The n e w e ng l a n d j o u r na l of m e dic i n e

Review Article

Dan L. Longo, M.D., Editor

Graves’ Disease
Terry J. Smith, M.D., and Laszlo Hegedüs, M.D., D.M.Sc.​​

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
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

Cl inic a l Pr e sen tat ion
The manifestations of Graves’ disease depend on the age of the patient at the
onset of hyperthyroidism, as well as the severity and the duration of hyperthyroid-
ism.15 Symptoms and signs result from hyperthyroidism (goiter in some cases) or
are a consequence of underlying autoimmunity (Table 1). Weight loss, fatigue, heat

1552 n engl j med 375;16  October 20, 2016

The New England Journal of Medicine
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Copyright © 2016 Massachusetts Medical Society. All rights reserved.

. 2016 1553 The New England Journal of Medicine Downloaded from nejm. Panel B shows moderate- to-severe. and lid retraction.16 Diffuse thyroid enlargement is who are younger. decreased appetite. Atrial fibrillation due to hyper. 2017. occurring in more than 50% Palpable goiter develops in most patients with of patients. tremor. All rights reserved. intolerance. 1A).org October 20.16 nejm. Gr aves’ Disease A B C D Figure 1. No other uses without permission. and hyperthyroidism who are younger than 60 years cardiac manifestations are more common in elder. as compared with less than 50% ly persons with hyperthyroidism than in those of older patients.17 n engl j med 375. 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. of age (Fig. Panel C shows the plaque form of pretibial dermopathy. For personal use only. and palpitations are the most 10% of patients who are 60 years of age or older. scleral injection. Panel A shows a diffuse. Weight on May 6. Panel D shows acropachy with clubbing of the fingers. common symptoms. Clinical Manifestations of Graves’ Disease. Copyright © 2016 Massachusetts Medical Society. moderately enlarged goiter in a woman with Graves’ hyperthyroidism. thyroid-associated ophthalmopathy characterized by bilateral proptosis. periorbital edema.

double vision) creased sympathetic tone. ocular pain. including proptosis. atrial fibrillation for each of the following manifestations: eyelid Systolic hypertension. moist skin gether with an evaluation of the severity of Palmar erythema and onycholysis symptoms. and Weight loss pain with eye movement. muscle weakness manifestations become stable. . All rights reserved. 1B). For personal use only. and impaired eye movement — guides Hair loss treatment decisions.16 nejm. and ocular Dyspnea discomfort early in the active phase. and diplopia Weight loss (weight gain in 10% of patients) may prompt initial medical attention. 1C) occurs in 1 to 4% Extrathyroidal physical signs of patients with Graves’ disease and is nearly Ophthalmopathy always seen in those with severe ophthalmopa- Eyelid lag. leading candidates for these factors. Major Symptoms and Physical Signs in Graves’ opment is heralded by an active phase lasting up Disease. Genetic and epigenetic determinants are Orbital involvement represents a parallel conse. chemosis. pain. hyperreflexia indicates active disease. 6%. insomnia Graves’ disease.18 Disease devel. retraction.19 Loss of libido Mild eyelid retraction or lag may occur in Neck fullness thyrotoxicosis from any cause. A score of 3 or higher Fine tremor. Optic neuropathy Localized dermopathy Patho gene sis Acropachy Initiating Factors Unambiguous identification of the factors un- derlying Graves’ disease has not yet been accom- Thyroid-Associated Ophthalmopathy plished. conjunctiva injection. eyelid swelling. Copyright © 2016 Massachusetts Medical Society. Some pa- Palpitations tients have dry  October 20.22 Large- quence of the underlying autoimmunity occur. especially after Double vision (extraocular-muscle dysfunction) trauma to the skin.2. carun­ Cardiac failure cular swelling. chemosis. The activity of oph- Physical signs of hyperthyroidism thalmopathy can be graded by assigning 1 point Tachycardia. These include disfiguring and can threaten sight. scale genetic analyses have identified several ring within the thyroid. 30%. tor.g. Table 1 lists the Heat intolerance. extraocular muscle dysfunc- Thirst and polyuria tion. 43%. reduced visual Muscle weakness acuity. or both thy.1. Acropachy resembles club- Periorbital edema. as a result of in- Eye symptoms (swelling. 2017. and optic neuropathy.20 Diffuse. 62%. altered mood. the prevalence of distinct abnor- Nervousness. No other uses without permission. retrobulbar pain.. The n e w e ng l a n d j o u r na l of m e dic i n e Table 1. Pruritus exophthalmos. hyperkinesis. Pro- Symptoms ptosis (Fig. 23%. increased lacrima- Menstrual disturbances in women (oligomenorrhea or amenorrhea) tion. phatase nonreceptor type 22 (PTPN22).21 It most frequently localizes to the pretibial Proptosis (exophthalmos) region but can occur elsewhere. to 3 years and dominated by evolving symptoms and signs of inflammation and congestion. Ophthalmopathy can be genes conferring on May 6. increased pulse pressure erythema and edema. This is fol- Tremor lowed by an inactive phase in which the ocular Tiredness. mania Localized Dermopathy and Acropachy or depression) Thyroid dermopathy (Fig. The activity score — to- Warm. 92%. palpable goiter and thyroid bruit Mental-status and mood changes (e. thyrotropin recep- course typically follows a pattern originally de. increased tearing. In a Increased stool frequency cohort of consecutively assessed patients with Anxiety. HLA-DRβ-Arg74. increased sweating most common features of ophthalmopathy. fatigue. redness. the protein tyrosine phos- scribed by Rundle and Wilson. scleral injection bing of the fingers or toes and occurs only in Exposure keratitis patients with dermopathy 21 (Fig. 1D). cytotoxic 1554 n engl j med 375. 2016 The New England Journal of Medicine Downloaded from nejm. hyperactivity malities was as follows: eyelid retraction. Its clinical genes encoding thyroglobulin.

