The new england journal of medicine

review article

current concepts

Thyroiditis
Elizabeth N. Pearce, M.D., Alan P. Farwell, M.D., and Lewis E. Braverman, M.D.

From the Section of Endocrinology, Diabe-

tes, and Nutrition, Boston Medical Center,
Boston University School of Medicine, Bos-
ton (E.N.P., L.E.B.); and the Division of En-
docrinology, University of Massachusetts
Medical Center, Worcester (A.P.F.). Address
t he term thyroiditis encompasses many relatively common
thyroid disorders, which have been classified according to various schemes
(Table 1). In this article we review the diagnosis and treatment of the different
types of thyroiditis.
reprint requests to Dr. Braverman at the
Section of Endocrinology, Diabetes, and Nu- mechanisms of autoimmune thyroid destruction
trition, Boston Medical Center, 88 E. New-
ton St., Evans 201, Boston, MA 02118, or at thyroid autoimmunity
lewis.braverman@bmc.org.
Hashimoto’s thyroiditis, painless sporadic thyroiditis, and painless postpartum thyroid-
N Engl J Med 2003;348:2646-55. itis all have an autoimmune basis (Table 2). In Hashimoto’s thyroiditis, the antithyroid
Copyright © 2003 Massachusetts Medical Society.
immune response begins with activation of thyroid antigen–specific helper T cells. Ac-
cording to one theory, this activation results from infection with a virus that has a pro-
tein similar to a thyroid protein, although clear evidence for a viral cause is lacking.2
According to another theory, thyroid epithelial cells present their own intracellular pro-
teins to T cells. In women, autoimmune thyroiditis may be induced by the accumulation
of fetal cells in the maternal thyroid gland during pregnancy (painless postpartum thy-
roiditis).3,4
Once helper T cells are activated, they induce B cells to secrete thyroid antibodies.
Increased serum concentrations of thyroid antibodies are present in up to 10 percent of
the general population in the United States5 and in approximately 25 percent of U.S.
women over 60 years of age.6 The prevalence of high serum concentrations of thyroid
antibodies varies according to race and ethnic background. In the third U.S. National
Health and Nutrition Examination Survey of persons 12 years of age or older, high serum
concentrations of thyroid antibodies were present in 14.3 percent of whites, in 10.9 per-
cent of Mexican Americans, and in only 5.3 percent of blacks.7 The majority of patients
with measurable thyroid antibody concentrations have normal thyroid function. In stud-
ies in England, 10 percent of postmenopausal women with high serum thyroid antibody
concentrations had subclinical hypothyroidism and 0.5 percent had overt hypothyroid-
ism, although euthyroid patients with high serum thyroid antibody concentrations had
progression to overt hypothyroidism at a rate of 2 to 4 percent a year.5,8 In a 10-year
prospective study conducted in Switzerland, high serum thyroid peroxidase antibody
concentrations predicted the progression of subclinical hypothyroidism to overt hy-
pothyroidism.9
The thyroid antibodies most frequently measured are those directed against thyroid
peroxidase and against thyroglobulin. The former are closely associated with overt thy-
roid dysfunction, and their presence tends to correlate with thyroidal damage and lym-
phocytic inflammation. Thyroid peroxidase antibodies are complement-fixing and thus
directly cytotoxic to thyrocytes,10 but there is limited evidence that this toxic effect is a
primary destructive mechanism in autoimmune thyroiditis. Antibodies that block thy-
rotropin receptors have been reported in up to 10 percent of patients with Hashimoto’s

