Graves Disease NEJM 2008

clinical practice
The new engl and j ournal o f medicine

n engl j med 358;24 www.nejm.org june 12, 2008
2594
Graves Disease
Gregory A. Brent, M.D.
From the Veterans Affairs Greater Los
Angeles Healthcare System, and the De-
partments of Medicine and Physiology,
David Geffen School of Medicine at UCLA
both in Los Angeles. Address reprint
requests to Dr. Brent at the Endocrinolo-
gy and Diabetes Division, 111D, Veterans
Affairs Greater Los Angeles Healthcare
System, 11301 Wilshire Blvd., Los Ange-
les, CA 90073, or at gbrent@ucla.edu.
N Engl J Med 2008;358:2594-605.
Copyright 2008 Massachusetts Medical Society.
A 23-year-old woman presents with palpitations. Over the past 6 months, she has
reported loose stools, a 10-lb (4.5-kg) weight loss despite a good appetite and food
intake, and increased irritability. She appears to be anxious and has a pulse of 119
beats per minute and a blood pressure of 137/80 mm Hg. Her thyroid gland is dif-
fusely and symmetrically enlarged to twice the normal size, and it is firm and non-
tender; a thyroid bruit is audible. She has an eyelid lag, but no proptosis or perior-
bital edema. The serum thyrotropin level is 0.02 U per milliliter (normal range,
0.35 to 4.50) and the level of free thyroxine is 4.10 ng per deciliter (normal range,
0.89 to 1.76). How should she be further evaluated and treated?
The Clinical Problem
Graves disease affects approximately 0.5% of the population and is the underlying
cause of 50 to 80% of cases of hyperthyroidism.
1,2
The hyperthyroidism of Graves
disease is the result of circulating IgG antibodies that bind to and activate the
G-proteincoupled thyrotropin receptor.
1
This activation stimulates follicular hyper-
trophy and hyperplasia, causing thyroid enlargement, as well as increases in thy-
roid hormone production and the fraction of triiodothyronine (T
3
) relative to thy-
roxine (T
4
) in thyroid secretion (from approximately 20% to as high as 30%).
3

Thyroid-function testing in Graves disease typically reveals a suppressed serum
thyrotropin level and elevated levels of serum T
4
and T
3
. A suppressed serum thyro-
tropin level with normal serum levels of T
4
and T
3
is referred to as subclinical hy-
perthyroidism.
4
Graves ophthalmopathy is clinically apparent in approximately 30
to 50% of patients with Graves disease, but it is detected in more than 80% of
patients who undergo assessment by means of orbital imaging.
1,5
Manifestations of
ophthalmopathy, which vary in severity and have a course that is typically indepen-
dent of the thyroid disease, can include proptosis, periorbital edema and inflam-
mation, exposure keratitis, photophobia, extraocular muscle infiltration, and eyelid
lag (which can also occur with augmented adrenergic stimulation).
1,5
The female-to-male ratio among patients with Graves disease is between 5:1 and
10:1. The peak incidence is between 40 and 60 years of age, although the disease
can occur at any age.
1
The concordance rate for Graves disease among monozy-
gotic twins is 35%.
6
Triggers of Graves disease in persons with genetic suscepti-
bility to the disease include stressful life events, infection, and recent childbirth.
2