and n engl j med 375.26 type. The balance between stimulatory gene use by clonally expanded intrathyroidal and blocking antibodies determines the level of T cells is biased as compared with peripheral- thyroid function. CD40 on the B-cell surface interacting with antibodies directed at thyroglobulin and thyro. 2017. Gr aves’ Disease T-lymphocyte–associated antigen 4 (CTLA4). are necessary for the devel. Thymic education of The precise role (or roles) of thyroid epithelial immune cells leads to the deletion of autoreac. subset remains controversial. B cells ini- pathological role. These cells ex- show proliferative responses through antigen. such as Graves’ disease. those that disease is biased to the Th1 or Th2 functional block the thyrotropin receptor can result in hy.23 How these diverse factors interact to CD25+Foxp3+ phenotype). including those en. coding thyrotropin receptor and proteins involved T cells rely on second signals.. multimeric form of the alpha subunit in promot. which can attenuate confer a risk of disease remains uncertain. Th2.32 Both T cells and B cells. The balance Anti–Thyrotropin-Receptor Antibodies between proinflammatory factors and factors Activating autoantibodies of the IgG1 subclass that dampen immune reactivity determines the that are directed against the thyrotropin recep. Anti–thyrotropin-receptor anti.28 are presumed to be the principal source for these antibodies. press important organ-specific antigens. and emotional stress are frequently tions of type 1. type 2. They (discussed below). blood T cells. Activating antibodies mimic the T cells are particularly reactive to thyroid anti- actions of thyrotropin at its receptor through the gens and predominantly have the Th2 pheno- initiation of similar. The first of these signals is provided by antigen ing affinity maturation of these immunoglobu. For personal use only. These T cells mains incompletely understood. reflects the tral (thymic) and peripheral editing. the thyrotropin receptor have escaped both cen- primarily by intrathyroidal B cells. Thyroid Epithelial-Cell Involvement opment of Graves’ disease. tor are both specific for and central to Graves’ In Graves’ disease. (Th1.24 immune reactivity. Some T cells differentiate as dietary iodine. cells in the pathogenesis of Graves’ disease re- tive T cells from the lymphocyte pool. Receptors disease’s primary autoimmune reaction. tially produce IgM. All rights reserved. 2A). or type 17 helper T cells cited.16 nejm.29 Each phenotype produces a characteristic pattern of cytokines. and CD40. which can be class-switched ing the insulin-like growth factor 1 receptor to IgG or IgE. .org on May 6.30 Variable-region pothyroidism. 2016 1555 The New England Journal of Medicine Downloaded from nejm. receptors and major-histocompatibility-complex CD25. CD40 ligand on T cells. exposure to tobacco smoke. which promote antibody secretion arise from antigen spreading and have no known and T-cell support of class switching. or Th17). such specific interactions occurring between T-cell as the thyrotropin receptor. No other uses without permission.  October 20. regulatory T cells with the disease. signaling. Activating antibodies target. critical components of adaptive immunity.22 Environmental factors such they become anergic. without which in T-cell signaling. Intrathyroidal pituitary axis. amplitude and duration of immune responses. binding to the B-cell receptor and the second by lins. Therapy with alemtuzumab. Others develop into regula- ing monoclonal antibody. thyroglobulin. Copyright © 2016 Massachusetts Medical Society.27 Besides thyrotropin-receptor antibodies. the issue of whether Graves’ In addition to activating antibodies. Intrathyroidal B cells have re- have also been detected in patients with Graves’ duced mitogenic responses but spontaneously disease and may play a role in ophthalmopathy secrete anti–thyrotropin-receptor antibodies. These interactions result peroxidase are frequently detected in patients with in the production of critical cytokines.25 Their oligoclonal generation.31 bodies recognize epitopes on the alpha subunit. into effector-cell phenotypes that have the func- infections. autoreactive T cells against disease (Fig. can induce Graves’ tory T cells (e. These on these CD4+ helper T cells interact with MHC antibodies stimulate thyroid hormone produc. and B cells. such as dendritic cells.g. These antibodies most likely interleukin-4. but not identical. a CD52-target. B cells develop into antibody-producing plas- A recent study has shown the importance of the ma cells in a process requiring second signals. class II molecules through which thyrotropin- tion that is uncontrolled by the hypothalamic– receptor peptides are presented.1 Hypermethylation of several (MHC) molecules on antigen-presenting cells genes has been identified.29 However. although peripheral-blood B cells are T Cells and B Cells also a likely source.