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 current concepts

thyroiditis.11 In some patients, these antibodies may

clinical and biochemical
have a role in the development and severity of hy- changes in thyroiditis
pothyroidism, although they are not directly in-
volved in the destruction of thyrocytes. Thyroglob- The various forms of thyroiditis may cause thyrotox-
ulin antibodies are present less frequently, and their icosis, hypothyroidism, or both (Fig. 2).
role is unclear. Antibodies to colloid antigen, thy-
roid hormones, and the sodium iodide symporter thyrotoxicosis
have also been detected in patients with autoim- In painless sporadic thyroiditis, painless postpar-
mune thyroiditis. tum thyroiditis, and painful subacute thyroiditis, in-
The mechanism for autoimmune destruction of flammatory destruction of the thyroid may lead to
the thyroid probably involves both cellular immuni- transient thyrotoxicosis as preformed thyroid hor-
ty and humoral immunity. Lymphocytic infiltration mones are released from the damaged gland. As thy-
of the thyroid gland by equal numbers of B cells and roid hormone stores are depleted, there is often a
cytotoxic T cells is a common histologic feature of progression through a period of euthyroidism to
all forms of autoimmune thyroiditis (Fig. 1). In pa- hypothyroidism. The first biochemical change in
tients with Hashimoto’s thyroiditis, thyrocytes ex- inflammatory thyroiditis before the onset of thyro-
press the Fas gene, a member of the closely linked toxicosis is an increase in the serum concentration
group of tumor necrosis factor genes, or supergene of thyroglobulin.23 As in other forms of thyrotox-
family, whereas thyrocytes from normal glands do icosis, the serum concentration of thyrotropin is
not. Apoptosis caused by the interaction of the Fas suppressed, and concentrations of total and free
gene and the Fas ligand on the surface of thyro- triiodothyronine (T3) and thyroxine (T4) are elevat-
cytes may be an underlying cause of thyroid-cell de- ed. Serum T4 concentrations are proportionally
struction.12 higher than T3 concentrations, reflecting the ratio
of stored hormone in the thyroid gland (whereas in
genetic susceptibility Graves’ disease and in toxic nodular goiter, T3 is
The genetics of autoimmune thyroid disease are preferentially elevated). The signs and symptoms
complex.13 Association of Hashimoto’s thyroiditis
and painless postpartum thyroiditis with HLA-DR3,
HLA-DR4, and HLA-DR5 has been reported in white
persons,14-16 but other associations have been ob- Table 1. Terminology for Thyroiditis.
served in other racial and ethnic groups. The cyto-
Type Synonyms
toxic-T-lymphocyte–associated protein 4 (CTLA-4)
gene region may be associated with familial Hashi- Hashimoto’s thyroiditis Chronic lymphocytic thyroiditis
moto’s thyroiditis, although a clear linkage has been Chronic autoimmune thyroiditis
Lymphadenoid goiter
difficult to demonstrate. Studies of the association
between painless postpartum thyroiditis and the Painless postpartum thyroiditis Postpartum thyroiditis
Subacute lymphocytic thyroiditis
CTLA-4 gene have been negative.17 There is a higher
incidence of subacute thyroiditis in those with the Painless sporadic thyroiditis Silent sporadic thyroiditis
Subacute lymphocytic thyroiditis
HLA-Bw35 haplotype.18
Painful subacute thyroiditis Subacute thyroiditis
environmental factors de Quervain’s thyroiditis
Giant-cell thyroiditis
Among patients with Hashimoto’s thyroiditis, hy- Subacute granulomatous thyroiditis
pothyroidism is more likely to develop in smokers Pseudogranulomatous thyroiditis
than in nonsmokers,19 a finding that may be related Suppurative thyroiditis Infectious thyroiditis
to the presence of thiocyanates in cigarette smoke. Acute suppurative thyroiditis
An increased prevalence of painless postpartum thy- Pyrogenic thyroiditis
Bacterial thyroiditis
roiditis has also been noted among smokers.20 In
addition, geographic variations in the incidence of Drug-induced thyroiditis
(amiodarone, lithium, interferon
Hashimoto’s thyroiditis, painless postpartum thy- alfa, interleukin-2)
roiditis, and painless sporadic thyroiditis suggest
that dietary iodine insufficiency may be protective Riedel’s thyroiditis Fibrous thyroiditis
against autoimmune thyroiditis.21,22

