ATA Guideline 2016

THYROID SPECIAL ARTICLE
Volume 26, Number 10, 2016

ª American Thyroid Association
ª Mary Ann Liebert, Inc.
DOI: 10.1089/thy.2016.0229
2016 American Thyroid Association Guidelines

for Diagnosis and Management of Hyperthyroidism
and Other Causes of Thyrotoxicosis
Douglas S. Ross,1* Henry B. Burch,2** David S. Cooper,3 M. Carol Greenlee,4 Peter Laurberg,5{
Ana Luiza Maia,6 Scott A. Rivkees,7 Mary Samuels,8 Julie Ann Sosa,9
Marius N. Stan,10 and Martin A. Walter11
Background: Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate
treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference.
This document describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be
useful to generalist and subspecialty physicians and others providing care for patients with this condition.
Methods: The American Thyroid Association (ATA) previously cosponsored guidelines for the management of
thyrotoxicosis that were published in 2011. Considerable new literature has been published since then, and the
ATA felt updated evidence-based guidelines were needed. The association assembled a task force of expert
clinicians who authored this report. They examined relevant literature using a systematic PubMed search sup-
plemented with additional published materials. An evidence-based medicine approach that incorporated the
knowledge and experience of the panel was used to update the 2011 text and recommendations. The strength of the
recommendations and the quality of evidence supporting them were rated according to the approach recommended
by the Grading of Recommendations, Assessment, Development, and Evaluation Group.
Results: Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management
of Graves’ hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multi-
nodular goiter or toxic adenoma using radioactive iodine or surgery; Graves’ disease in children, adolescents, or
pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves’ orbitopathy; and
management of other miscellaneous causes of thyrotoxicosis. New paradigms since publication of the 2011
guidelines are presented for the evaluation of the etiology of thyrotoxicosis, the management of Graves’ hyper-
thyroidism with antithyroid drugs, the management of pregnant hyperthyroid patients, and the preparation of
patients for thyroid surgery. The sections on less common causes of thyrotoxicosis have been expanded.
Conclusions: One hundred twenty-four evidence-based recommendations were developed to aid in the care of
patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical
practice.
1
Massachusetts General Hospital, Boston, Massachusetts.
2
Endocrinology – Metabolic Service, Walter Reed National Military Medical Center, Bethesda, Maryland.
3
Division of Endocrinology, Diabetes, and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
4
Western Slope Endocrinology, Grand Junction, Colorado.
5
Departments of Clinical Medicine and Endocrinology, Aalborg University and Aalborg University Hospital, Aalborg, Denmark.
6
Thyroid Section, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
7
Pediatrics – Chairman’s Office, University of Florida College of Medicine, Gainesville, Florida.
8
Division of Endocrinology, Diabetes and Clinical Nutrition, Oregon Health & Science University, Portland, Oregon.
9
Section of Endocrine Surgery, Duke University School of Medicine, Durham, North Carolina.
10
Division of Endocrinology, Mayo Clinic, Rochester, Minnesota.
11
Institute of Nuclear Medicine, University Hospital Bern, Switzerland.
*Authorship listed in alphabetical order following the Chairperson.
**One or more of the authors are military service members (or employees of the U.S. Government). The views expressed in this
manuscript are those of the authors and do not reflect the official policy of the Department of the Army, the Department of Defense or the
United States Government. This work was prepared as part of the service member’s official duties.
{Deceased.
1343
1344 ROSS ET AL.
DEDICATION of interest at the initial meeting of the group and periodi-

