graves’ disease - tasmc.org.illibrary.tasmc.org.il/ disease.pdf · graves’ disease alone or to...

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

n engl j med 358;24 www.nejm.org june 12, 20082594

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.

Copyright © 2008 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at TEL AVIV SOURASKY MEDICAL CENTER on February 15, 2009 .

clinical pr actice

n engl j med 358;24 www.nejm.org june 12, 2008 2595

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.




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.


clinical pr actice


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




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


clinical pr actice


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

.




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.)


clinical pr actice


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.)



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

.


clinical pr actice


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-




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.

References

Weetman AP. Graves’ disease. N Engl J Med 2000;343:1236-48.

Cooper DS. Hyperthyroidism. Lancet 2003;362:459-68.

Woeber KA. Triiodothyronine produc-tion in Graves’ hyperthyroidism. Thyroid 2006;16:687-90.

Toft AD. Subclinical hyperthyroidism. N Engl J Med 2001;345:512-6.

Khoo TK, Bahn RS. Pathogenesis of Graves’ ophthalmopathy: the role of auto-antibodies. Thyroid 2007;17:1013-8.

Brix TH, Kyvik KO, Christensen K, Hegedüs L. Evidence for a major role of heredity in Graves’ disease: a population-based study of two Danish twin cohorts. J Clin Endocrinol Metab 2001;86:930-4.

Jacobson EM, Tomer Y. The genetic basis of thyroid autoimmunity. Thyroid 2007;17:949-61.

Manji N, Carr-Smith JD, Boelaert K, et al. Inf luences of age, gender, smoking, and family history on autoimmune thy-roid disease phenotype. J Clin Endocrinol Metab 2006;91:4873-80.

Motomura K, Brent GA. Mechanism of thyroid hormone action: implications for the clinical manifestations of thyro-toxicosis. Endocrinol Metab Clin North Am 1998;27:1-23.

Brenta G, Danzi S, Klein I. Potential therapeutic applications of thyroid hor-mone analogs. Nat Clin Pract Endocrinol Metab 2007;3:632-40.

Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001;344:501-9.

Schwartz KM, Fatourechi V, Ahmed DDF, Pond GR. Dermopathy of Graves’

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

disease (pretibial myxedema): long-term outcome. J Clin Endocrinol Metab 2002; 87:438-46.

Carani C, Isidori AM, Granata A, et al. Multicenter study on the prevalence of sexual symptoms in male hypo- and hyper-thyroid patients. J Clin Endocrinol Metab 2005;90:6472-9.

Jacobsen R, Lundsgaard C, Lorenzen J, et al. Subnormal energy expenditure: a putative casual factor in the weight gain induced by treatment of hyperthyroidism. Diabetes Obes Metab 2006;8:220-7.

Abraham-Nordling M, Törring O, Ham-berger B, et al. Graves’ disease: a long-term quality-of-life follow up of patients randomized to treatment with antithyroid drugs, radioiodine, or surgery. Thyroid 2005;15:1279-86.

Estcourt S, Vaidya B, Quinn A, Shep-herd M. The impact of thyroid eye disease upon patients’ wellbeing: a qualitative analysis. Clin Endocrinol (Oxf) 2008;68: 635-9.

Nordyke RA, Gilbert FI Jr, Harada AS. Graves’ disease: influence of age on clini-cal findings. Arch Intern Med 1988;148: 626-31.

Osman F, Franklyn JA, Holder RL, Sheppard MC, Gammage MD. Cardiovas-cular manifestations of hyperthyroidism before and after antithyroid therapy: a matched case-control study. J Am Coll Cardiol 2007;49:71-81.

Davies TF, Roti E, Braverman LE, De-Groot LJ. Thyroid controversy — stimu-lating antibodies. J Clin Endocrinol Metab 1998;83:3777-85.

Cappelli C, Pirola I, De Martino E, et

13.

14.

15.

16.

17.

18.

19.

20.

al. The role of imaging in Graves’ disease: a cost-effectiveness analysis. Eur J Radiol 2008;65:99-103.

Ota H, Amino N, Morita S, et al. Quantitative measurement of thyroid blood flow for differentiation of painless thy-roiditis from Graves’ disease. Clin Endo-crinol (Oxf) 2007;67:41-5.

Pellegriti G, Belfiore A, Giuffrida D, Lupo L, Vigneri R. Outcome of differenti-ated thyroid cancer in Graves’ patients. J Clin Endocrinol Metab 1998;83:2805-9.