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 The new england journal of medicine

Table 2. Characteristics of Thyroiditis Syndromes.*

Painless Painless Painful

Hashimoto’s Postpartum Sporadic Subacute Suppurative Riedel’s
Characteristic Thyroiditis Thyroiditis Thyroiditis Thyroiditis Thyroiditis Thyroiditis

Age at onset (yr) All ages, peak Childbearing age All ages, peak 20–60 Children, 20–40 30–60
30–50 30–40
Sex ratio (F:M) 8–9:1 — 2:1 5:1 1:1 3–4:1
Cause Autoimmune Autoimmune Autoimmune Unknown Infectious Unknown
Pathological findings Lymphocytic infiltra- Lymphocytic Lymphocytic infil- Giant cells, Abscess forma- Dense fibrosis
tion, germinal infiltration tration granulomas tion
centers, fibrosis
Thyroid function Hypothyroidism Thyrotoxicosis, Thyrotoxicosis, Thyrotoxicosis, Usually euthy- Usually euthy-
hypothyroid- hypothyroid- hypothyroid- roidism roidism
ism, or both ism, or both ism, or both
TPO antibodies High titer, High titer, High titer, Low titer, or ab- Absent Usually present
persistent persistent persistent sent, tran-
sient
ESR Normal Normal Normal High High Normal
24-Hour 123I uptake Variable <5% <5% <5% Normal Low or normal

* Information is from Farwell and Braverman.1 TPO denotes thyroid peroxidase, ESR erythrocyte sedimentation rate, and 123I iodine-123.

of thyrotoxicosis due to thyroiditis are usually not

types of thyroiditis
severe.
hashimoto’s thyroiditis
hypothyroidism Hashimoto’s thyroiditis (Fig. 1A), which is charac-
The hypothyroid phase of thyroiditis results from terized by the presence of high serum thyroid anti-
the gradual depletion of stored thyroid hormones. body concentrations and goiter, is the most com-
Although chronic hypothyroidism is most closely mon type of thyroiditis. In the United States and
associated with Hashimoto’s thyroiditis, all types of other countries where the ordinary diet provides suf-
thyroiditis may progress to permanent hypothyroid- ficient iodine (median urinary iodine levels, >100 µg
ism. This outcome is more likely in patients with per liter), Hashimoto’s thyroiditis is the most fre-
higher serum concentrations of thyroid antibodies quent cause of hypothyroidism and goiter. In an oc-
or in patients in whom a more severe hypothyroid casional patient, hyperthyroidism alternates with
phase develops. As thyroid function diminishes, se- hypothyroidism, most likely owing to the intermit-
rum thyrotropin concentrations rise. The combina- tent presence of thyroid-stimulating and thyroid-
tion of elevated serum thyrotropin concentrations blocking antibodies.25
and normal free T4 and T3 concentrations is termed A firm, bumpy, symmetric, painless goiter is fre-
“subclinical hypothyroidism,” or “mild thyroid fail- quently the initial finding in Hashimoto’s thyroidi-
ure.”24 As thyroid failure progresses, serum T4 con- tis. About 10 percent of patients with chronic au-
centrations fall, and the combination of elevated toimmune hypothyroidism have atrophic thyroid
thyrotropin concentrations and low T4 concentra- glands (rather than goiter), which may represent
tions is termed “overt hypothyroidism.” Serum total the final stage of thyroid failure in Hashimoto’s
and free T3 concentrations may not fall until the dis- thyroiditis.26 High serum thyroid peroxidase anti-
ease is far advanced, because increased serum thy- body concentrations are present in 90 percent of pa-
rotropin concentrations stimulate the thyroid to tients with Hashimoto’s thyroiditis, and high serum
release T3. In most patients, once the serum T3 con- thyroglobulin antibody concentrations are present
centrations fall below the normal level, the classic in 20 to 50 percent of these patients.27 The thyroid
symptoms and signs of hypothyroidism appear. appears hypoechogenic on ultrasound examination.