These guidelines are dedicated to the memory of Peter cally during the course of deliberations. Funding for the
Laurberg, our friend and colleague, who died tragically during guidelines was derived solely from the general funds of the
their preparation. ATA, and thus the task force functioned without com-
mercial support.
INTRODUCTION
The task force reviewed the 2011 guidelines and pub-
lished editorials regarding those guidelines. It then de-
T hyrotoxicosis is a condition having multiple eti-

ologies, manifestations, and potential therapies. The
term ‘‘thyrotoxicosis’’ refers to a clinical state that results
veloped a revised list of the most common causes of
thyrotoxicosis and the most important questions that a
practitioner might pose when caring for a patient with a
from inappropriately high thyroid hormone action in tis- particular form of thyrotoxicosis or special clinical con-
sues generally due to inappropriately high tissue thyroid dition. One task force member was assigned as the primary
hormone levels. The term ‘‘hyperthyroidism,’’ as used in writer for each topic. One or more task force members
these guidelines, is a form of thyrotoxicosis due to inappro- were assigned as secondary writers for each topic, pro-
priately high synthesis and secretion of thyroid hormone(s) by viding their specific expertise and critical review for the
the thyroid. Appropriate treatment of thyrotoxicosis requires primary writer. The relevant literature was reviewed using
an accurate diagnosis. For example, thyroidectomy is an ap- a systematic PubMed search for primary references and
propriate treatment for some forms of thyrotoxicosis and not reviews published after the submission of the 2011 guidelines,
for others. Additionally, b-blockers may be used in almost all supplemented with additional published materials found on
forms of thyrotoxicosis, whereas antithyroid drugs (ATDs) are focused PubMed searches. Recommendations were based on
useful in only some. the literature and expert opinion where appropriate. A pre-
In the United States, the prevalence of hyperthyroidism is liminary document and a series of recommendations con-
approximately 1.2% (0.5% overt and 0.7% subclinical); the cerning all the topics were generated by each primary writer
most common causes include Graves’ disease (GD), toxic and then critically reviewed by the task force at large. The panel
multinodular goiter (TMNG), and toxic adenoma (TA) (1). agreed recommendations would be based on consensus of the
Scientific advances relevant to this topic are reported in a panel and that voting would be used if agreement could not be
wide range of literature, including subspecialty publications reached. Task force deliberations took place between 2014 and
in endocrinology, pediatrics, nuclear medicine, and surgery, 2016 during several lengthy committee meetings and through
making it challenging for clinicians to keep abreast of new electronic communication.
developments. Although guidelines for the diagnosis and
management of patients with thyrotoxicosis were published
Rating of the recommendations
previously by the American Thyroid Association (ATA) and
the American Association of Clinical Endocrinologists These guidelines were developed to combine the best
(AACE) in 2011, the ATA determined that thyrotoxicosis scientific evidence with the experience of seasoned clini-
represents a priority area in need of updated evidence-based cians and the pragmatic realities inherent in implementa-
practice guidelines. tion. The task force elected to rate the recommendations
The target audience for these guidelines includes general according to the system developed by the Grading of Re-
and subspecialty physicians and others providing care for commendations, Assessment, Development, and Evalua-
patients with thyrotoxicosis. In this document, we outline tion Group (3–6). The balance between benefits and risks,
what we believe is current, rational, and optimal medical quality of evidence, applicability, and certainty of the
practice. These guidelines are not intended to replace clin- baseline risk are all considered in judgments about the
ical judgment, individual decision making, or the wishes strength of recommendations (7). Grading the quality of
of the patient or family. Rather, each recommendation the evidence takes into account study design, study quality,
should be evaluated in light of these elements so that opti- consistency of results, and directness of the evidence. The
mal patient care is delivered. In some circumstances, the strength of a recommendation is indicated as a strong rec-
level of care required may be best provided in centers with ommendation (for or against) that applies to most patients
specific expertise, and referral to such centers should be in most circumstances with benefits of action clearly out-
considered. weighing the risks and burdens (or vice versa), or a weak
recommendation or a suggestion that may not be appro-
METHODS OF DEVELOPMENT priate for every patient, depending on context, patient
OF EVIDENCE-BASED GUIDELINES values, and preferences. The quality of the evidence is in-
dicated as low-quality evidence, moderate-quality evi-
Administration
dence, or high-quality evidence, based on consistency of
The ATA Executive Council selected a chairperson to results between studies and study design, limitations, and
lead the task force and this individual (D.S.R.) identified the directness of the evidence. In several instances, the
the other 10 members of the panel in consultation with the evidence was insufficient to recommend for or against a test
ATA board of directors. Membership on the panel was or a treatment, and the task force made a statement labeled
based on clinical expertise, scholarly approach, and rep- ‘‘no recommendation.’’ Table 1 describes the criteria to be
resentation of adult and pediatric endocrinology, nuclear met for each rating category. Each recommendation is
medicine, and surgery. The task force included individuals preceded by a description of the evidence and, is followed in
from North America, South America, and Europe. Panel some cases by a remarks section including technical sug-
members declared whether they had any potential conflict gestions on issues such as dosing and monitoring.
HYPERTHYROIDISM MANAGEMENT GUIDELINES 1345
Table 1. Grading of Recommendations, Assessment, Development, and Evaluation System