Bartalena L, Baldeschi L, Dickinson AJ, et al. Consensus statement of the European Group on Graves’ Orbitopathy (EUGOGO) on management of Graves’ orbitopathy. Thyroid 2008;18:333-46.

Kahaly GJ. Imaging in thyroid-associ-ated orbitopathy. Eur J Endocrinol 2001; 145:107-18.

Törring O, Tallstedt L, Wallin G, et al. Graves’ hyperthyroidism: treatment with antithyroid drugs, surgery, or radioiodine — a prospective, randomized study. J Clin Endocrinol Metab 1996;81:2986-93.

Cooper DS. Antithyroid drugs. N Engl J Med 2005;352:905-17.

Vaidya B, Williams GR, Abraham P, Pearce SHS. Radioiodine treatment for benign thyroid disorders: results of a na-tionwide survey of UK endocrinologists. Clin Endocrinol (Oxf) 2008;68:814-20.

Wartofsky L, Glinoer D, Solomon B, et al. Differences and similarities in the diagnosis and treatment of Graves’ dis-ease in Europe, Japan, and the United States. Thyroid 1991;1:129-35.

Nakamura H, Noh JY, Itoh K, Fukata S, Myauchi A, Hamada N. Comparison of

21.

22.

23.

24.

25.

26.

27.

28.

29.


clinical pr actice


methimazole and propylthiouracil in pa-tients with hyperthyroidism caused by Graves’ disease. J Clin Endocrinol Metab 2007;92:2157-62.

Kubota S, Amino N, Matsumoto Y, et al. Serial changes in liver function tests in patients with thyrotoxicosis induced by Graves’ disease and painless thyroiditis. Thyroid 2008;18:283-7.

Allahabadia A, Daykin J, Holder RL, Sheppard MC, Gough SCL, Franklyn JA. Age and gender predict the outcome of treatment for Graves’ hyperthyroidism. J Clin Endocrinol Metab 2000;85:1038-42.

Maugendre D, Gatel A, Campion L, et al. Antithyroid drugs and Graves’ disease — prospective randomized assessment of long-term treatment. Clin Endocrinol (Oxf) 1999;50:127-32.

Abraham P, Avenell A, Park CM, Wat-son WA, Bevan JS. A systematic review of drug therapy for Graves’ hyperthyroidism. Eur J Endocrinol 2005;153:489-98.

Weetman AP. Radioiodine treatment for benign thyroid diseases. Clin Endocri-nol (Oxf) 2007;66:757-64.

Radioiodine in the management of benign thyroid disease: clinical guide-lines: report of a working party. London: Royal College of Physicians, 2007.

Walter MA, Briel M, Christ-Crain M, et al. Effects of antithyroid drugs on radio-iodine treatment: systematic review and meta-analysis of randomised controlled trials. BMJ 2007;334:514-20.

Walter MA, Christ-Crain M, Schindler C, Müller-Brand J, Müller B. Outcome of radioiodine therapy without, on or 3 days off carbimazole: a prospective interven-tional three-group comparison. Eur J Nucl Med Mol Imaging 2006;33:730-7.

Alexander EK, Larsen PR. High dose (131)I therapy for the treatment of hyper-thyroidism caused by Graves’ disease. J Clin Endocrinol Metab 2002;87:1073-7.

30.

31.

32.

33.

34.

35.

36.

37.

38.

Leslie WD, Ward L, Salamon EA, Lud-wig S, Rowe RC, Cowden EA. A random-ized comparison of radioiodine doses in Graves’ hyperthyroidism. J Clin Endocri-nol Metab 2003;88:978-83.

Franklyn JA, Sheppard MC, Maison-neuve P. Thyroid function and mortality in patients treated for hyperthyroidism. JAMA 2005;294:71-80.

Metso S, Jaatinen P, Huhtala H, Auvinen A, Oksala H, Salmi J. Increased cardiovascular and cancer mortality after radioiodine treatment for hyperthyroidism. J Clin Endocrinol Metab 2007;92:2190-6. [Erratum, J Clin Endocrinol Metab 2007; 92:4008.]

Bartalena L, Marcocci C, Bogazzi F, et al. Relation between therapy for hyper-thyroidism and the course of Graves’ oph-thalmopathy. N Engl J Med 1998;338:73-8.

Perros P, Kendall-Taylor P, Neoh C, Frewin S, Dickinson J. A prospective study of the effects of radioiodine therapy for hyperthyroidism in patients with minimal-ly active Graves’ ophthalmopathy. J Clin Endocrinol Metab 2005;90:5321-3.

Ceccarelli C, Canale D, Battisti P, et al. Testicular function after 131I therapy for hyperthyroidism. Clin Endocrinol (Oxf) 2006;65:446-52.