All rights reserved.16 nejm. although thy. they have the the recruitment of these and other immune potential to present thyroid antigens to T October 20. 2016 The New England Journal of Medicine Downloaded from on May 6. The aggregate of cur- 1556 n engl j med 375. Thyroid epithelial cells release roid epithelial cells are not considered profes- several chemokines and thus may participate in sional antigen-presenting 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 B Theoretical Model of the Pathogenesis of Thyroid-Associated Ophthalmopathy 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. their CD40 expression35. Copyright © 2016 Massachusetts Medical Society. 2017.34 Thus. The n e w e ng l a n d j o u r na l of m e dic i n e A Theoretical Model of Intrathyroidal Graves’ Disease 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. probably as a the potential for direct. No other uses without permission. productive interactions consequence of infiltrating. proptosis. Overactive dendritic cells. lymphocyte-produced between thyroid epithelium and antigen-specific interferon-γ action in situ. For personal use only. thyroid epithelial cells In addition. and fibroblast optic nerve compression thyroperoxidase. .33 In Graves’ disease. T cells in Graves’ disease.36 suggests also express MHC class II molecules. Inflammatory molecules expansion fibroblast regulation Differentiation Thyrotropin receptor Thyroglobulin Other thyroid antigens Orbital tissue volume CD34+ expansion. cells.

39. CXCR4. In later stages of the dis- alter the behavior of thyroid epithelial cells. the immune pathogenesis of serum antibodies against this receptor can be ophthalmopathy and that of hyperthyroidism detected in some persons with the disease. Fibroblasts (TNF-α).38 These events are mediated by roid hormones by activating the thyrotropin receptor. and Extrathyroidal Manifestations B cells in Graves’ disease.37 Interactions between T cells and Panel A shows a theoretical model of the pathogenesis fibroblasts result in tissue activation and induc- of intrathyroidal Graves’ disease. T cells. 6. These cyto. It remains uncer- modulate the autoimmune on May 6. characterized. Copyright © 2016 Massachusetts Medical Society.40. Panel B shows a tain what provokes lymphocyte infiltration. which expand orbital tissue and cause propto. During controversial. ocular muscles expand from accumulating hy- terleukins 1β. thy suggests that they play a part in disease de- leading to the expression of inflammatory molecules velopment. The orbital process though the interpretation of this finding remains primarily targets fibroblasts (Fig. proteins previously thought to be restricted to globulins directed against the IGF-1 receptor can acti. infiltrating immune cells such as leukin-6. These include thyrotropin receptor. In addition. mopathy. 8. thyroid-stimulating immunoglobulins. Gr aves’ Disease Figure 2 (facing page).42 sis and optic-nerve compression. All rights reserved. several cytokines.12 factor α. and collagen 1 are ap- expressed and secreted).28.12.44 Furthermore. sue remodeling. the orbital Moreover. 6. and when duce cytokines. tumor necrosis aluronidase-digestible material and adipogenesis. The CD34+ which are monocyte-lineage progenitor cells with fibroblasts express low levels of thyrotropin receptor. Pathogenesis of Graves’ Disease variable-region gene use have been partially Affecting the Thyroid Gland and Orbit. Fibrocytes can differentiate into adipocytes or myofibroblasts and thus might rent information suggests that the epithelium contribute to the tissue remodeling in ophthal- plays a secondary. receptor in ophthalmopathy is suggested by its overexpression by orbital  October 20. CD40 ligand. in turn. Graves’ disease are heterogeneous. For personal use only. parently derived from circulating fibrocytes.12 B and T cells and CD34+ fibrocytes. The unique pres- thyroglobulin. esis of Graves’ disease after immune cells have Involvement of the insulin-like growth factor 1 infiltrated the thyroid gland. probably as a consequence of adipogene. including interleukin-1β. immuno. Cytokine-activated fibro- thyroglobulin. A functional and physical relation- active disease. and 12.41 kines. In addition. and 16. their phenotypes and ceptor and the thyrotropin receptor has been n engl j med 375. interferon-γ. 2016 1557 The New England Journal of Medicine Downloaded from nejm. depending on the molecular signals activated by cytokines. seems likely. the thyroid. orbital tissues are variably infil. Orbital fat and extra- B and T cells and antigen-presenting cells produce in. ciated ophthalmopathy. Thyroid-stimulating tion of genes involved in inflammation and tis- immunoglobulins provoke the overproduction of thy. These cyto. 2017. but theoretical model of the pathogenesis of thyroid-asso. and other thyroid antigens. CD34+ fibroblasts coinhabit the orbit with blasts. No other uses without permission. iodide symporter. and other cytokines.43. tumor necrosis factor α and several inflammatory mediators. This view is supported by the relatively low level which can further differentiate into myofibroblasts or of expression in orbital fat and orbital fibro- adipocytes. These include interleukins 1β. al- are presumed to be similar. thyroperoxidase. leading to cytokine and hyaluronan production. in turn. the expression of which is glycans. ship between the insulin-like growth factor 1 re- trated with lymphocytes. In Graves’ disease. to T cells. When activated by thyrotropin or sis. fibrocytes efficiently present antigens fat expands. they produce hyaluronan they encounter in the microenvironment. but fibers be- kines. fibrocytes release cytokines that have been implicated in Graves’ disease.41.16 nejm. and CD40 ligand. passive role in the pathogen. normal T-cell that display CD34. MHC denotes major histocompatibility complex. and the expression of intrathyroidal cytokines and thus resulting in restricted motility. activate orbital fibroblasts.40 Fibroblasts inhabiting the orbit in residential CD34− fibroblasts. driven by the autoimmune regulator protein. 2B). and TGF-β transforming growth factor β. The orbit becomes infiltrated by such as the thyrotropin receptor. Extraocular muscles remain intact. and sodium– blasts synthesize hyaluronan and other glycosamino. In addition. The bone marrow– derived fibrocytes differentiate into CD34+ fibroblasts. . Fibrocytes promiscuously express and glycosaminoglycan synthesis. vate signaling in orbital fibroblasts. inflammatory characteristics. RANTES (regulated on activation. inter- thus abrogating the normal regulatory role of thyro­ tropin. Thyroid- stimulating immunoglobulins activate the thyrotropin– ence of fibrocytes in the orbit in ophthalmopa- insulin-like growth factor 1 (IGF-1) receptor complex. and CD40 ligand. These cells can all pro. Antithyroid drugs can attenuate the production of thyroid hormones ease. activate and sustain inflammation and come widely separated. a shared antigen in the orbit and thyroid gland. extraocular muscles can become fibrotic.