Type of grading Definition of grades
Strength of the recommendation Strong recommendation (for or against)
Applies to most patients in most circumstances
Benefits clearly outweigh the risk (or vice versa)
Weak recommendation (for or against)
Best action may differ depending on circumstances or patient values
Benefits and risks or burdens are closely balanced, or uncertain
No recommendation (insufficient evidence for or against)
Quality of the evidence High quality; evidence at low risk of bias, such as high quality
randomized trials showing consistent results directly applicable
to the recommendation
Moderate quality; studies with methodological flaws, showing
inconsistent or indirect evidence
Low quality; case series or unsystematic clinical observations
Insufficient evidence
Presentation of recommendations the main body of the text. Location keys can be copied into
the Find or Search function in a file or Web page to rap-
The organization of the task force’s recommendations is idly navigate to a particular section. A listing of the recom-
presented in Table 2. The page numbers and the location key mendations without text is provided as Supplementary
can be used to locate specific topics and recommendations. Appendix A (Supplementary Data are available online at
Specific recommendations are presented within boxes in www.liebertpub.com/thy).
Table 2. Organization of the Task Force’s Recommendations

Location key Description Page
[A] Background 1347
[A1] Causes of thyrotoxicosis 1347
[A2] Clinical consequences of thyrotoxicosis 1347
[B] How should clinically or incidentally discovered thyrotoxicosis be evaluated and 1348
initially managed?
[B1] Assessment of disease severity 1348
[B2] Biochemical evaluation 1348
[B3] Determination of etiology 1349
[B4] Symptomatic management 1350
[C] How should overt hyperthyroidism due to GD be managed? 1350
[D] If RAI therapy is chosen, how should it be accomplished? 1352
[D1] Preparation of patients with GD for RAI therapy 1352
[D2] Administration of RAI in the treatment of GD 1353
[D3] Patient follow-up after RAI therapy for GD 1354
[D4] Treatment of persistent Graves’ hyperthyroidism following RAI therapy 1355
[E] If ATDs are chosen as initial management of GD, how should the therapy be 1355
managed?
[E1] Initiation of ATD therapy for the treatment of GD 1355
[E2] Adverse effects of ATDs 1356
[E3] Agranulocytosis 1356
[E4] Hepatotoxicity 1356
[E5] Vasculitis 1356
[E6] Monitoring of patients taking ATDs 1357
[E7] Management of allergic reactions 1358
[E8] Duration of ATD therapy for GD 1358
[E9] Persistently elevated TRAb 1358
[E10] Negative TRAb 1358
[F] If thyroidectomy is chosen for treatment of GD, how should it be accomplished? 1359
[F1] Preparation of patients with GD for thyroidectomy 1359
[F2] The surgical procedure and choice of surgeon 1359
[F3] Postoperative care 1360
[G] How should thyroid nodules be managed in patients with GD? 1361
[H] How should thyroid storm be managed? 1361
[I] Is there a role for iodine as primary therapy in the treatment of GD? 1363
(continued)
1346 ROSS ET AL.
Table 2. (Continued)
[J] How should overt hyperthyroidism due to TMNG or TA be treated? 1363
[K] If RAI therapy is chosen as treatment for TMNG or TA, how should it be 1365
accomplished?
[K1] Preparation of patients with TMNG or TA for RAI therapy 1365
[K2] Evaluation of thyroid nodules prior to RAI therapy 1366
[K3] Administration of RAI in the treatment of TMNG or TA 1366
[K4] Patient follow-up after RAI therapy for TMNG or TA 1366
[K5] Treatment of persistent or recurrent hyperthyroidism following RAI therapy for 1367
