clinical practice
T h e n e w e ng l a nd j o u r na l o f m e dic i n e
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Graves’ DiseaseGregory 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 [email protected].
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 μU 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 Cl inic a l 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-protein–coupled 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 (T3) relative to thy-roxine (T4) 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 T4 and T3. A suppressed serum thyro-tropin level with normal serum levels of T4 and T3 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 Hashimoto’s 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 author’s clinical recommendations.
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clinical pr actice
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primary care practitioners, but in my opinion, when possible they should be referred to or cared for with input from an endocrinologist.
S tr ategies a nd E v idence
EvaluationClinical ManifestationsOvert 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 life15 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 effects16 (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 StudiesThe primary diagnostic considerations in a pa-tient with a suppressed thyrotropin level and clin-ical hyperthyroidism are shown in Table 2.2 Se-rum T4 and T3 levels vary among these conditions (Tables 2 and 3). Tests for Graves’ disease–asso-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 β subunit and common α subunit
Cardiac Increased heart rate and contractility Increased expression of HCN2, voltage-gated potassium channel (Kv1.5, Kv4.2, Kv4.3), and SERCA; increased α-MHC and decreased β-MHC expression; increased serum atrial natriuretic peptide
Hepatic Increased peripheral T3 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 sodium–potassium 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 T3 and T4 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 α-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 element–binding protein 2, T3 triiodothyronine, T4 thyroxine, and VLDL very-low-density lipoprotein.
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Tabl
e 2.
Pot
entia
l Dia
gnos
es in
Pat
ient
s w
ith H
yper
thyr
oidi
sm a
nd S
uppr
esse
d Se
rum
Thy
rotr
opin
.*
Con
ditio
nSy
mpt
oms
and
Ass
ocia
ted
Feat
ures
Te
st R
esul
ts
Thyr
oid-
Func
tion
Test
s24
-hr
Rad
ioio
dine
Upt
ake
an
d Pa
tter
nA
dditi
onal
Stu
dies
an
d Fa
ctor
s in
Eva
luat
ion
Gra
ves’
dis
ease
Usu
ally
sym
ptom
s fo
r at
leas
t 2–3
mo;
thyr
oid
en-
larg
emen
t, th
yroi
d br
uit,
Gra
ves’
oph
thal
mop
athy
Elev
ated
ser
um T
4 an
d T 3
(us
ually
hi
gher
ele
vatio
n of
T3
than
T4)
El
evat
ed u
ptak
e w
ith h
omog
e-ne
ous
sym
met
ric d
istr
ibut
ion
Elev
ated
TSI
or
thyr
otro
pin-
rece
ptor
ant
ibod
ies
Pain
less
thyr
oidi
tisU
sual
ly m
odes
t sym
ptom
s of
sho
rt d
urat
ion
(<
3 m
o); c
an o
ccur
in th
e po
stpa
rtum
per
iod
Elev
ated
ser
um T
4 an
d T 3
(us
ually
eq
ual e
leva
tion
of T
4 an
d T 3
) Lo
w u
ptak
eSe