Grodski S, Stalberg P, Robinson BG, Delbridge LW. Surgery versus radioiodine therapy as definitive management for Graves’ disease: the role of patient prefer-ence. Thyroid 2007;17:157-60.

Panzer C, Beazley R, Braverman L. Rapid preoperative preparation for severe hyperthyroid Graves’ disease. J Clin Endo-crinol Metab 2004;89:2142-4.

Erbil Y, Ozluk Y, Giris M, et al. Effect of lugol solution on thyroid gland blood flow and microvessel density in the pa-tients with Graves’ disease. J Clin Endo-crinol Metab 2007;92:2182-9.

Chan GW, Mandel SJ. Therapy insight:

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

management of Graves’ disease during pregnancy. Nat Clin Pract Endocrinol Metab 2007;3:470-8.

Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: an En-docrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007;92:Suppl:S1-S47.

Luton D, Le Gac I, Vuillard E, et al. Management of Graves’ disease during pregnancy: the key role of fetal thyroid gland monitoring. J Clin Endocrinol Metab 2005;90:6093-8.

Laurberg P. Remission of Graves’ dis-ease during anti-thyroid drug therapy: time to reconsider the mechanism? Eur J Endocrinol 2006;155:783-6.

Kempers MJ, van Trotsenburg AS, van Rijn RR, et al. Loss of integrity of thyroid morphology and function in children born to mothers with inadequately treated Graves’ disease. J Clin Endocrinol Metab 2007;92:2984-91.

Singer PA, Cooper DS, Levy EG, et al. Treatment guidelines for patients with hy-perthyroidism and hypothyroidism. JAMA 1995;273:808-12.

American Association of Clinical En-docrinologists. American Association of Clinical Endocrinologists medical guide-lines for clinical practice for the evalua-tion and treatment of hyperthyroidism and hypothyroidism. Endocr Pract 2002;8: 457-69.

Vanderpump MPJ, Ahlquist JAO, Frank-lyn JA, Clayton RN. Consensus statement for good practice and audit measures in the management of hypothyroidism and hyperthyroidism. BMJ 1996;313:539-44.Copyright © 2008 Massachusetts Medical Society.

49.

50.

51.

52.

53.

54.

55.

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

entry points to clinical content. In each collection, articles are cited in reverse chronologic order, with the most recent first.


New England Journal of Medicine

CORRECTION

Graves’ Disease

To the Editor: In his Clinical Practice article on Graves’ disease,

Brent (June 12 issue)1 comments on the combined use of antithyroid

drugs and radioiodine and refers to the results of our trial,2 showing

no effects of antithyroid drugs on radioiodine therapy after a 3-day-

withdrawal. However, in a subsequent meta-analysis,3 we found that

antithyroid drugs significantly reduced the success of radioiodine ther-

apy, even when the drugs were discontinued for a week. This conclu-

sion contradicted those of most of the included trials (including our

own), which were most likely underpowered to detect significant dif-

ferences. We now discontinue antithyroid drugs for more than a week

before radioiodine therapy, if clinically feasible. Adequately powered

trials are needed to better inform this issue.

Martin A. Walter, M.D.

Mirjam Christ-Crain, M.D.

Beat Muller, M.D.

University Hospital

CH-4031 Basel, Switzerland

[email protected]

References

1. Brent GA. Graves’ disease. N Engl J Med 2008;358:2594-2605.

2. Walter MA, Christ-Crain M, Schindler C, Müller-Brand J, Müller B.

Outcome of radioiodine therapy without, on or 3 days off carbima-

zole: a prospective interventional three-group comparison. Eur J

Nucl Med Mol Imaging 2006;33:730-737.

3. Walter MA, Briel M, Christ-Crain M, et al. Effects of antithy-

roid drugs on radioiodine treatment: systematic review and meta-

analysis of randomised controlled trials. BMJ 2007;334:514-514.

To the Editor: As noted by Brent and others,1 thyroid volume, circu-

lating titers of thyrotropin-receptor antibodies, sex, and age are pre-

dictors of remission in Graves’ disease and are commonly used as

indicators for choosing the best therapeutic option. However, several

studies2,3,4 have shown that an older age at presentation and not

the contrary, as stated by Brent, characterizes patients with Graves’

disease who are most likely to undergo a prolonged remission af-

ter treatment with antithyroid drugs. Thus, especially in patients with

Graves’ disease who are older than 40 years, a full course of an-

tithyroid drugs is a reasonable therapeutic option, which could avoid

unnecessary thyroid surgery, radioiodine ablation, or both, with the

subsequent need for lifelong levothyroxine treatment.