Several associated genetic loci have been identified, conferring susceptibility to
Graves disease alone or to both Hashimotos thyroiditis and Graves disease.
7
A
family history of thyroid disease, especially in maternal relatives, is associated with
an increased incidence of Graves disease and a younger age at onset.
8
This review focuses on the management of Graves disease in adults. Most pa-
tients with Graves disease are initially evaluated by and receive the diagnosis from
This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the authors clinical recommendations.
The New England Journal of Medicine
Downloaded from nejm.org at NEW YORK METHODIST HOSP on August 11, 2011. For personal use only. No other uses without permission.
Copyright 2008 Massachusetts Medical Society. All rights reserved.
clinical practice
2595
primary care practitioners, but in my opinion,
when possible they should be referred to or cared
for with input from an endocrinologist.
Strategies and Evidence
Evaluation
Clinical Manifestations
Overt hyperthyroidism due to Graves disease is
characterized by a variety of signs and symptoms
(Table 1).
1,9,11
Symptoms include weight loss, heat
intolerance, difficulty sleeping, tremor, increased
frequency of defecation, proximal-muscle weak-
ness, irritability, and menstrual irregularity. Signs
include tachycardia, stare, eyelid lag, proptosis,
goiter, resting tremor, hyperreflexia, and warm,
moist, and smooth skin. Rare findings (in <1% of
patients) include localized dermopathy (i.e., pre-
tibial myxedema) and thyroid acropachy (i.e., club-
bing).
12
Men with Graves disease may have gyne-
comastia, reduced libido, and erectile dysfunction.
13

Women often have irregular menses. Weight loss
(loss of both fat and lean body mass) is common,
despite increased appetite and food intake.
14

Graves disease is associated with a decreased
quality of life
15
because of both the metabolic
effects of elevated levels of thyroid hormone and
thyrotropin-receptor antibodies (e.g., disturbed
sleep and emotional lability) and the cosmetic
effects
16
(e.g., goiter and ophthalmopathy).
As compared with younger patients, older pa-
tients are less likely to have tachycardia and
tremor, and they present more often with weight
loss or depression (referred to as apathetic hyper-
thyroidism).
2,17
Cardiovascular manifestations, es-
pecially atrial fibrillation, are common presenting
symptoms in patients over 50 years of age.
11,18
Laboratory Studies
The primary diagnostic considerations in a pa-
tient with a suppressed thyrotropin level and clin-
ical hyperthyroidism are shown in Table 2.
2
Se-
rum T
4
and T
3
levels vary among these conditions
(Tables 2 and 3). Tests for Graves diseaseasso-
ciated antibodies are useful in the evaluation of
some conditions, but they are not usually re-
quired for diagnosis or to monitor disease activ-
ity (Tables 2 and 3).
19
Table 1. Manifestations of Graves Disease.*
System Clinical Finding or Manifestation Marker of Direct or Indirect Thyroid Hormone Action
Pituitary Suppressed thyrotropin Reduced expression of thyrotropin subunit and common
subunit
Cardiac Increased heart rate and contractility Increased expression of HCN2, voltage-gated potassium
channel (Kv1.5, Kv4.2, Kv4.3), and SERCA; increased
-MHC and decreased -MHC expression; increased
serum atrial natriuretic peptide
Hepatic Increased peripheral T
3
production; reduced
total and LDL cholesterol, lipoprotein(a)
Increased type 1 5-deiodinase, LDL and VLDL receptor,
lipase, SREBP-2, CYP7A, and CETP
Skeletal Increased bone turnover, osteopenia,
osteoporosis, and fractures
Increased osteocalcin, alkaline phosphatase, and urinary
N-telopeptide
Reproductive
Male Erectile dysfunction, reduced libido Increased sex hormone globulin, reduced free testosterone
Female Irregular menses Antagonism of estrogen action; impaired gonadotropin
regulation
Metabolic Increased thermogenesis and oxygen
consumption
Increased fatty acid oxidation and sodiumpotassium
ATPase
White fat Reduced fat mass Augmented adrenergic-mediated lipolysis
Muscle Proximal-muscle weakness, easy fatigability Increased SERCA activity and serum creatine kinase
Thyroid Increased thyroid secretion of T
3
and T
4
Increased type 1 and type 2 5-deiodinase activity in thyroid
* Data are from Motomura and Brent,
9
Brenta et al.
10
and Klein and Ojamaa.
11
CETP denotes cholesterol ester transfer
protein, CYP7A cholesterol 7 -hydroxylase, HCN2 hyperpolarization-activated cyclic nucleotide-gated cation channel 2,
LDL low-density lipoprotein, MHC myosin heavy chain, SERCA sarcoplasmic reticulum calcium-activated ATPase, SREBP-
2 sterol regulatory elementbinding protein 2, T
3
triiodothyronine, T
4
thyroxine, and VLDL very-low-density lipoprotein.
2596
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clinical practice
2597
Imaging Studies
A scan obtained 24 hours after the administration
of radioiodine provides a measure of iodine up-
take as well as an image of functioning thyroid
tissue (Fig. 1). A radioiodine-uptake study should
be performed in patients in whom painless thy-
roiditis is considered to be a diagnostic possibil-
ity and in patients with an irregular or nodular
thyroid gland (Table 3).
20
Increased blood flow
detected by means of Doppler ultrasonography
indicates Graves disease, and low blood flow is
characteristic of thyroiditis, although there is over-
lap between these two conditions, and the find-
ings are likely to depend on the instrument and
operator (Fig. 2).
21
Nonfunctioning nodules should
be evaluated for the presence of thyroid cancer,
usually by means of an ultrasound examination
of the thyroid and fine-needle aspiration for cy-
tology.
20
Some studies have shown that papillary
thyroid cancer within a Graves gland is more ag-
gressive than it is in patients without Graves dis-
ease,
22
although this is controversial.
Tests for Ophthalmopathy
A detailed discussion of ophthalmopathy is be-
yond the scope of this article, but it has been re-
viewed previously.
5,23,24
The measurement of eye
prominence by means of an exophthalmometer
in the clinicians office can be used to track
changes over time. Formal visual-field testing, as
well as orbital imaging, is needed in some pa-
tients (Table 3).
24
Patients with clinically signifi-
cant symptoms or findings should be referred to
an ophthalmologist.
23
Other Diagnostic Studies
In a patient with an irregular heart rhythm, an
electrocardiogram should be obtained to deter-
mine whether atrial fibrillation is present.
11
Post-
menopausal women and other patients at risk for
bone loss who have active or previously treated
Graves disease should have a bone-density test.
Large goiters can be associated with airway or
esophageal obstruction, causing shortness of
breath or difficulty swallowing, and computed
tomography of the neck (without the use of con-
trast material) or magnetic resonance imaging of
the neck may be required.
THERAPY
The treatment options for Graves disease include
antithyroid drugs, radioiodine, and surgery.
1,2
A
randomized trial comparing these treatments
showed that all were similarly effective as initial
treatment, although the relapse rate was highest
among patients who received antithyroid drugs
(approximately 40%) as compared with patients
who received radioiodine (21%) and those who
underwent surgery (5%).
25
Pharmacologic Therapy
Antithyroid drugs, specifically thionamides (ei-
ther propylthiouracil or methimazole), are com-
monly used as initial therapy (Table 4) and pri-
marily interfere with thyroid hormone synthesis.
26