rum
thyr
oid
pero
xida
se a
nti-
bodi
es u
sual
ly p
ositi
ve
Pain
ful s
ubac
ute
thyr
oidi
tisTh
yroi
d te
nder
ness
, mod
est s
ympt
oms
of s
hort
du
ratio
n; o
ften
occ
urs
afte
r a
vira
l illn
ess
Elev
ated
ser
um T
4 an
d T 3
(us
ually
eq
ual e
leva
tion
of T
4 an
d T 3
) Lo
w u
ptak
eTh
yroi
d-re
late
d an
tibod
ies
usua
lly n
egat
ive
Toxi
c m
ultin
odul
ar g
oite
rV
aria
ble
onse
t and
ran
ge o
f sev
erity
; in
iodi
ne-
suffi
cien
t loc
atio
ns, m
ultin
odul
ar g
oite
r mor
e co
mm
on in
old
er p
erso
ns (
appr
oxim
atel
y
>50
yr);
in io
dine
-insu
ffici
ent l
ocat
ions
, may
be
com
mon
in y
oung
er p
erso
ns
Elev
ated
ser
um T
3; s
erum
T4
ca
n be
low
, nor
mal
, or
high
Incr
ease
d up
take
with
pat
chy
dist
ribu
tion
Thyr
oid-
rela
ted
antib
odie
s us
ually
neg
ativ
e
Solit
ary
hype
rfun
ctio
ning
no
dule
Var
iabl
e on
set a
nd r
ange
of s
ever
ity; i
ncid
ence
in
crea
ses
with
incr
easi
ng a
ge; m
ore
com
mon
in
wom
en th
an in
men
; usu
ally
clin
ical
ly s
igni
f-ic
ant h
yper
thyr
oidi
sm w
hen
nodu
le >
3 cm
in
diam
eter
Elev
ated
ser
um T
3; s
erum
T4
ca
n be
low
, nor
mal
, or
high
Incr
ease
d up
take
with
foca
l up-
take
in n
odul
e an
d su
ppre
s-si
on in
sur
roun
ding
gla
nd
Thyr
oid-
rela
ted
antib
odie
s us
ually
neg
ativ
e
Iodi
ne-in
duce
d hy
per-
thyr
oidi
smU
sual
ly r
apid
ons
et o
f sym
ptom
s (h
ours
to d
ays)
af
ter e
xpos
ure
to e
xces
s io
dine
(e.g
., fr
om a
con
-tr
ast s
tudy
or m
edic
atio
ns s
uch
as a
mio
daro
ne)
Elev
ated
ser
um T
3; s
erum
T4
ca
n be
low
, nor
mal
, or
high
Var
iabl
e, d
epen
ding
on
dose
and
fo
rm o
f iod
ine
(and
tim
e re
-qu
ired
for
excr
etio
n) a
nd a
ny
unde
rlyi
ng th
yroi
d di
seas
e
Usu
ally
in th
e se
ttin
g of
an
unde
rlyin
g m
ultin
odul
ar
goite
r or i
n ge
ogra
phic
ar-
eas
of io
dine
def
icie
ncy
Exog
enou
s in
gest
ion
of
thyr
oid
horm
one
Var
iabl
e, r
elat
ed to
dur
atio
n of
inge
stio
nR
efle
cts
cont
ent o
f pre
para
tion
of
thyr
oid
horm
one;
usu
ally
T4
prim
arily
ele
vate
d, a
lthou
gh in
so
me
prep
arat
ions
bot
h T 4
and
T 3
or
T 3 a
lone
is e
leva
ted
Low
upt
ake
Seru
m th
yrog
lobu
lin c
once
n-tr
atio
n us
ually
low
* T 3
den
otes
tri
iodo
thyr
onin
e, T
4 th
yrox
ine,
and
TSI
thy
roid
-stim
ulat
ing
imm
unog
lobu
lin.
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Imaging StudiesA 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 OphthalmopathyA 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 clinician’s 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 StudiesIn 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.
THER A PY
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-cytosis26; 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
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Tabl
e 3.
Eva
luat
ion
and
Mon
itori
ng o
f Gra
ves’
Dis
ease
.*
Test
Des
crip
tion
Rol
e in
Eva
luat
ion
Rol
e in
Mon
itori
ng
Labo
rato
ry s
tudi
es
Thyr
otro
pin
Dire
ct s
erum
mea
sure
men
t, hi
ghly
sen
sitiv
e fo
r det
ectin
g ab
norm
ally
sup
pres
sed
leve
ls
whe
n th
yroi
d ho
rmon
e le
vels
are
exc
essi
ve
Supp
ress
ed th
yrot
ropi
n re
quir
ed fo
r
diag
nosi
sU
sual
ly r
emai
ns s
uppr
esse
d fo
r ≥2
mo,