Algorithm for Investigating the Clinical Suspicion of Graves’ Disease. 2017. Figure 3 shows a commonly used infiltrated with hyaluronan and are typically not diagnostic algorithm. 2016 The New England Journal of Medicine Downloaded from nejm. The n e w e ng l a n d j o u r na l of m e dic i n e Suspected Graves’ disease Measure serum thyrotropin and free thyroxine levels 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 Hyperthyroidism Measure free Thyrotropin-secreting Hyperthyroidism ruled out triiodothyronine pituitary tumor Thyroid hormone resistance Assay interference Measure thyrotropin- receptor antibodies High free Normal free triiodothyronine triiodothyronine Present Absent Graves’ Assess radioiodine Triiodothyronine Subclinical disease uptake. identified. Copyright © 2016 Massachusetts Medical Society. for most cases. At diagnosis. which is a sufficient tool inflammatory.16 nejm. . Patchy uptake Excess thyroid hormone Low or no uptake intake increased uptake or single nodule Nonthyroidal illness Graves’ Toxic nodular Subacute thyroiditis disease goiter Excess thyroid hormone intake HCG-secreting tumor Figure 3. obtain toxicosis hyperthyroidism radionuclide scan. or both Evolving Graves’ disease Evolving toxic nodular goiter Homogeneous. Graves’ Hyperthyroidism vation that has subsequently been confirmed.45 an obser. No other uses without permission. For personal use only. If pathognomonic features such 1558 n engl j med 375. The lesions are abnormalities. Some favor measurement of total thyroid hormone levels corrected for serum protein binding.46 The diagnosis of hyperthyroidism is based on Mechanisms involved in pretibial myxedema characteristic clinical features and biochemical are even less well understood. HCG denotes human chorionic gonadotropin. many favor measurement of both free thyroxine and free (or total) triiodothyronine  October 20.45 Interrupting the insulin-like growth Di agnosis factor 1 receptor attenuates signaling down- stream from the thyrotropin receptor. All rights on May 6. Not all experts rely on measurement of free thyroid hormone levels to determine the presence or absence of Graves’ disease.