The use of antithyroid drugs as initial treatment
varies according to geographic location; they are
used in the majority of patients in Europe and
Asia, but radioiodine is used more often than
medications in the United States.
27,28
The superi-
ority of either propylthiouracil or methimazole is
not clearly established; however, methimazole has
a longer intrathyroidal half-life, often allowing
for once-daily dosing (as compared with propyl-
thiouracil, which is administered three times
daily), and some studies have shown that it has
greater efficacy and fewer side effects.
26,29
Patients who receive either drug should be
cautioned regarding the potential side effects of
rash, joint pain, liver inflammation, and agranulo-
cytosis
26
; agranulocytosis occurs in approximate-
ly 0.1 to 0.3% of patients treated with either of
these drugs. Patients should be advised to dis-
continue antithyroid drugs if any potential signs
of agranulocytosis develop; these signs include a
fever, sore throat, or mouth ulcers. If these signs
occur, a white-cell count should be obtained im-
mediately. Prospective monitoring of the white-
cell count on follow-up visits is not recommend-
ed, since the onset of agranulocytosis is typically
acute and not detected by periodic surveillance.
Agranulocytosis is slightly more likely in older
patients and with larger doses of antithyroid
drugs, and it can occur at any time in the course
of therapy.
26
Elevations in aminotransferase levels
may be due to the direct effects of thyroid hor-
mone on the liver as well as to antithyroid
drugs.
30
The treatment of Graves disease often
results in weight gain as the increased metabolic
rate that is characteristic of Graves disease nor-
malizes; the average weight gain reported in
several studies is approximately 10 lb (4.5 kg).
14
Marked improvement in most symptoms gen-
erally occurs within 3 to 4 weeks after the initia-
tion of antithyroid medication.
26
A short course
2598
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clinical practice
2599
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2600
of therapy with a beta-adrenergic blocker may be
used in the interim, since it provides rapid relief
of such symptoms as tremor, palpitations, and
sweating. The dose of the antithyroid drug
should be adjusted to normalize the serum levels
of T
4
and T
3
and eventually to maintain the se-
rum level of thyrotropin in the normal range.
Among patients with Graves disease who are
treated with antithyroid drugs, the average rate
of remission (defined as a serum level of thyro-
tropin in the normal range when the patient is
not receiving medication) is 30 to 50%, but re-
lapse occurs in more than 50% of patients.
26