ev
en w
hen
seru
m T
4 an
d T 3
are
nor
mal
or
low
; aft
er s
uppr
essi
on, t
hyro
trop
in
test
ing
is th
e st
anda
rd fo
r m
onito
ring
an
d ad
just
ing
ther
apy
T 4
Free
T4
inde
x Pr
oduc
t of t
otal
thyr
oxin
e m
easu
rem
ent a
nd
estim
ate
of th
yrox
ine-
bind
ing
glob
ulin
(e
.g.,
resi
n up
take
rat
io)
Elev
ated
leve
ls in
Gra
ves’
dis
ease
Ef
fect
ive
for
mon
itori
ng r
espo
nse
to th
erap
y
Free
T4
by a
nalo
gue
met
hod
Mea
sure
s fr
ee T
4 in
dire
ctly
; use
d in
the
auto
-m
ated
pla
tfor
m in
stru
men
ts in
mos
t clin
i-ca
l lab
orat
orie
s
Elev
ated
leve
ls in
Gra
ves’
dis
ease
; ass
ay c
an
be in
fluen
ced
by e
xtre
mes
of s
erum
pro
-te
in le
vels
Effe
ctiv
e fo
r m
onito
ring
res
pons
e to
ther
apy
Free
T4
by d
ialy
sis
Onl
y di
rect
mea
sure
men
t of f
ree
or u
nbou
nd
frac
tion
of T
4; fr
ee T
4 is
dia
lyze
d fr
om th
e bo
und
T 4 a
nd th
en m
easu
red
Elev
ated
leve
ls in
Gra
ves’
dis
ease
Ef
fect
ive
for
mon
itori
ng r
espo
nse
to th
era-
py; m
ore
expe
nsiv
e th
an th
e ot
her
ap-
proa
ches
and
ava
ilabl
e in
onl
y a
few
spe
-ci
alty
labo
rato
ries
T 3
Tota
l T3
Dir
ect s
erum
mea
sure
men
t of t
otal
hor
mon
e El
evat
ed le
vels
in G
rave
s’ d
isea
se; m
easu
res
boun
d an
d fr
ee, s
o to
tal i
s in
fluen
ced
by
leve
ls o
f thy
roid
-bin
ding
glo
bulin
; can
be
corr
ecte
d to
inde
x w
ith b
indi
ng e
stim
ate
(e.g
., re
sin
upta
ke r
atio
)
Impo
rtan
t ear
ly in
trea
tmen
t to
asse
ss le
vel
of a
ctiv
e ho
rmon
e; r
atio
of T
3 to
T4
in-
crea
sed
in G
rave
s’ d
isea
se
Free
T3
by a
nalo
gue
met
hod
Mea
sure
s fr
ee T
3 in
dire
ctly
; use
d in
the
auto
-m
ated
pla
tfor
m in
stru
men
ts in
mos
t clin
i-ca
l lab
orat
orie
s
Elev
ated
leve
ls in
Gra
ves’
dis
ease
; mea
sure
-m
ent c
an b
e in
fluen
ced
by e
xtre
mes
of s
e-ru
m p
rote
in le
vels
Effe
ctiv
e fo
r m
onito
ring
res
pons
e to
ther
apy
Free
T3
by d
ialy
sis
Onl
y di
rect
mea
sure
men
t of f
ree
or u
nbou
nd
frac
tion
of T
3; fr
ee T
3 is
dia
lyze
d fr
om th
e bo
und
T 3 a
nd th
en m
easu
red
Elev
ated
leve
ls in
Gra
ves’
dis
ease
Ef
fect
ive
for
mon
itori
ng r
espo
nse
to th
era-
py; m
ore
expe
nsiv
e th
an o
ther
ap-
proa
ches
and
ava
ilabl
e in
onl
y a
few
spe
-ci
alty
labo
rato
ries
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clinical pr actice
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Thyr
oid
antib
odie
s
Thyr
otro
pin-
rece
ptor
ant
ibod
ies
Thyr
otro
pin-
rece
ptor
–bin
ding
in
hibi
tion
Ass
ay fo
r ser
um im
mun
oglo
bulin
s th
at in
hibi
t bi
ndin
g of
labe
led
thyr
otro
pin
to th
e th
yro-
trop
in r
ecep
tor
Doe
s no
t dis
tingu
ish
betw
een
bloc
king
and
st
imul
atin
g th
yrot
ropi
n re
cept
or Ig
G, b
ut
prov
ides
sup
port
for
diag
nosi
s; u
sed
in
som
e ca
ses
for
diag
nosi
s, fo
r ev
alua
ting
euth
yroi
d G
rave
s’ o
phth
alm
opat
hy, a
nd
duri
ng p
regn
ancy
(hi
gher
leve
ls a
ssoc
iat-
ed w
ith in
crea
sed
risk
of n
eona
tal G
rave
s’
dise
ase)
Pers
iste
nt e
leva
tion
corr
elat
es w
ith d
isea
se
activ
ity, a
nd r
emis
sion
is a
ccom
pani
ed
by a
dec
reas
e in
leve
ls, b
ut n
ot u
sual
ly
nece
ssar
y fo
r m
onito
ring
TSI
Bio
assa
y m
easu
ring
cyc
lic A
MP
prod
uctio
n af
ter
patie
nt’s
ser