placement. scintigraphy with radiolabeled octreo. ence. Patients may be switched from ation. quality of life was similar among the various with concomitant nodular goiter. radionuclide ingly favored over radioiodine in North America. supported by consensus opinion. before and during antithyroid drug therapy is immune hypothyroidism develops in 10 to 20% advocated by some experts but is not currently of patients during long-term follow-up. helps guide therapy. It remains uncertain whether remis- Ther a py sion results from immunomodulation by these Hyperthyroidism drugs. antithyroid drugs remain the domized study showed no benefit from granulo- n engl j med 375.54. side effects. Especially in cases of asymmetric roidal deiodination of thyroxine to triiodothyro- proptosis. Monitoring by medical therapy is reduced. oxidase and thus block thyroid hormone synthesis ing extraocular muscle enlargement from fat (Table 2). These Ablative therapy resulting in hypothyroidism.52 and are increas- and a diffuse goiter is not detected. withdrawn. ruling out orbital tumor and arterio. Thyroid-Associated Ophthalmopathy Antithyroid Drugs Computed tomography or magnetic resonance Methimazole. In un.47 They are also a randomized study with 14 to 21 years of follow- helpful in diagnosing Graves’ disease in patients up.52 Both meth­ which can usually be accomplished by clinical i­m­azole and propylthiouracil are associated with examination.53 Treatments for routinely distinguish anti–thyrotropin-receptor Graves’ hyperthyroidism and ophthalmopathy antibodies that stimulate thyroid hormone pro. since the management of Graves’ dis. gallium scanning.14.55 In our opinion. and propylthiouracil inhibit thyroid per- These imaging studies are useful in distinguish. Durable orbital disease.9 scanning can confirm the diagnosis.55 One ran- complicated cases. Propylthiouracil also blocks extrathy- expansion. have been reviewed in detail previously. but 30 to 50% of patients have a although data on patients with durable remission similar reaction to each drug. but when such as.49 Several other a high risk of recurrence after treatment has been imaging techniques.16 nejm. Spontaneous remission occurs in a small one drug to another when necessitated by minor proportion of patients with Graves’ disease. may be useful in more precisely defining the after 1 to 2 years of therapy (Table 2). of its favorable side-effect profile. Methimazole is preferred for initial ther- venous malformation is important. The recurrence rate is not further de- The discussion of treatment is limited to adult creased by providing treatment for more than 18 patients.9.48 bles 2 and 3. Re- peated therapy carries an even lower likelihood of success. are unavailable. they have 99% sensitivity and a critical factor in therapy decisions. Several variables appear to be asso- nography. months or by combining antithyroid drugs with ease in the young warrants separate consider. levothyroxine. All rights reserved. nine. necessitates lifelong thyroid hormone re- disease from other causes of thyrotoxicosis. remains says are performed.51 and the importance means of liver-function tests and white-cell counts of smoking cessation cannot be overstated.9. 2016 1559 The New England Journal of Medicine Downloaded from nejm. including orbital ultraso.17 Assays that can treatment options. States). Thus. ciated with durable disease remission. Gr aves’ Disease as ophthalmopathy or dermopathy are absent first-line treatment in Europe9.8. defined as tide. According to specificity for Graves’ disease.55 The duction from those that block thyroid hormone most salient information is summarized in Ta- production are under development. .org  October 20. The patient’s prefer- antibodies is not on May 6. after receiving adequate counseling. Assessment apy in both Europe and North America because of the activity and severity of ophthalmopathy. each treatment approach has Routine measurement of thyrotropin-receptor advantages and drawbacks. 2017. and thermal imaging. carbimazole (which is converted to imaging of the orbit is warranted when the cause methimazole and is not available in the United of ocular manifestations remains uncertain. Copyright © 2016 Massachusetts Medical Society. ther from radioactive iodine or surgical thyroidec- surement can be used to distinguish Graves’ tomy. ei- scanning studies and radioiodine uptake mea. Auto. biochemical euthyroidism for at least 12 months. as was cost. No other uses without permission. For personal use only.50 remission occurs in 40 to 50% of patients. the efficacy of further exposed to either drug. For patients who currently smoke patients with severe side effects should not be or formerly smoked tobacco.

‡ The risks of hypothyroidism and persistent or recurrent hyperthyroidism are related to the volume of residual thyroid tissue. elevated ratio of serum free triiodothyronine to free thyroxine. are pregnant or breast-feeding and uptake and turn. has stopped n e w e ng l a n d j o u r na l eventual hypothyroidism The New England Journal of Medicine of in most patients Thyroidectomy Most or all thyroid tissue Rapid euthyroidism. definitive therapy. intravenously in acute ­anxiety. block β-adrenergic re. radiation thyroiditis. arthralgia. propylthio. toxicity in ≤0.Potential radiation hazards. Given as either a single.* Treatment Mode of Action Route of Administration Advantages Disadvantages Special Considerations Beta-blockers Beta-blockers competitively Oral. during preg- no radiation hazard. No other uses without permission.3% of imazole. adherence to a country’s active thyroid ophthalmopathy. antibody–associated vasculitis ism (“block–replace” in ≤0. euthyroidism is generally sustained for at least 12 months after therapy has been withdrawn. the thionamides and hepatocel- version of thyroxine to roidism is achieved or nausea. high titers of serum anti–thyrotropin-receptor antibodies. of hypothyroidism. few side ef. and propylthiouracil high fixed dose (e. 40–50%56† in ≤5% of patients (rash.g. contraindicated in women who ­basis of goiter size fects. large goiter. hypo.. Main Treatment Options for Graves’ Hyperthyroidism. fever. effectively reduces tions. scarring). * COPD denotes chronic obstructive pulmonary disease.58 regimen) Radioactive iodine Irradiation causes thyroid Oral. carbimazole. may be administered Ameliorates sweating. or Raynaud’s thyronine phenomenon Antithyroid drugs (meth­ Methimazole. and tachy. frequent Major side effects in 0. 1560 Table 2. All rights reserved. ­results.Does not influence course of Graves’ is removed surgically rence extremely rare. associated with surgery nancy. cigarette smoking. major com- plications in 1–4% (hypo- parathyroidism. For personal use only. risks ophthalmopathy. COPD. low risk High recurrence rate. Does not influence course of Use cardioselective beta-blockers. rapid relief of complications in 1–2% of m e dic i n e pressure symptoms patients (bleeding. recur.blockers as alternative of thyroxine to triiodo.g. infec- tion. disease. † The following factors are associated with an increased risk of recurrence after antithyroid drug therapy: previous recurrence of Graves’ disease. abnormalities of lular necrosis for propylthioura- 54 triiodothyronine combined with thyroxine taste and smell) cil. remission is used. patients with asthma. 2016 ­definitive histologic and anesthesiology. activity either fixed Normally outpatient proce. particular radiation regula. . block-replacement therapy 3 mo of on May 6. carbimazole.1%.57 usually within first and propylthiouracil) block thyroid peroxidase 10–30 mg of methima. 15 mCi [555 MBq]) dure.‡ thyroidism is the aim. urticaria. minor side effects sis in <0. death or calculated on the low cost.2–0. and adjusted as euthy. and persistent need for high-dose antithyroid drugs after 12 to 18 months of treatment. is best performed during n engl j med 375. goiter size decreasing efficacy with and for 6 wk after breast-feeding over investigations ­increasing goiter size. arrhythmias. agranulocyto- and thyroid hormone zole or 200–600 mg of gical risk. cholestatic for uracil also blocks con. con. use cautiously in especially in patients with ceptors.56. hepato- The synthesis. no testing required unless patients. antineutrophil cytoplasmic to prevent hypothyroid. In the absence of these risk factors. tremulousness. Should not be used in patients with (iodine-131) cell damage and cell (e. 2017. propranolol cases palpitations. brady. recurrent laryngeal-nerve damage) Downloaded from nejm..1% of patients57. Most expensive therapy.2% of patients. minor the second trimester8 Copyright © 2016 Massachusetts Medical Society. use calcium-channel may block conversion cardia gestive heart failure. radiation hazard or sur. propylthiouracil daily)  October 20.16 nejm. Outpatient therapy. ophthalmopathy.