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 current concepts

The 24-hour radioactive iodine (iodine-123 [123I])

uptake is not helpful in establishing the diagnosis. H G
Once overt hypothyroidism is present, levothy- C P
roxine sodium is the treatment of choice for Hashi-
moto’s thyroiditis. We also use levothyroxine sodi-
um to treat patients with subclinical hypothyroidism
and high serum thyroid antibody concentrations,
because the progression to overt hypothyroidism is
common9 and because hyperlipidemia and ath-
erosclerotic heart disease may develop in patients
with subclinical hypothyroidism.28,29 The goal of
replacement therapy with levothyroxine sodium is A
normalization of serum thyrotropin values.
In patients with Hashimoto’s thyroiditis and a
WG
large goiter, thyrotropin-suppressing doses of levo-
thyroxine sodium can be given over the short term H
(i.e., six months) to decrease the size of the goiter. In
most patients with Hashimoto’s thyroiditis (wheth-
er their condition is euthyroid or hypothyroid), goi-
ter size will decrease by 30 percent after six months
of therapy with levothyroxine sodium.30 Replace-
ment doses should be resumed if the size of the
goiter does not decrease. Because serum thyroid an-
tibody concentrations do not decrease with levothy- B
roxine sodium therapy,31,32 except in some patients
I
with hypothyroidism,33 monitoring of these con-
centrations is not indicated once the diagnosis of M
Hashimoto’s thyroiditis has been made.
Although thyroid lymphoma is very rare, the risk F
of this disease is increased by a factor of 67 in pa- R
tients with Hashimoto’s thyroiditis.34 Patients with
Hashimoto’s thyroiditis and a dominant thyroid
nodule should undergo fine-needle aspiration biop-
sy to rule out lymphoma and thyroid carcinoma. C
When thyroid carcinoma occurs in patients with this
type of thyroiditis or other lymphocytic infiltration, Figure 1. Specimens from Patients with Hashimoto’s
the prognosis appears to be more favorable than Thyroiditis (Panel A), Painless Postpartum Thyroiditis
when it does not.35 (Panel B), and Painful Subacute Thyroiditis (Panel C)
(Hematoxylin and Eosin, ¬200).
painless postpartum thyroiditis The specimen in Panel A shows typical changes of Ha-
Painless postpartum thyroiditis (Fig. 1B) causes shimoto’s thyroiditis, including lymphoid follicles with
germinal centers (G), small lymphocytes and plasma
lymphocytic inflammation of the thyroid within the cells (P), thyroid follicles with Hürthle-cell metaplasia
first few months after delivery. It occurs in up to 10 (H), and minimal colloid material (C). The specimen in
percent of women in the United States, although es- Panel B, obtained from a patient with painless postpar-
timates vary.36,37 The disease is most common in tum thyroiditis, shows normal follicles with minimal
women who have high serum thyroid peroxidase Hürthle-cell metaplasia (H) and dense lymphocytic infil-
tration (WG) without germinal centers. The specimen in
antibody concentrations during the first trimester Panel C, obtained from a patient with painful subacute
of pregnancy or immediately after delivery and in thyroiditis, shows characteristic residual follicles (R), fi-
those with other autoimmune disorders, such as brotic bands (F), mixed inflammation (I), and a multinu-
type 1 diabetes mellitus, or with a family history of cleated giant cell (M).
autoimmune thyroid disease.
In only one third of patients with painless post-