um is
app
lied
to th
yroi
d fo
llicu
lar
cells
or
thyr
otro
pin
rece
ptor
– ex
pres
sing
eng
inee
red
cells
Spec
ific
for
thyr
otro
pin-
rece
ptor
–stim
ulat
ing
activ
ity; m
ore
expe
nsiv
e an
d lo
nger
turn
-ar
ound
as
com
pare
d w
ith th
yrot
ropi
n-
rece
ptor
ant
ibod
ies
Pers
iste
nt e
leva
tion
corr
elat
es w
ith d
isea
se
activ
ity, r
emis
sion
usu
ally
acc
ompa
nied
by
a d
ecre
ase
in a
ctiv
ity
TPO
ant
ibod
ies
Mea
sure
s an
tibod
y to
enz
yme
thyr
oid
per-
ox
idas
e TP
O a
ntib
odie
s el
evat
ed in
mos
t pat
ient
s w
ith H
ashi
mot
o’s
dise
ase,
but
als
o of
ten
elev
ated
in G
rave
s’ d
isea
se; e
leva
tion
not
spec
ific
for
diag
nosi
s of
Gra
ves’
dis
ease
Not
use
ful f
or m
onito
ring
Imag
ing
Thyr
oid
ultr
ason
ogra
phy
Prov
ides
hig
h-re
solu
tion
imag
e of
thyr
oid,
ca
n be
use
d to
det
erm
ine
bloo
d flo
w
by D
oppl
er
Use
ful f
or d
etec
ting
nodu
les;
if a
radi
oiod
ine-
upta
ke s
tudy
can
not b
e pe
rfor
med
, in-
crea
sed
bloo
d flo
w b
y D
oppl
er c
orre
late
s w
ith in
crea
sed
radi
oiod
ine
upta
ke
Not
rou
tinel
y us
ed b
ut h
elpf
ul fo
r ev
alua
-tio
n of
nod
ules
Rad
ioio
dine
-upt
ake
scan
Cap
sule
of i
odin
e-12
3 gi
ven
oral
ly, t
hyro
id
upta
ke m
easu
red
on s
can
obta
ined
24
hr
late
r
Use
ful f
or d
istin
guis
hing
Gra
ves’
dis
ease
(h
igh
upta
ke)
from
sub
acut
e th
yroi
ditis
(l
ow u
ptak
e); a
lso
usef
ul fo
r id
entif
ying
m
ultin
odul
ar to
xic
goite
r (p
atch
y up
take
) or
sol
itary
toxi
c no
dule
Usu
ally
onl
y ne
eded
to m
easu
re u
ptak
e fo
r pl
anne
d ra
dioi
odin
e tr
eatm
ent
Nec
k C
T or
MR
IIm
agin
g of
thyr
oid
in th
e co
ntex
t of t
rach
ea,
esop
hagu
s, a
nd c
hest
U
sed
only
if th
ere
are
sym
ptom
s or
sig
ns o
f up
per-
airw
ay o
r th
orac
ic-in
let o
bstr
uctio
nR
epea
t onl
y if
wor
seni
ng s
igns
of o
b-
stru
ctio
n
Orb
ital i
mag
ing
Tech
niqu
es in
clud
e C
T, M
RI,
and
ultr
a-so
nogr
aphy
Use
ful i
n ca
ses
of u
nila
tera
l pro
ptos
is,
mar
ked
asym
met
ry o
f oph
thal
mop
athy
, or
vis
ual l
oss
and
in s
ome
case
s of
impa
ir-
men
t of e
xtra
ocul
ar m
uscl
e m
ovem
ent
Rep
eat o
nly
if w
orse
ning
oph
thal
mop
athy
* C
T de
note
s co
mpu
ted
tom
ogra
phy,
T3
triio
doth
yron
ine,
T4
thyr
oxin
e, T
PO t
hyro
id p
erox
idas
e, a
nd T
SI t
hyro
id-s
timul
atin
g im
mun
oglo
bulin
.
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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 T4 and T3 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 T4 and T3 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 T4 (the so-called block-replace regimen) may improve remission rates as compared with the use of antithyroid drugs alone, but many trials33 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-CH/T
RETAKE
SIZE
ICM
CASE
EMail LineH/TCombo
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.)
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Copyright © 2008 Massachusetts Medical Society. All rights reserved.
clinical pr actice
n engl j med 358;24 www.nejm.org june 12, 2008 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-CH/T
RETAKE
SIZE
ICM
CASE
EMail LineH/TCombo
Revised
AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset.