Remission is less likely in men, older patients
(over 40 years of age), and patients with more ac-
tive disease (e.g., a large thyroid gland, higher
serum T
4
and T
3
concentrations, and elevated
levels of thyrotropin-receptor antibodies).
31
A
longer duration of antithyroid drug therapy (1 year
or more vs. 6 months) has been reported to im-
prove remission rates, although a randomized
trial showed no significant improvement in re-
mission rates 2 years after discontinuation of
therapy when treatment was continued well be-
yond 18 months as compared with discontinua-
tion at 18 months.
32
Adjuvant treatment with T
4

(the so-called block-replace regimen) may improve
remission rates as compared with the use of
antithyroid drugs alone, but many trials
33
have
shown no benefit, and this regimen is not cur-
rently recommended.
Radioiodine Therapy
Radioiodine therapy may be used either as initial
therapy or after treatment with medication.
34,35

Antithyroid drugs, when used, are generally dis-
continued for 3 to 7 days before radioiodine ther-
apy, since the effectiveness of radioiodine may be
diminished when antithyroid drugs are given
concurrently.
36
A recent randomized trial showed
that withdrawal of an antithyroid drug 3 days
before treatment with radioiodine does not di-
minish the effectiveness of radioiodine, as com-
pared with no antithyroid drug treatment, or re-
sult in exacerbation of symptoms, as compared
with continuous antithyroid drug treatment.
37

Before the initiation of radioiodine therapy, a
24-hour radioiodine-uptake study is usually per-
formed. When the diagnosis of Graves disease is
in question, the finding of diffuse radioiodine up-
take throughout the thyroid is confirmatory. The
percentage of uptake (either alone or in combina-
tion with the gland size) is also often used to cal-
culate the dose of radioiodine,
38
although some
clinicians deliver a fixed dose of radioiodine with-
out measuring uptake.
39
The goal of radioiodine
therapy is induced hypothyroidism in order to
prevent a recurrence of Graves disease. This goal
is achieved in approximately 80% of patients,
39

regardless of the approach to dosing, although
calculated dosing may have an efficacy similar
to that of fixed dosing but with less radiation
exposure.
16p6
AUTHOR:
FIGURE:
JOB:
4-C
H/T
RETAKE
SIZE
ICM
CASE
EMail
Line
H/T
Combo
Revised
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
Please check carefully.
REG F
Enon
1st
2nd
3rd
Brent
1 of 2
06-12-08
ARTIST: ts
35824 ISSUE:
B
A
Figure 1. Radioiodine Scans of the Thyroid.
Images were obtained 24 hours after ingestion of io-
dine-123 by a patient with a normal thyroid (Panel A)
and a patient with Graves disease (Panel B). The thy-
roid of the patient with Graves disease is larger and
concentrates a higher fraction of radioiodine. (Images
courtesy of Dr. Jerome Hershman, David Geffen
School of Medicine at UCLA, Los Angeles.)
clinical practice
2601
All women of reproductive age should have a
pregnancy test immediately before treatment. Un-
incorporated radioiodine is excreted in the urine,
exposing the pelvic contents to radiation, and it
crosses the placenta, where it can be taken up by
the fetal thyroid gland late in the first trimester
of pregnancy or thereafter. Although the half-life
of iodine-131 is only about 1 week, it is generally
recommended that women not attempt conception
for 6 to 12 months after radioiodine treatment.
Acute side effects of radioactive iodine include
a form of radiation thyroiditis that causes neck
tenderness and in some cases a transient increase
in thyroid hormone levels.
34,35
Although longitu-
dinal studies have reported increased risks of
cardiovascular disease and some cancers in pa-
tients who have received radioiodine for hyper-
thyroidism due to toxic multinodular goiter,
40,41