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 The new england journal of medicine

breast milk and 123I has a half-life of 13 hours, nurs-

ing mothers need to pump and discard milk for at
Serum T4 Serum TSH 123I uptake least two days after the test.
Increased
Mild thyrotoxicosis rarely requires therapy, but
when the disease is severe, it is treated with beta-
blockers. Antithyroid drug therapy is contraindicat-
ed, because there is no excess thyroid hormone pro-
Normal
duction. Treatment of the hypothyroid phase may
not be necessary, but if this phase is prolonged or if
the patient is symptomatic, levothyroxine sodium
Decreased
should be given, then withdrawn after six to nine
months to determine whether thyroid function has
normalized.
0 1 2 3 4 5 6 7 8 9
Month painless sporadic thyroiditis
Painless postpartum thyroiditis and painless spo-
Figure 2. Clinical Course of Painful Subacute Thyroiditis, Painless Postpartum radic thyroiditis are indistinguishable except by the
Thyroiditis, and Painless Sporadic Thyroiditis.
relation of the former to pregnancy.42 The latter dis-
Measurements of serum thyrotropin (TSH) and iodine-123 (123I) uptake
show thyrotoxicosis during the first three months, followed by hypothyroid-
ease is more difficult to study because of its sporadic
ism for three months and then by euthyroidism. T4 denotes thyroxine. nature. These syndromes may represent a subacute
form of Hashimoto’s thyroiditis. Painless sporadic
thyroiditis43 may account for about 1 percent of all
cases of thyrotoxicosis. The clinical course is similar
partum thyroiditis will the classic triphasic thyroid to that of painless postpartum thyroiditis. Although
hormone pattern develop (Fig. 2). Thyrotoxicosis abnormalities in thyroid function resolve in most
typically begins one to six months after delivery and patients, 20 percent of patients will have residual
lasts for one to two months. That phase may be fol- chronic hypothyroidism.44 Symptoms are usually
lowed by a hypothyroid phase starting four to eight mild. A small, nontender, very firm, diffuse goiter is
months after delivery and lasting four to six months. present in 50 percent of these patients.45 High se-
Eighty percent of women recover normal thyroid rum thyroid peroxidase antibody concentrations are
function within a year; in one follow-up study, how- present in 50 percent of patients at the time of diag-
ever, permanent hypothyroidism developed within nosis, with lower titers, on average, than in Hashi-
seven years in 50 percent of the women studied.38 moto’s thyroiditis.45 A low or undetectable concen-
Chronic hypothyroidism is more likely in multipa- tration of 123I at 24 hours can be diagnostic, and
rous women or in those with a history of spontane- the test should be performed when the cause of the
ous abortion.39 After a first episode of painless post- thyrotoxicosis is unclear, in order to avoid inappro-
partum thyroiditis, there is a 70 percent chance of priate treatment with antithyroid drugs. Therapy is
recurrence with subsequent pregnancies.40 the same as that for painless postpartum thyroidi-
In most cases of painless postpartum thyroiditis, tis. Overall recurrence rates have not been well es-
a small, nontender, firm goiter is present. High tablished.
serum concentrations of thyroid peroxidase anti-
bodies, thyroglobulin antibodies, or both, are also painful subacute thyroiditis
present.41 The erythrocyte sedimentation rate is nor- Painful subacute thyroiditis (Fig. 1C), which is a self-
mal. The 24-hour 123I uptake may be used to distin- limited inflammatory disorder, is the most common
guish painless postpartum thyroiditis from postpar- cause of thyroid pain. It occurs in up to 5 percent of
tum Graves’ disease; the uptake is low (<5 percent) patients with clinical thyroid disease.46 It frequent-
in women with painless postpartum thyroiditis, ly follows an upper respiratory tract infection, and
whereas it is elevated in those with Graves’ disease. its incidence is highest in summer, correlating with
This test should be performed in patients with symp- the peak incidence of enterovirus.47 A viral cause of
tomatic thyrotoxicosis when there are no clear signs subacute thyroiditis has therefore been proposed,48
of Graves’ disease, such as large goiter or ophthal- but so far clear evidence for it is lacking.
mopathy. Because radioactive iodine is secreted in Subacute thyroiditis begins with a prodrome of

