways
IGF-1
receptor Increased cyclic
AMP-dependent
T cell signaling
T HY ROI D
Interferon-γ
MHC
T H YRO ID C O LLO ID
class II
E PIT H E LIA L C E LL
Infiltration of T-cell
receptor
the orbit
T cell MHC Differentiation
class II
B cell
Thyroid
antigen
Thyroid-stimulating Myofibroblast
antibodies
Fibrocyte Activation
Thyrotropin
CD40 ligand
receptor
IGF-1 receptor CD40
antibodies Differentiation
Interleukin-1β CD40
Interleukin-6 TNF-α IGF-1
OR B I T Interleukin-12 TGF-β receptor
Interleukin-16 Interferon-γ Adipocyte
Activation
Interleukin-17
Interleukin-1 RANTES Hyaluronan and other
glycosaminoglycans
Orbital fat
Resident CD34−
CD34 Down- Inflammatory molecules expansion
fibroblast regulation
Differentiation
Thyrotropin receptor
Thyroglobulin
Other thyroid antigens Orbital tissue volume
CD34+ expansion, proptosis, and
fibroblast optic nerve compression
thyroperoxidase. Thyroid epithelial cells release roid epithelial cells are not considered profes-
several chemokines and thus may participate in sional antigen-presenting cells, they have the
the recruitment of these and other immune potential to present thyroid antigens to T cells.
cells.33 In Graves’ disease, thyroid epithelial cells In addition, their CD40 expression35,36 suggests
also express MHC class II molecules, probably as a the potential for direct, productive interactions
consequence of infiltrating, lymphocyte-produced between thyroid epithelium and antigen-specific
interferon-γ action in situ.34 Thus, although thy- T cells in Graves’ disease. The aggregate of cur-
Normal thyrotropin Low thyrotropin and Low thyrotropin Normal or high serum
and free thyroxine high free thyroxine and normal thyrotropin and
free thyroxine high free thyroxine
Present Absent
as ophthalmopathy or dermopathy are absent first-line treatment in Europe9,52 and are increas-
and a diffuse goiter is not detected, radionuclide ingly favored over radioiodine in North America.9
scanning can confirm the diagnosis. These Ablative therapy resulting in hypothyroidism, ei-
scanning studies and radioiodine uptake mea- ther from radioactive iodine or surgical thyroidec-
surement can be used to distinguish Graves’ tomy, necessitates lifelong thyroid hormone re-
disease from other causes of thyrotoxicosis. placement. Thus, each treatment approach has
Routine measurement of thyrotropin-receptor advantages and drawbacks. The patient’s prefer-
antibodies is not mandatory, but when such as- ence, after receiving adequate counseling, remains
says are performed, they have 99% sensitivity and a critical factor in therapy decisions. According to
specificity for Graves’ disease.47 They are also a randomized study with 14 to 21 years of follow-
helpful in diagnosing Graves’ disease in patients up, quality of life was similar among the various
with concomitant nodular goiter.17 Assays that can treatment options, as was cost.53 Treatments for
routinely distinguish anti–thyrotropin-receptor Graves’ hyperthyroidism and ophthalmopathy
antibodies that stimulate thyroid hormone pro- have been reviewed in detail previously.14,54,55 The
duction from those that block thyroid hormone most salient information is summarized in Ta-
production are under development.48 bles 2 and 3.
synthesis; propylthio- propylthiouracil daily) rate, 40–50%56† in ≤5% of patients (rash, toxicity in ≤0.1%; cholestatic for
uracil also blocks con- and adjusted as euthy- urticaria, arthralgia, fever, the thionamides and hepatocel-
version of thyroxine to roidism is achieved or nausea, abnormalities of lular necrosis for propylthioura-
54
triiodothyronine combined with thyroxine taste and smell) cil; antineutrophil cytoplasmic
to prevent hypothyroid- antibody–associated vasculitis
ism (“block–replace” in ≤0.1% of patients57,58
regimen)
Radioactive iodine Irradiation causes thyroid Oral; activity either fixed Normally outpatient proce- Potential radiation hazards, Should not be used in patients with
(iodine-131) cell damage and cell (e.g., 15 mCi [555 MBq]) dure, definitive therapy, adherence to a country’s active thyroid ophthalmopathy;
death or calculated on the low cost, few side ef- particular radiation regula- contraindicated in women who
basis of goiter size fects, effectively reduces tions, radiation thyroiditis, are pregnant or breast-feeding
and uptake and turn- goiter size decreasing efficacy with and for 6 wk after breast-feeding
over investigations increasing goiter size, has stopped
n e w e ng l a n d j o u r na l
eventual hypothyroidism
in most patients
Thyroidectomy Most or all thyroid tissue Rapid euthyroidism, recur- Most expensive therapy, hypo- Does not influence course of Graves’
is removed surgically rence extremely rare,‡ thyroidism is the aim, risks ophthalmopathy; during preg-
no radiation hazard, associated with surgery nancy, is best performed during
Downloaded from nejm.org on October 2, 2017. For personal use only. No other uses without permission.