Mario Rotondi, M.D., Ph.D.

Rodolfo Fonte, M.D.

Luca Chiovato, M.D., Ph.D.

Fondazione S. Maugeri IRCCS

27100 Pavia, Italy

References

1. Cooper DS. Antithyroid drugs. N Engl J Med 2005;352:905-917.

2. Yamada T, Aizawa T, Koizumi Y, Komiya I, Ichikawa K, Hashizume

K. Age-related therapeutic response to antithyroid drug in patients

with hyperthyroid Graves’ disease. J Am Geriatr Soc 1994;42:513-

516.

3. Vitti P, Rago T, Chiovato L, et al. Clinical features of patients with

Graves’ disease undergoing remission after antithyroid drug treat-

ment. Thyroid 1997;7:369-375.

4. Allahabadia A, Daykin J, Holder RL, Sheppard MC, Gough SC,

Franklyn JA. Age and gender predict the outcome of treatment for

Graves’ hyperthyroidism. J Clin Endocrinol Metab 2000;85:1038-

1042.

To the Editor: Brent does not discuss the adverse effects of cigarette

smoking in patients with Graves’ disease. Research findings support

associations between cigarette smoking and both Graves’ disease

and Graves’ ophthalmopathy. For example, a meta-analysis showed

an odds ratio for Graves’ disease of 3.30 (95% confidence interval

[CI], 2.09 to 5.22, based on data from eight studies) among current

smokers as compared with persons who had never smoked.1 The

meta-analysis also showed that the odds ratio for Graves’ ophthal-

mopathy among persons who had ever smoked was 4.40 (95% CI,

2.88 to 6.73, based on data from six studies). Among current smok-

ers, the hazard ratio for Graves’ disease increases with the intensity

of smoking.2

Cigarette smoking is also associated with a higher degree of sever-

ity in Graves’ ophthalmopathy and a lower effectiveness of medical

treatment.3 Cigarette smoking increases the risk of progression of

ophthalmopathy after radioiodine therapy and decreases the efficacy

of orbital radiation therapy and glucocorticoid therapy.4

Therefore, clinicians treating patients with Graves’ disease, including

those with Graves’ ophthalmopathy, should strongly advise these pa-

tients not to smoke cigarettes and, wherever possible, to avoid expo-

sure to environmental tobacco smoke.

Barry S. Levy, M.D., M.P.H.

Tufts University School of Medicine

Boston, MA 02111

[email protected]

References

1. Vestergaard P. Smoking and thyroid disorders – a meta-analysis.

Eur J Endocrinol 2002;146:153-161.

N Engl J Med 2008;359:1407



2. Holm IA, Manson JE, Michels KB, Alexander EK, Willett WC,

Utiger RD. Smoking and other lifestyle factors and the risk of

Graves’ hyperthyroidism. Arch Intern Med 2005;165:1606-1611.

3. Wiersinga WM, Bartalena L. Epidemiology and prevention of

Graves’ ophthalmopathy. Thyroid 2002;11:855-860.

4. Bartalena L, Marcocci C, Tanda ML, et al. Cigarette smoking and

treatment outcomes in Graves ophthalmopathy. Ann Intern Med

1998;129:632-635.

To the Editor: Brent refers to a study we performed to support the

claim that no increased risk of cancer has been reported after treat-

ment with radioactive iodine in patients with Graves’ disease. On the

contrary, we have reported an increased risk of cancer both among

patients with Graves’ disease and among those with toxic multinodular

goiter.1 The incidence of cancers of the stomach, kidney, and breast

was increased. However, the increase in overall and cancer-related

mortality was seen only among the patients with toxic multinodular

goiter, who were older than the patients with Graves’ disease.2 We

recommend that the small but significant risk of cancer should be

considered in planning the treatment for hyperthyroidism, at least in

children and young adults.

Saara Metso, M.D.

Tampere University Hospital

33520 Tampere, Finland

[email protected]

Pia Jaatinen, M.D., Ph.D.

University of Tampere


Jorma Salmi, M.D., Ph.D.

Tampere University Hospital


References

1. Metso S, Auvinen A, Huhtala H, Salmi J, Oksala H, Jaatinen

P. Increased cancer incidence after radioiodine treatment for hy-

perthyroidism. Cancer 2007;109:1972-1979. [Erratum, Cancer

2007;110:1875.]