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 current concepts

generalized myalgias, pharyngitis, low-grade fever, tion, high iodide content, rich blood supply, and
and fatigue. Patients then present with fever and se- extensive lymphatic drainage, and suppurative thy-
vere neck pain, swelling, or both. Up to 50 percent of roiditis is therefore rare.54 It is most likely to occur
patients have symptoms of thyrotoxicosis. In most in patients with preexisting thyroid disease (thyroid
patients, thyroid function will be normal after sever- cancer, Hashimoto’s thyroiditis, or multinodular
al weeks of thyrotoxicosis, and hypothyroidism will goiter), those with congenital anomalies such as a
subsequently develop, lasting four to six months, as pyriform sinus fistula (the most common source of
in painless sporadic thyroiditis and painless post- infection in children), and those who are immuno-
partum thyroiditis. Although thyroid function nor- suppressed, elderly, or debilitated; it is particularly
malizes spontaneously in 95 percent of patients over likely to occur in patients with the acquired immu-
a period of 6 to 12 months, residual hypothyroid- nodeficiency syndrome (AIDS), in whom Pneumocys-
ism persists in 5 percent of patients.1,49 Painful sub- tis carinii and other opportunistic thyroid infections
acute thyroiditis recurs in only about 2 percent of have been reported.55,56
patients.50 Patients with suppurative bacterial thyroiditis
The hallmark of painful subacute thyroiditis is a are usually acutely ill with fever, dysphagia, dyspho-
markedly elevated erythrocyte sedimentation rate. nia, anterior neck pain and erythema, and a tender
The C-reactive protein concentration is similarly el- thyroid mass. Symptoms may be preceded by an
evated.51 The leukocyte count is normal or slightly acute upper respiratory infection. The presentation
elevated. Peripheral-blood thyroid hormone con- of fungal infection, parasitic infection, mycobacte-
centrations are elevated, with ratios of T4 to T3 of rial thyroiditis, and opportunistic thyroid infection
less than 20, reflecting the proportions of stored in patients with AIDS tends to be chronic and in-
hormone within the thyroid,52 and serum concen- sidious.
trations of thyrotropin are low or undetectable. Se- Thyroid function is generally normal in patients
rum thyroid peroxidase antibody concentrations are with suppurative thyroiditis, but both thyrotoxico-
usually normal. The 24-hour 123I uptake is low sis and hypothyroidism have been reported.54 Leu-
(<5 percent) in the toxic phase of subacute thyroid- kocyte counts and erythrocyte sedimentation rates
itis, distinguishing this disease from Graves’ dis- are elevated. Suppurative areas appear “cold” on ra-
ease. Color-flow Doppler ultrasonography may also dioactive-iodine scanning. Fine-needle aspiration
help to make this distinction; in patients with biopsy with Gram’s staining and culture is the di-
Graves’ disease the thyroid gland is hypervascular, agnostic test of choice. The therapy for suppurative
whereas in patients with painful subacute thyroid- thyroiditis consists of appropriate antibiotics and
itis the gland is hypoechogenic and has low-to-nor- drainage of any abscess. The disease may prove fatal
mal vascularity.53 if diagnosis and treatment are delayed.
The treatment for painful subacute thyroiditis
is to provide symptomatic relief only. Nonsteroidal drug-induced thyroiditis
medications or salicylates are adequate to control Many medications can alter thyroid function or the
mild thyroid pain. For more severe thyroid pain, results of thyroid-function tests. However, only a
high doses of glucocorticoids (e.g., 40 mg of pred- few are known to provoke autoimmune or destruc-
nisone daily) provide immediate relief; doses should tive inflammatory thyroiditis.
be tapered over a period of four to six weeks. Corti-
costeroids should be discontinued when the 123I up- Amiodarone
take returns to normal. Beta-blockade controls the The various effects of amiodarone on the thyroid
symptoms of thyrotoxicosis. Therapy with levothy- (Table 3) and the peripheral metabolism of the
roxine sodium is rarely required, because the hy- thyroid hormones have recently been reviewed.57
pothyroid phase is generally mild and transient, but Amiodarone-induced hypothyroidism, which is due
it is indicated for symptomatic patients. to excess iodine, occurs in up to 20 percent of pa-
tients in iodine-sufficient regions. Patients with pre-
suppurative thyroiditis existing thyroid autoimmunity are at increased risk
Suppurative thyroiditis is usually caused by bacteri- for the development of hypothyroidism while receiv-
al infection, but fungal, mycobacterial, or parasitic ing amiodarone. Treatment with levothyroxine so-
infections may also occur as the cause. The thyroid dium is indicated in hypothyroid patients, and amio-
is resistant to infection, because of its encapsula- darone may be continued. The dose of levothyroxine