Both propylthiouracil and methima- Radioactive iodine therapy has been used widely zole are associated with birth defects. since calculation of activity is costly partum relapse is common.72 Breast-feed- Instead. These include enhancement of tear- to minimize the risk of complications or a poor film quality and maintenance of ocular surface outcome.61.62 Orbital decompression surgery dur- thyroxine therapy before attempting conception.77 The combi- roid drugs or radioiodine.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. 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. These situations constitute sur- Graves’ disease affects approximately 0. and tion of severely affected orbits is used in some patients who want to avoid exposure to is safe with either methimazole or propyl- sociated with Graves’ disease appear to be related thiouracil. Rituximab.used alone. identifies pregnancies at is known to provoke or worsen ophthalmopathy.64 maintain thyroid function at the upper limit of the normal range in order to avoid fetal hypo- Radioactive Iodine thyroidism. beginning at a gestational associated with an increased risk of cancer67 but age of 18 to 24 weeks. vascularity. which is higher for total thyroidectomy moisture.16 nejm.71 oped or is imminent. Copyright © 2016 Massachusetts Medical Society.1% of gical emergencies. Ophthalmopathy Treatment for ophthalmopathy depends on the Surgery phase and severity of the disease. Patients with disease that is severely than for subtotal thyroidectomy.70 Surgery may be an attractive option but most experts do not believe that they modify for patients with large currently recommended on the basis of a con- thyroid drugs may be suspended 3 to 7 days sideration of potentially severe birth defects. All rights reserved. severe n engl j med 375. 2016 1561 The New England Journal of Medicine Downloaded from nejm. No other uses without permission. antithyroid drugs may be troversial. increased morbidity and mortality as. 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. of patients require only conservative measures their thyroid hormone levels should be normal (Table 3).ly effective in reducing inflammatory symptoms. its efficacy.60. gical risk.76 Glucocorticoids are frequent- blood loss but does not otherwise influence sur.69 Treatment with inorganic favorable side-effect profile than glucocorticoids iodide commencing 1 week before surgery may administered orally. it should be treated immediately.4-7 Postablation thyroid postpartum therapy and does not affect infant function should be monitored throughout life. randomized pi- it is inadequately treated.20.14 risk for neonatal hyperthyroidism. women wishing the course of the disease. although this interval remains con.78 Decompression surgery is also indicated when the ocular surface is severely Treatment during Pregnancy compromised.72 The lowest effective lot studies involving patients with active.specialized centers but not others.57 The use in patients with Graves’ disease for seven de. and without risks. thyroid function in the doses commonly used.65 Radioiodine is not receptor antibodies.65 It offers relief from symptoms of hyper. Treatment with anti.73 before and after radiotherapy in order to enhance Thyroid function should be monitored monthly. which appears to have a more of residual on May 6. but methimazole is recommended for to hyperthyroidism itself. 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. External-beam irradia- to become pregnant shortly after treatment. .of propylthiouracil in the first trimester and cades. especially if ed recently in two prospective.66 Many clinicians use fixed doses of discontinued after the first trimester. but post- radioiodine.74. 2017. although pulse therapy is not decrease thyroid blood  October 20. has been evaluat- verse effects in mother and child.methimazole during the remainder of pregnancy thyroidism within weeks.that depletes CD20+ B cells.75 and if hypothyroidism develops. Gr aves’ Disease cyte colony-stimulating factor in patients with dose of an antithyroid drug should be used to agranulocytosis.In up to 50% of cases. a biologic agent pregnancies and carries a substantial risk of ad. For personal use only.68. The majority Before patients undergo surgical thyroidectomy.