these risks have not been reported in patients
with Graves disease,
41
and they are thought like-
ly to be attributable to hyperthyroidism rather
than to the radioiodine treatment. Several studies
have shown an association between radioiodine
and worsening of Graves ophthalmopathy,
42
al-
though this association has not been shown in
patients with mild ophthalmopathy.
43
In a ran-
domized trial, prednisone therapy for 3 months
after radioiodine treatment reduced the number
of patients who had worsening of ophthalmopa-
thy.
42
A transient reduction in the testosterone
level has been reported in men after radioiodine
treatment, but no effects on sperm concentration
or permanent effects on testicular function have
been shown.
44
Surgery
Surgical thyroidectomy is the treatment that is
least often used, but it can be effective in selected
33p9
C
A
D
B
AUTHOR:
FIGURE:
JOB:
4-C
H/T
RETAKE
SIZE
ICM
CASE
EMail
Line
H/T
Combo
Revised
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
Please check carefully.
REG F
Enon
1st
2nd
3rd
Brent
2 of 2
06-12-08
ARTIST: ts
35824 ISSUE:
Figure 2. Ultrasonographic and Doppler Flow Images of the Thyroid.
Longitudinal ultrasonographic views of the left lobe of the thyroid are shown for a normal thyroid (Panel A) and the
thyroid of a patient with Graves disease (Panel B). Doppler flow is shown for the same images with a normal thy-
roid (Panel C) and the thyroid of a patient with Graves disease (Panel D). Increased blood flow (red) is seen in the
thyroid gland of the patient with Graves disease as compared with the normal thyroid. (Images courtesy of Drs.
Hisashi Ota and Shuji Fukata, Kuma Hospital, Kobe, Japan.)
2602
clinical practice
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.
clinical practice
2603
clinical situations,
45
such as in patients with com-
plications of antithyroid drugs, pregnant women
requiring high doses of antithyroid drugs, patients
who decline treatment with radioiodine or who
have large goiters or suspicious nodules, and pa-
tients wanting rapid and definitive treatment.
Preoperative treatment with supersaturated potas-
sium iodide, Lugols iodine solution, or ipodate
(Oragrafin), an iodinated radiographic contrast
agent, for approximately 1 week is recommended,
since these agents decrease the production and
release of thyroid hormone and reduce thyroid
vascularity.
46,47
Treatment for Ophthalmopathy
A discussion of treatments for ophthalmopathy is
beyond the scope of this article, but they include
systemic and intraocular glucocorticoid agents,
antiinflammatory and immunosuppressive agents,
radiation, and a range of corrective surgical pro-
cedures.
23
Graves Disease and Pregnancy
Both propylthiouracil and methimazole cross the
placenta and can affect fetal thyroid function, es-
pecially at higher doses.
48,49
In the United States,
propylthiouracil is the recommended antithyroid
drug during pregnancy,
48,49
since in rare cases,
methimazole has been associated with aplasia
cutis and gastrointestinal defects in the fetus.
Monitoring by means of ultrasonography is use-
ful to assess fetal development and check for the
presence of a fetal goiter, which indicates either
excessive antithyroid drug treatment in the moth-
er or fetal Graves disease.
50
In women with
Graves disease who do not wish to become preg-
nant immediately, definitive treatment with radio-
iodine or surgery should be offered in order to
minimize the potential need for antithyroid
drugs during pregnancy. Most women with Graves
disease, however, can be treated medically dur-
ing pregnancy, with a target T
4
level at or slightly
higher than the upper limit of the reference range
to ensure normal thyroid hormone levels in the
fetus.
48
Maternal complications of Graves disease
in pregnancy include preeclampsia and preterm
delivery. Graves disease generally improves in the
second and third trimesters of pregnancy, allow-
ing reduction or discontinuation of antithyroid
drug therapy, although the disease can flare dur-
ing the postpartum period.
48
Areas of Uncertainty
Further study of genetic factors associated with
susceptibility to Graves disease and of factors
that trigger the disease is needed.
7
The pathogen-
esis of Graves orbitopathy and dermopathy also
warrants further study.
5,12
The choice of treat-
ment with antithyroid drugs versus radioiodine
remains controversial, with varying practices in
different areas of the world. The appropriate dura-
tion of treatment with antithyroid drugs in order
to induce remission, the mechanism of remis-
sion, and the timing of drug treatment before and
after radioiodine treatment are not established.
51