Please check carefully.
REG F
Enon
1st2nd3rd
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.)
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Copyright © 2008 Massachusetts Medical Society. All rights reserved.
n engl j med 358;24 www.nejm.org june 12, 20082602
clinical pr actice
Tabl
e 4.
For
ms
of T
reat
men
t for
Gra
ves’
Dis
ease
.*
Trea
tmen
tM
echa
nism
sIn
dica
tions
Expe
cted
Res
pons
eA
dver
se E
ffec
ts
Med
icat
ions
Prop
ylth
iour
acil
(at a
typi
cal
star
ting
dose
of 1
50–6
00 m
g da
ily, u
sual
ly s
plit
into
3–4
do
ses
per
day)
Inhi
bits
thyr
oid
horm
one
synt
hesi
s an
d T 4
-to-
T 3 c
onve
rsio
nFo
r in
itial
trea
tmen
t; in
sev
ere
hy-
pert
hyro
idis
m, m
ay b
e us
ed fo
r ra
pid
low
erin
g of
ser
um T
3
Red
uctio
n in
T4
and
T 3, a
nd im
-pr
ovem
ent i
n sy
mpt
oms
in
appr
oxim
atel
y 3–
4 w
k
Min
or: r
ash,
urt
icar
ia, a
bnor
mal
ta
ste;
maj
or: a
gran
uloc
ytos
is,
hepa
tic n
ecro
sis,
cho
lest
asis
Met
him
azol
e (a
t a ty
pica
l st
artin
g do
se o
f 10–
40 m
g da
ily, u
sual
ly g
iven
as
a si
ngle
dai
ly d
ose
or in
a
divi
ded
dose
twic
e a
day)
Inhi
bits
thyr
oid
horm
one
synt
hesi
sFo
r in
itial
trea
tmen
t R
educ
tion
in T
4 an
d T 3
, and
im-
prov
emen
t in
sym
ptom
s in
ap
prox
imat
ely
3–4
wk
Min
or: r
ash,
urt
icar
ia; m
ajor
: ag
ranu
locy
tosi
s, h
epat
ic n
ecro
-si
s, c
hole
stas
is; i
n pr
egna
ncy,
ra
re c
ompl
icat
ion
of a
plas
ia
cutis
and
em
bryo
path
y (c
har-
acte
rize
d by
cho
anal
or
esop
h-ag
eal a
tres
ia)
Bet
a-ad
rene
rgic
rec
epto
r bl
ocke
rs (
at a
typi
cal d
ose
of 5
0–20
0 m
g of
met
opro
-lo
l dai
ly a
nd 2
5–10
0 m
g
of a
teno
lol d
aily
)
Blo
cks
adre
nerg
ic s
igna
ling,
whi
ch
is p
oten
tiate
d in
hyp
erth
yroi
d-is
m; t
issu
es w
ith a
ugm
ente
d ac
-tio
n of
cat
echo
lam
ines
incl
ude
hear
t, sk
elet
al m
uscl
e, b
one,
fat
For
rece
ntly
dia
gnos
ed d
isea
se in
pa
tient
s w
ith s
igni
fican
t sym
pa-
thet
ic s
ympt
oms
(e.g
., tr
emor
, ta
chyc
ardi
a, s
wea
ting)
Rap
id im
prov
emen
t of s
ympt
oms,
us
ually
with
in 1
–2 d
ays
Air
way
obs
truc
tion
in p
atie
nts
w
ith a
sthm
a or
obs
truc
tive
lung
dis
ease
Supe
rsat
urat
ed p
otas
sium
io
dide
and
ipod
ate
(Ora
graf
in),
an
iodi
nate
d ra
diog
raph
ic c
ontr
ast
agen
t not
cur
rent
ly a
vail-
able
in th
e U
nite
d St
ates
Acu
te in
hibi
tion
of th
yroi
d ho
rmon
e sy
nthe
sis
and
rele
ase,
red
uced
va
scul
arity
; ipo
date
red
uces
T4-
to-T
3 co
nver
sion
For
rapi
d re
duct
ion
of th
yroi
d ho
r-m
one
leve
ls, s
uch
as in
pat
ient
s w
ith s
ever
e ca
rdia
c di
seas
e or
th
yroi
d st
orm
,† o
r in
pre
para
-tio
n fo
r su
rger
y
Rap
id r
educ
tion
(in
hour
s to
day
s)
in s
erum
T4
and
T 3 fo
r 5–
7 da
ysSa
livar
y-gl
and
infla
mm
atio
n
Glu
coco
rtic
oid
agen
t (e.