2. Metso S, Jaatinen P, Huhtala H, Auvinen A, Oksala H, Salmi

J. Increased cardiovascular and cancer mortality after ra-

dioiodine treatment for hyperthyroidism. J Clin Endocrinol

Metab 2007;92:2190-2196. [Erratum, J Endocrinol Metab

2007;92:4008.]

The author replies: Walter and colleagues detected an influence of

antithyroid-drug treatment on the effectiveness of radioiodine therapy

in their meta-analysis,1 although half the studies included did not dis-

continue the antithyroid drug before radioiodine therapy; the effec-

tiveness of radioiodine therapy was also improved with higher doses

of radioiodine.1 Their practice of discontinuing antithyroid drugs for

more than 1 week before administering radioiodine is at the limit of the

range of 3 to 7 days recommended in the review and by most clinical

guidelines. The risk of a prolonged interval of antithyroid-drug cessa-

tion is worsening hyperthyroidism, which is clinically relevant primarily

for patients with more severe hyperthyroidism or increased suscepti-

bility, such as those with active cardiac disease. I concur with the

recommendation for an adequately powered trial.

Rotondi and colleagues correctly state that younger patients with

Graves’ disease are less likely to have a remission with antithyroid-

drug therapy; I regret the error. The study cited in the review2

showed that patients with Graves’ disease who were less than 40

years old had a lower remission rate after long-term antithyroid-drug

treatment (32.6%) than patients who were 40 years or older (47.8%).

Younger patients, as compared with older patients, have higher levels

of thyrotropin-receptor antibodies and the associated manifestations

of increased thyroid volume and increased thyroid hormone levels,

especially serum triiodothyronine.

Levy emphasizes the important role of cigarette smoking in Graves’

disease, especially Graves’ ophthalmopathy. Patients should be in-

formed that cigarette smoking is likely to worsen ophthalmopathy

and reduce the response to treatment. Most studies have shown

a cigarette dose effect, so a reduction in the number of cigarettes

smoked may also be beneficial. Smoking is also associated with a

larger goiter at presentation among patients with Graves’ disease and

a reduced likelihood of remission with antithyroid drugs.3

Metso and colleagues refer to the association of cancer with radioio-

dine therapy for hyperthyroidism. The references cited in the review

from their group and others focused on cancer-related mortality after

radioiodine therapy, and this should have been clarified in the discus-

sion. Metso and colleagues report a small but significant dose-related

increase in the incidence of stomach, kidney, and breast cancers

in long-term follow-up of patients with hyperthyroidism who received

treatment with radioiodine.4 A larger series5 showed an overall reduc-

tion in the incidence of cancer among patients treated with radioiodine

for hyperthyroidism but an increase in the incidence of a few cancers.

The finding, from several long-term studies, of no increase in cancer-

related mortality after radioiodine treatment for Graves’ disease is re-

assuring. The small increase in the incidence of some cancers, in-

cluding several potentially linked to direct exposure to or uptake of

iodine, may be relevant for treatment decisions.

Gregory A. Brent, M.D.

Veterans Affairs Greater Los Angeles Healthcare System

Los Angeles, CA 90073

[email protected]

References

1. Walter MA, Briel M, Christ-Crain M, et al. Effects of antithy-

roid drugs on radioiodine treatment: systematic review and meta-

N Engl J Med 2008;359:1407



analysis of randomised controlled trials. BMJ 2007;334:514-514.

2. Allahabadia A, Daykin J, Holder RL, Sheppard MC, Gough SC,

Franklyn JA. Age and gender predict the outcome of treatment for

Graves’ hyperthyroidism. J Clin Endocrinol Metab 2000;85:1038-

1042.

3. Glinoer D, de Nayer P, Bex M. Effects of L-thyroxine administra-

tion, TSH-receptor antibodies and smoking on the risk of recur-

rence in Graves’ hyperthyroidism treated with antithyroid drugs:

a double-blind prospective randomized study. Eur J Endocrinol

2001;144:475-483.

4. Metso S, Auvinen A, Huhtala H, Salmi J, Oksala H, Jaatinen

P. Increased cancer incidence after radioiodine treatment for hy-

perthyroidism. Cancer 2007;109:1972-1979. [Erratum, Cancer

2007;110:1875.]

5. Franklyn JA, Maisonneuve P, Sheppard M, Betteridge J, Boyle

P. Cancer incidence and mortality after radioiodine treatment

for hyperthyroidism: a population-based cohort study. Lancet

1999;353:2111-2115.

N Engl J Med 2008;359:1407


graves’ disease - tasmc.org.illibrary.tasmc.org.il/ disease.pdf · graves’ disease alone or to...

Documents