The optimal therapeutic targets in women with
Graves disease during pregnancy are uncertain,
since both low and high serum levels of T
4
in the
mother are associated with risks to the fetus.
48,52

In animal models, thyroid hormonereceptor
antagonists rapidly block the action of thyroid
hormone,
10
but these agents are not available for
clinical use.
Guidelines from Professional
Societies
Guidelines based on expert opinion for the man-
agement of hyperthyroidism have been published
by both the American Thyroid Association
53
and
the American Association of Clinical Endocrinolo-
gists,
54
and a joint evidence-based revision is in
preparation. The Royal College of Physicians has
issued treatment recommendations for the man-
agement of hyperthyroidism
55
and radioiodine
therapy.
35
A multidisciplinary European group has
developed guidelines for the evaluation and treat-
ment of ophthalmopathy.
23
The recommendations
provided here are consistent with these guidelines.
Conclusions and
Recommendations
In the patient described in the vignette, the dura-
tion of symptoms, elevated serum T
4
and T
3
levels
and suppressed thyrotropin level, and character-
istic clinical features strongly suggest Graves
disease. A radioiodine-uptake study is not neces-
sary to make the diagnosis in this patient. Treat-
ment options should be discussed with the pa-
tient. I often recommend that antithyroid therapy
be tried first, since in many patients, this treat-
2604
ment is followed by a sustained remission. Initial
treatment with radioiodine is also an option, and
it would eliminate the need for the use of an anti-
thyroid drug during any future pregnancy. If treat-
ment with an antithyroid drug is planned, I would
first check the white-cell count and aminotrans-
ferase levels. In a nonpregnant patient, I gener-
ally recommend methimazole, which can often be
given once daily. I explain to the patient the need
to discontinue the medication and have a white-
cell count checked if a fever or other evidence of
infection develops, and I recommend the use of
reliable contraception. A beta-adrenergic blocker
should be considered initially, since it generally
results in prompt symptomatic improvement.
Thyroid-function tests should be repeated in ap-
proximately 3 weeks; the serum level of thyrotro-
pin typically remains suppressed for up to sev-
eral months. Treatment is recommended for up
to 18 months in order to increase the likelihood
of remission. If the patients disease recurred af-
ter discontinuing medication, I would encourage
consideration of radioiodine therapy, although
surgery or further antithyroid drug therapy would
also be options.
Resources for patients with Graves disease
include the National Graves Disease Foundation
(www.ngdf.org), the American Thyroid Association
Alliance for Patient Education (www.thyroid.org/
patients/patients.html), and the Thyroid Foun-
dation of Canada (www.thyroid.ca).
Supported by a grant from the National Institutes of Health
(RO1 DK 67233) and Merit Review research funds from the De-
partment of Veterans Affairs.
No potential conflict of interest relevant to this article was
reported.
I thank my colleagues, Drs. Jerome Hershman and Masahiro
Sugawara, for their support in preparation of an earlier version
of this manuscript.
An audio version of this article is available at www.nejm.org.
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