* COPD denotes chronic obstructive pulmonary disease.
† The following factors are associated with an increased risk of recurrence after antithyroid drug therapy: previous recurrence of Graves’ disease, cigarette smoking, ophthalmopathy, large
goiter, elevated ratio of serum free triiodothyronine to free thyroxine, high titers of serum anti–thyrotropin-receptor antibodies, and persistent need for high-dose antithyroid drugs after
12 to 18 months of treatment. In the absence of these risk factors, euthyroidism is generally sustained for at least 12 months after therapy has been withdrawn.
‡ The risks of hypothyroidism and persistent or recurrent hyperthyroidism are related to the volume of residual thyroid tissue.
Gr aves’ Disease
cyte colony-stimulating factor in patients with dose of an antithyroid drug should be used to
agranulocytosis.64 maintain thyroid function at the upper limit of
the normal range in order to avoid fetal hypo-
Radioactive Iodine thyroidism. Both propylthiouracil and methima-
Radioactive iodine therapy has been used widely zole are associated with birth defects.57 The use
in patients with Graves’ disease for seven de- of propylthiouracil in the first trimester and
cades.65 It offers relief from symptoms of hyper- methimazole during the remainder of pregnancy
thyroidism within weeks. Treatment with anti- is currently recommended on the basis of a con-
thyroid drugs may be suspended 3 to 7 days sideration of potentially severe birth defects.73
before and after radiotherapy in order to enhance Thyroid function should be monitored monthly.
its efficacy, although this interval remains con- In up to 50% of cases, antithyroid drugs may be
troversial.66 Many clinicians use fixed doses of discontinued after the first trimester, but post-
radioiodine, since calculation of activity is costly partum relapse is common.72 If elevated by a fac-
and fails to reduce rates of hypothyroidism or tor of more than 3, the level of anti–thyrotropin-
recurrent hyperthyroidism.65 Radioiodine is not receptor antibodies, beginning at a gestational
associated with an increased risk of cancer67 but age of 18 to 24 weeks, identifies pregnancies at
is known to provoke or worsen ophthalmopathy.14 risk for neonatal hyperthyroidism.72 Breast-feed-
Instead, increased morbidity and mortality as- ing is safe with either methimazole or propyl-
sociated with Graves’ disease appear to be related thiouracil, but methimazole is recommended for
to hyperthyroidism itself.4-7 Postablation thyroid postpartum therapy and does not affect infant
function should be monitored throughout life, thyroid function in the doses commonly used.74,75
and if hypothyroidism develops, it should be
treated immediately. Ophthalmopathy
Treatment for ophthalmopathy depends on the
Surgery phase and severity of the disease. The majority
Before patients undergo surgical thyroidectomy, of patients require only conservative measures
their thyroid hormone levels should be normal (Table 3). These include enhancement of tear-
to minimize the risk of complications or a poor film quality and maintenance of ocular surface
outcome, which is higher for total thyroidectomy moisture. Patients with disease that is severely
than for subtotal thyroidectomy. The risks of symptomatic and sight-threatening may benefit
hypothyroidism and recurrent hyperthyroidism from intravenously administered pulse glucocor-
are inversely related and depend on the volume ticoid therapy, which appears to have a more
of residual tissue.68,69 Treatment with inorganic favorable side-effect profile than glucocorticoids
iodide commencing 1 week before surgery may administered orally, although pulse therapy is not
decrease thyroid blood flow, vascularity, and without risks.60,61,76 Glucocorticoids are frequent-
blood loss but does not otherwise influence sur- ly effective in reducing inflammatory symptoms,
gical risk.70 Surgery may be an attractive option but most experts do not believe that they modify
for patients with large goiters, women wishing the course of the disease. External-beam irradia-
to become pregnant shortly after treatment, and tion of severely affected orbits is used in some
patients who want to avoid exposure to antithy- specialized centers but not others.77 The combi-
roid drugs or radioiodine. It is recommended that nation of glucocorticoids and radiotherapy may
women who have undergone surgery wait until provide a greater benefit than either treatment