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 The new england journal of medicine

Table 3. Features of Amiodarone-Induced Thyroid Dysfunction.

Feature Type I Thyrotoxicosis Type II Thyrotoxicosis Hypothyroidism

Mechanism Excess iodine (common in Destructive inflammatory Excess iodine (common in

iodine-deficient areas) thyroiditis iodine-sufficient areas)
Thyroid antibodies Often present Usually absent Often present
Thyroid function Thyrotoxicosis Thyrotoxicosis Hypothyroidism
24-Hour 123I uptake* Low in iodine-sufficient re- <5% Usually low in iodine-
gions but may be normal sufficient regions
or increased in iodine-
deficient areas
Findings on color Doppler Hypervascularity Reduced blood flow Variable
ultrasonography
Therapy High-doses of antithyroid High doses of cortico- Levothyroxine sodium
drugs — possibly potas- steroids, iopanoic
sium perchlorate, or acid
iopanoic acid before
thyroidectomy

* 123I denotes iodine-123.

sodium needed to normalize the serum concentra- imazole or propylthiouracil), sometimes with the
tion of thyrotropin is often higher than the usual addition of potassium perchlorate to prevent fur-
dose, because amiodarone decreases 5'-deiodinase ther uptake of iodine by the thyroid. Lithium has
activity in peripheral tissues, thus also decreasing also been suggested as therapy for type I disease.61
production of T3. Type II amiodarone-induced thyrotoxicosis re-
Amiodarone-induced thyrotoxicosis occurs in up sponds to high-dose corticosteroids. Iopanoic acid
to 23 percent of patients receiving amiodarone and has recently been reported to be effective in patients
is far more prevalent in iodine-deficient regions.58 with type II amiodarone-induced thyrotoxicosis,62
Type I amiodarone-induced thyrotoxicosis is de- although less so than corticosteroids,63 and in those
fined as synthesis and release of excessive thyroid with type I disease who require thyroidectomy.64
hormone; it is iodine-induced, and it is more likely Careful examination of the thyroid, base-line thy-
to occur in patients with preexisting subclinical thy- roid-function tests, and measurements of serum
roid disorders, especially nodular goiter. Type II concentrations of thyroid peroxidase and thyroglob-
amiodarone-induced thyrotoxicosis is a destructive ulin antibodies should be performed before amio-
thyroiditis that causes the release of preformed thy- darone therapy is instituted, and thyroid function
roid hormone from the damaged thyroid gland. Dis- should be monitored every six months as long as pa-
tinguishing between the two forms of amiodarone- tients are receiving the drug (Fig. 3).
induced thyrotoxicosis is difficult, especially since
some patients have both types. In patients in the Lithium
United States, 123I uptake values are typically low In patients with preexisting thyroid autoimmunity,
in type I and type II amiodarone-induced thyrotox- lithium may increase the serum thyroid antibody
icosis. Color-flow Doppler ultrasonography may concentrations and lead to subclinical or overt hy-
show hypervascularity in type I disease but reduced pothyroidism.65 Estimates of the prevalence of high
blood flow in type II.59 Although the serum inter- serum thyroid antibody concentrations in patients
leukin-6 concentration was initially reported to be receiving long-term treatment with lithium range
more elevated in type II amiodarone-induced thyro- from 10 to 33 percent.66 In addition, thyrotoxicosis
toxicosis than in type I,60 subsequent studies have has been reported after long-term lithium use,67
not replicated this finding. possibly caused by lithium’s direct toxic effects on
Type I amiodarone-induced thyrotoxicosis is best thyroid cells or by lithium-induced painless sporad-
treated with high doses of antithyroid drugs (meth- ic thyroiditis.68,69