used depends on the primary objective of the to-severe ophthalmopathy usually involves reha. Up to 100 mg of oral prednisone orbital congestion osteoporosis daily. beginning with orbital decompression.  October 20.82 Cosmetic and functional con- sequence. followed by tapering of the dose60 Intravenous Reduce inflammation and Rapid onset of anti-inflamma­ Methylprednisolone. reduces irritation Elevation of head during sleep Reduces orbital congestion Avoidance of eye cosmetics Reduces irritation Benefits not yet confirmed Selenium 59 Uncertain Benefits not yet confirmed Moderate or severe active disease Systemic glucocorticoids Oral Reduce inflammation and Hyperglycemia. hypertension. Therapy Mode of Action Pros and Cons Common Doses Mild active disease Topical solutions Artificial tears Maintain tear film Rapid action. No other uses without permission. with diplopia. 500 mg/wk orbital congestion tory effect. Postoperative diplopia.81 whereas the other did not. surgical decompression is followed restoring function. minimal side effects Avoidance of wind.79 relative efficacies have not been performed. fewer side effects for 6 wk followed by 250 mg/wk than oral delivery.16 nejm. For personal use only.62 damage on rare occasions Orbital irradiation Reduces inflammation Can induce retinopathy 2 Gy daily for 2 wk (20 Gy total)63 B-cell depletion* Reduces autoreactive B cells Very expensive. and enhancing appearance. Copyright © 2016 Massachusetts Medical Society. One trial suggested efficacy. tissue Multiple approaches to surgical decompression fillers. reduces lagophthalmos. ophthalmopathy. smoke Reduces ocular surface desic- cation. 2016 The New England Journal of Medicine Downloaded from nejm. pain Bony decompression of the lateral and Reduces proptosis by enlarg. 2017. cerebro- spinal fluid leak Strabismus repair Improves eye alignment. All rights reserved. dust. medial walls ing orbital space sinus bleeding.80 The decision about which approach should be Therapy during the stable phase of moderate. Two 1000-mg doses of intrave- tion. † Emergency orbital decompression is indicated for optic neuropathy or severe corneal exposure. liver for 6 wk61. but controlled studies of their Most assessments of therapy for Graves’ hyper- 1562 n engl j med 375. The n e w e ng l a n d j o u r na l of m e dic i n e Table 3. minimal side effects Glucocorticoids Reduce inflammation Rapid action. with facelifts. and improves function * B-cell depletion with the use of rituximab is currently considered an experimental treatment for ophthalmopathy. have been perfected. cancer. light. risks of infec. . by strabismus surgery to correct abnormalities The procedures are usually performed in a set of eye motility. surgery and the skill of the surgeon. rituximab is not approved by the Food and Drug Administration for this indication.78 In patients bilitative surgery aimed at reducing proptosis. Treatments for Thyroid-Associated Ophthalmopathy. cerns are addressed last. and eyelid repair. reduces diplopia Eyelid repair Improves on May 6. allergic re­ nous rituximab 2 wk apart action Emergency orbital decompression† Reduces orbital volume Stable disease (inactive) Orbital decompression (fat removal) Reduces orbital volume Postoperative diplopia.