the serum thyrotropin level stabilizes with levo- used alone.62 Orbital decompression surgery dur-
thyroxine therapy before attempting conception. ing active disease is usually reserved for patients
The course of ophthalmopathy appears to be in whom compressive optic neuropathy has devel-
unaffected by surgical thyroidectomy.8,20,71 oped or is imminent.78 Decompression surgery is
also indicated when the ocular surface is severely
Treatment during Pregnancy compromised. These situations constitute sur-
Graves’ disease affects approximately 0.1% of gical emergencies. Rituximab, a biologic agent
pregnancies and carries a substantial risk of ad- that depletes CD20+ B cells, has been evaluat-
verse effects in mother and child, especially if ed recently in two prospective, randomized pi-
it is inadequately treated.72 The lowest effective lot studies involving patients with active, severe
* B-cell depletion with the use of rituximab is currently considered an experimental treatment for ophthalmopathy; rituximab is not approved
by the Food and Drug Administration for this indication.
† Emergency orbital decompression is indicated for optic neuropathy or severe corneal exposure.
ophthalmopathy. One trial suggested efficacy,79 relative efficacies have not been performed.81
whereas the other did not.80 The decision about which approach should be
Therapy during the stable phase of moderate- used depends on the primary objective of the
to-severe ophthalmopathy usually involves reha- surgery and the skill of the surgeon.78 In patients
bilitative surgery aimed at reducing proptosis, with diplopia, surgical decompression is followed
restoring function, and enhancing appearance. by strabismus surgery to correct abnormalities
The procedures are usually performed in a set of eye motility.82 Cosmetic and functional con-
sequence, beginning with orbital decompression. cerns are addressed last, with facelifts, tissue
Multiple approaches to surgical decompression fillers, and eyelid repair.
have been perfected, but controlled studies of their Most assessments of therapy for Graves’ hyper-
thyroidism suggest that radioactive iodine abla- arthritis appears to be an attractive approach, but
tion increases the risk of new or worsening oph- controlled, prospective trials are necessary. Agents
thalmopathy.8 Glucocorticoids appear to mitigate blocking the thyrotropin and insulin-like growth
this risk.83 In contrast, most studies have failed factor receptors are under consideration.45,46 For
to detect differences in the effect on ophthal- example, a randomized, placebo-controlled clinical
mopathy between surgical thyroidectomy and trial of the efficacy and safety of teprotumumab,
medical therapy. an insulin-like growth factor 1 receptor–blocking
monoclonal antibody, in patients with active,
Dermopathy and Acropachy severe ophthalmopathy has recently been com-
Topical glucocorticoids can be used for symptom- pleted (ClinicalTrials.gov number, NCT01868997).
atic and extensive dermopathy but are usually in- Graves’ disease appears to be an ideal candidate
effective.21 The observation of a striking improve- for antigen-specific therapy, since the identity of
ment in dermopathy after rituximab infusion84 a dominant self-antigen is known. Restoring im-
suggests that B-cell depletion may benefit affect- mune tolerance to the thyrotropin receptor and
ed patients. However, this treatment is experi- other relevant autoantigens remains the ultimate
mental and has not been approved by the Food goal, sparing patients nonspecific immunosup-
and Drug Administration. No specific therapy is pression and toxic drugs.
available for acropachy. Dr. Smith reports holding patents related to the detection of
antibody-mediated inflammatory auto-immune disorders (US
6936426), the diagnosis and therapy of antibody-mediated
Future Therapies inflammatory autoimmune disorders (US 7998681 and US
As we gain a clearer understanding of Graves’ 8153121), and diagnostic methods related to Graves’ disease
disease, the potential for “smart drug” develop- and other autoimmune disorders (US 8178304). No other poten-
tial conflict of interest relevant to this article was reported.
ment increases. Repurposing agents that effec- Disclosure forms provided by the authors are available with
tively disrupt cytokine networks in rheumatoid the full text of this article at NEJM.org.
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