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 current concepts

At Base Line
Thyroid examination and measurements of thyroid peroxidase antibodies, thyroglobulin (Tg) antibodies, thyrotropin (TSH), thyroxine (T4),
free T4 (or free T4 index), total triiodothyronine (T3)

Every 6 mo
Thyroid examination and measurements of TSH, T4, free T4 (or free T4 index), total T3

Decrease in serum thyrotropin Increase in serum thyrotropin

No change in T4, free T4 Increased T4 (or free T4 index)

(or free T4 index), or total T3 or total T3 vs. previous values

Frequent observations Drug-induced thyrotoxicosis Drug-induced hypothyroidism

Figure 3. Monitoring Thyroid Function in Patients Receiving Amiodarone Therapy.

Adapted from Martino et al.,57 with the permission of the publisher.

Interferon Alfa and Interleukin-2 tinued, affected patients are at increased risk for au-
In up to 15 percent of patients without previous thy- toimmune thyroid dysfunction in the future. Thy-
roid autoimmunity, high serum thyroid peroxidase roid-function tests and measurements of serum
antibody concentrations or thyroid dysfunction will thyroid antibodies should be performed before ther-
develop during interferon alfa therapy.70 High se- apy with interferon alfa or interleukin-2 is initiated
rum thyroid peroxidase antibody concentrations in and every six months thereafter.
such patients and in patients receiving interleukin-2
therapy may be associated with overt or subclinical riedel’s thyroiditis
hyperthyroidism (Graves’ disease) or hypothyroid- Riedel’s thyroiditis, a local manifestation of a sys-
ism.71 Interferon alfa has also been reported to temic fibrotic process,74 is a progressive fibrosis of
cause destructive inflammatory thyroiditis.72,73 The the thyroid gland that may extend to surrounding
measurement of 123I uptake helps to distinguish tissues. The prevalence of this disease is only 0.05
between drug-induced Graves’ disease, in which the percent among patients with thyroid disease requir-
uptake is elevated, and drug-induced inflammatory ing surgery, and its cause is unknown. High serum
thyroiditis, in which the uptake is low, in patients thyroid antibody concentrations are present in up to
with thyrotoxicosis. 67 percent of patients, but it is unclear whether the
When Graves’ disease develops in patients re- antibodies are a cause or effect of the fibrotic thy-
ceiving interferon alfa therapy, they should be treat- roid destruction.
ed with antithyroid drugs. While treatment with Patients with Riedel’s thyroiditis present with a
interferon alfa or interleukin-2 is continued, the rock-hard, fixed, painless goiter. They may have
thyrotoxic phase of inflammatory thyroiditis can be symptoms due to tracheal or esophageal compres-
treated with beta-blockers and, if necessary, with sion or hypoparathyroidism due to extension of the
nonsteroidal antiinflammatory drugs or corticoster- fibrosis into adjacent parathyroid tissue. Most pa-
oids, and the hypothyroidism can be treated with tients are euthyroid at presentation but become hy-
levothyroxine sodium. Although thyroid function pothyroid once replacement of normal thyroid tis-
usually normalizes when cytokine therapy is discon- sue is nearly complete. A definitive diagnosis is

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 The new england journal of medicine

made by open biopsy. The treatment is surgical, al- Dr. Braverman reports having received consulting or lecture fees
from Abbott Laboratories, Genzyme, and Monarch Pharmaceuticals.
though therapy with glucocorticoids, methotrexate, We are indebted to Dr. Antonio de las Morenas for providing pho-
and tamoxifen has been reported to be successful tomicrographs of thyroid tissue.
in the early stages of the disease.75,76

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