Endocrinol (Oxf) 2001. 19. Repurposing agents that effec. J Clin Endocrinol Metab 2012. Perrild H. Lancet of two competitive binding assays. Restoring im- suggests that B-cell depletion may benefit affect. Limbach M. Cooper DS. 17. Gr aves’ Disease thyroidism suggest that radioactive iodine abla.​360:​994. atic and extensive dermopathy but are usually in. Graves’ ophthalmopathy in relation to and course of exophthalmos and ophthal- Hyperthyroidism and psychiatric morbid. and diagnostic methods related to Graves’ disease disease. prospective trials are necessary. Arch Intern Med 1988. (EUGOGO) on management of Graves’ Green A. For personal use only.​ in the management of Graves’ disease. register study. cigarette smoking and ethnic origin. income: a Danish register-based study in strate a high frequency of extraocular 20.21 The observation of a striking improve. J Clin Endocrinol Metab 2012. Thvilum M. 21. Clinical features of Graves’ oph- TH. a randomized. Zimmermann MB.​170:​ 12. Thvilum M. Psychosocial morbidity of Graves’ A 2011 survey of clinical practice patterns Ovesen L.​5:​177-94. ican Association of Clinical Endocrinolo. Almind D. Thyroid 2008. on May 6. orbitopathy. Am J work disability and loss of labour market without clinical ophthalmopathy demon. Graves’ disease appears to be an ideal candidate effective. Smith reports holding patents related to the detection of antibody-mediated inflammatory auto-immune disorders (US 6936426). Knudsen N. 148:​626-31. Hegedüs L. medical therapy.​95:​ J Clin Endocrinol Metab 2001. Hegedüs L.​55:​381-90. et al.​ ­European Group on Graves’ Orbitopathy 7. Cooper J. Izumi M. Consensus statement of the pairs. Kyvik KO. Bartalena L. Kadrmas 6. Clin of hyperthyroidism: a nationwide register. arthritis appears to be an attractive approach.​8(6):​e66711.​26:​553-65. mortality in hyperthyroidism: the influ. No other uses without permission. Thyroid dermopathy and ence of preexisting comorbidity and ge. et al. 18. Bartalena L. Dermopathy and Acropachy severe ophthalmopathy has recently been com- Topical glucocorticoids can be used for symptom. Rundle FF. reference to the effect of thyroidectomy. et al. J Clin Endocrinol Metab 1995.​36:​291-4. in patients with active. since the identity of ment in dermopathy after rituximab infusion84 a dominant self-antigen is known. Bahn RS. Evidence for a major role of rotoxicosis: management guidelines of the thyroidism present with a paucity of symp- heredity in Graves’ disease: a population. Almind D. J Clin Endocrinol Metab 2010. Brix TH. available for acropachy. . acropachy. N Engl J Med  October 20. other relevant autoantigens remains the ultimate mental and has not been approved by the Food goal. Brandt F.​362:​726-38. Cooper DS.​86:​930-4. Pedersen IB.46 For to detect differences in the effect on ophthal. Petrak F. toms and signs: a large cross-sectional based study of two Danish twin cohorts. Brandt F. Wilson CW. No specific therapy is pression and toxic drugs. Pitz S. example. 10. placebo-controlled clinical mopathy between surgical thyroidectomy and trial of the efficacy and safety of teprotumumab.​121:​284-90. 2715-26. Graves’ disease: influence of age on 22. Brix TH.​17:​456-520. Clin Sci 1945. Nordyke RA. Eur J Endocrinol 2014. Fatourechi V. controlled. Gilbert FI Jr. No other poten- tial conflict of interest relevant to this article was reported. Brandt F. Development 5. NCT01868997). thalmopathy. hyperthyroidism into Graves’ disease and 4.8 Glucocorticoids appear to mitigate blocking the thyrotropin and insulin-like growth this risk. Copyright © 2016 Massachusetts Medical Society. Boelaert K. 11. et al. Brix 13. Thvilum M. Burch HB. Saare M. body measurement for differentiation of 63:​395-402. Brandt F. 3. and other autoimmune disorders (US 8178304).​3:​286-95. 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). gists.​18:​333-46. number. 341-8. American Thyroid Association and Amer. Baldeschi L. Yokoyama N. 1001. pleted (ClinicalTrials. Older subjects with hyper- Hegedüs L. 9. Fatourechi V. Egle UT. Christensen K. 2017. et al. 2. N Engl J Med 2010. Tanda ML. Hyperthyroidism and other causes of thy. Tellez M. Franklyn JA. Annu Rev Pathol 2014. Tomer Y. EF. Holder RL. Clin Endocrinol (Oxf) 2005. Disclosure forms provided by the authors are available with tively disrupt cytokine networks in rheumatoid the full text of this article at NEJM. an insulin-like growth factor 1 receptor–blocking monoclonal antibody.​97:​4549-58. Kahaly GJ. this treatment is experi. Diabetes Endocrinol 2015. All rights reserved. Burman KD.​173:​595-602. study. based study. Untreated Graves’ disease patients thalmopathy in an incidence cohort. Bahn RS.45. Endocr Pract 2011. for antigen-specific therapy. resonance.​ clinical findings.​9:​147-56.​ thyroid diseases: from genetics to epi. Mechanisms of autoimmune singletons. Ophthalmol sparing patients nonspecific immunosup- and Drug Administration. Christensen K. Villadolid MC. most studies have failed factor receptors are under consideration. genetics.16 nejm. Bartley GB. Graves’ oph. n engl j med 375. 80:​2830-3. Harada Metab 2012. mune tolerance to the thyrotropin receptor and ed patients. Agents thalmopathy. Hardt J. Dr. PLoS One 2013. ment increases. 2016 1563 The New England Journal of Medicine Downloaded from nejm. Laurberg P. Boelaert K. Clin moplegia in Graves’ disease with special ity: evidence from a Danish nationwide Endocrinol (Oxf) 1992. 97:​4123-9. Hyperthyroidism is associated with et al. Eur J Endocrinol 2015. Iodine multinodular toxic goitre: a comparison Morbidity before and after the diagnosis deficiency and thyroid disorders. Burch HB. TSH-receptor anti- orbitopathy. the potential for “smart drug” develop. Excess 14. Torlinska B. et al. Graves’ ophthalmopathy. register-based cohort study of twins and ASM. Edmonds C. Best Pract Res Clin Endocrinol netic confounding: a Danish nationwide 15. However. Almind D. Dickinson singletons and disease-discordant twin muscle (EOM) enlargement by magnetic AJ.83 In contrast. References 1. but tion increases the risk of new or worsening oph. Tserel L.

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tion in wholly breast-feeding infants Mourits MP. Garrity JA. Smith TJ.16 nejm. et al. Salvi M. ophthalmopathy and acute liver damage: on anti-TSH receptor antibodies and clin- Chatterjee K. Uddin J. Thyroid function and intel. rituximab in patients with active moder- spective. At the discretion of the editor. Surgery 2014. crinol 2013.​ tolerability of intravenous or oral gluco. 82. Mikropoulos does not improve recovery from antithy. Azizi F. Tanda ML. Hommel Pract Res Clin Endocrinol Metab 2012. Walter MA. 70. ence of Graves’ ophthalmopathy. Yamashita R. 80. guideline. et al. Kahaly GJ. Rettori M. Clin Endocrinol (Oxf) 2000.​9:​29-31. 78.​ a systematic review and literature search. 79. Feroci F. Bahrainian M. thalmopathy. safety of orbital radiotherapy for Graves’ Copyright © 2016 Massachusetts Medical Society. Ran- single blind trial. compression for the treatment of com- 62. trials. Menconi F. the electronic version. Hegedüs L. Thyroid 1999. Ophthal Plast Reconstr Surg 2011. 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