g.,
pred
niso
ne o
r de
xam
eth-
ason
e)
Inhi
bits
T4-
to-T
3 co
nver
sion
For
rapi
d re
duct
ion
in s
erum
T3,
su
ch a
s in
pat
ient
s w
ith th
yroi
d st
orm
,† s
ever
e ca
rdia
c di
seas
e,
or in
pre
para
tion
for
surg
ery
Rap
id r
educ
tion
in s
erum
T3
Shor
t-te
rm m
inim
al c
ompl
ica-
tions
; lon
g-te
rm c
ompl
icat
ions
in
clud
e gl
ucos
e in
tole
ranc
e,
bone
loss
, mus
cle
brea
kdow
n
Rad
ioio
dine
(io
dine
-131
giv
en a
s an
ora
l cap
sule
or
liqui
d)O
ral d
ose
of io
dine
-131
res
ults
in
radi
atio
n-in
duce
d th
yroi
d de
-st
ruct
ion
For
defin
itive
initi
al tr
eatm
ent a
nd
for
patie
nts
who
do
not g
o in
to
rem
issi
on a
fter
initi
al tr
eatm
ent
with
ant
ithyr
oid
drug
s
Hyp
othy
roid
ism
dev
elop
s in
abo
ut
80%
of p
atie
nts
with
in 2
–6 m
o,
lifel
ong
T 4 r
epla
cem
ent t
hen
requ
ired
Acu
te r
adia
tion
thyr
oidi
tis (
i.e.,
thyr
oid
pain
and
tran
sien
tly in
-cr
ease
d th
yroi
d ho
rmon
e le
vels
)
Thyr
oide
ctom
yD
irec
tly r
emov
es a
ll or
mos
t hyp
er-
func
tioni
ng th
yroi
d tis
sue
For
imm
edia
te, d
efin
itive
trea
tmen
t; in
dica
ted
if si
gnifi
cant
sid
e ef
fect
s of
ant
ithyr
oid
drug
s, e
xces
sive
an
tithy
roid
dru
g do
se r
equi
red
in p
regn
ancy
, lar
ge g
oite
r, o
r su
spic
ious
nod
ule,
or
if pa
tient
de
clin
es r
adio
activ
e io
dine
Usu
ally
com
plet
e re
spon
se, w
ill
requ
ire
lifel
ong
T 4 r
epla
cem
ent
Rar
e co
mpl
icat
ion
of h
ypop
arat
hy-
roid
ism
(<1
% w
ith e
xper
ienc
ed
surg
eons
) an
d re
curr
ent l
aryn
-ge
al-n
erve
dam
age
* T 3
den
otes
tri
iodo
thyr
onin
e, a
nd T
4 th
yrox
ine.
† In
rar
e ca
ses,
sev
ere
thyr
otox
icos
is (
refe
rred
to
as t
hyro
id s
torm
) co
mpl
icat
es G
rave
s’ d
isea
se w
hen
som
e or
all
of t
he fo
llow
ing
occu
r: fe
ver,
alte
red
men
tal s
tatu
s, a
nd h
epat
ic, g
astr
o-in
test
inal
, and
car
diac
dys
func
tion.
The
rapi
es t
hat
prom
ote
rapi
d in
hibi
tion
of T
4-to
-T3
conv
ersi
on a
re e
spec
ially
use
ful i
n su
ch c
ases
.
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clinical pr actice
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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, Lugol’s 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 T4 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
A r e a s of Uncerta in t y
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 T4 in the mother are associated with risks to the fetus.48,52 In animal models, thyroid hormone–receptor antagonists rapidly block the action of thyroid hormone,10 but these agents are not available for clinical use.
Guidel ines from Professiona l So cie ties
Guidelines based on expert opinion for the man-agement of hyperthyroidism have been published by both the American Thyroid Association53 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 hyperthyroidism55 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 a nd R ecommendations
In the patient described in the vignette, the dura-tion of symptoms, elevated serum T4 and T3 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-
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T h e n e w e ng l a nd j o u r na l o f m e dic i n e
n engl j med 358;24 www.nejm.org june 12, 20082604
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 patient’s 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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collections of articles on the journal’s web site
The Journal’s Web site (www.nejm.org) sorts published articles into more than 50 distinct clinical collections, which can be used as convenient
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