TMNG or TA
[L] If surgery is chosen, how should it be accomplished? 1367
[L1] Preparation of patients with TMNG or TA for surgery 1367
[L2] The surgical procedure and choice of surgeon 1367
[L3] Postoperative care 1368
[L4] Treatment of persistent or recurrent disease following surgery for 1368
TMNG or TA
[M] If ATDs are chosen as treatment of TMNG or TA, how should the therapy be managed? 1368
[N] Is there a role for ethanol or radiofrequency ablation in the management of TA or 1369
TMNG?
[N1] Ethanol ablation 1369
[N2] Radiofrequency ablation 1369
[O] How should GD be managed in children and adolescents? 1369
[O1] General approach 1369
[P] If ATDs are chosen as initial management of GD in children, how should the therapy be 1370
managed?
[P1] Initiation of ATD therapy for the treatment of GD in children 1370
[P2] Symptomatic management of Graves’ hyperthyroidism in children 1371
[P3] Monitoring of children taking MMI 1371
[P4] Monitoring of children taking PTU 1371
[P5] Management of allergic reactions in children taking MMI 1371
[P6] Duration of MMI therapy in children with GD 1372
[Q] If radioactive iodine is chosen as treatment for GD in children, how should it be 1372
accomplished?
[Q1] Preparation of pediatric patients with GD for RAI therapy 1372
[Q2] Administration of RAI in the treatment of GD in children 1373
[Q3] Side effects of RAI therapy in children 1373
[R] If thyroidectomy is chosen as treatment for GD in children, how should it be 1374
accomplished?
[R1] Preparation of children with GD for thyroidectomy 1374
[S] How should subclinical hyperthyroidism be managed? 1375
[S1] Prevalence and causes of SH 1375
[S2] Clinical significance of SH 1375
[S3] When to treat SH 1376
[S4] How to treat SH 1377
[S5] End points to be assessed to determine effective therapy of SH 1378
[T] How should hyperthyroidism in pregnancy be managed? 1378
[T1] Diagnosis of hyperthyroidism in pregnancy 1378
[T2] Management of hyperthyroidism in pregnancy 1379
[T3] The role of TRAb level measurement in pregnancy 1384
[T4] Postpartum thyroiditis 1385
[U] How should hyperthyroidism be managed in patients with GO? 1386
[U1] Assessment of disease activity and severity 1386
[U2] Prevention of GO 1387
[U3] Treatment of hyperthyroidism in patients with no apparent GO 1389
[U4] Treatment of hyperthyroidism in patients with active GO of mild severity 1389
[U5] Treatment of hyperthyroidism in patients with active and moderate-to-severe or 1390
sight-threatening GO
[U6] Treatment of GD in patients with inactive GO 1390
[V] How should iodine-induced and amiodarone-induced thyrotoxicosis be managed? 1390
[V1] Iodine-induced thyrotoxicosis 1390
[V2] Amiodarone-induced thyrotoxicosis 1391
(continued)
Table 2. (Continued)
[W] How should thyrotoxicosis due to destructive thyroiditis be managed? 1394
[W1] Subacute thyroiditis 1394
[W2] Painless thyroiditis 1395
[W3] Acute thyroiditis 1395
[W4] Palpation thyroiditis 1395
[X] How should other causes of thyrotoxicosis be managed? 1395
[X1] Interferon-a and interleukin-2 1395
[X2] Tyrosine kinase inhibitors 1396
[X3] Lithium 1396
[X4] TSH-secreting pituitary tumors 1397
[X5] Struma ovarii 1397
[X6] Choriocarcinoma 1398
[X7] Thyrotoxicosis factitia 1398
[X8] Functional thyroid cancer metastases 1398
ATD, antithyroid drug; GD, Graves’ disease; GO, Graves’ orbitopathy; MMI, methimazole; PTU, propylthiouracil; RAI, radioactive
iodine; SH, subclinical hyperthyroidism; TA, toxic adenoma; TMNG, toxic multinodular goiter; TRAb, thyrotropin receptor antibody;
TSH, thyrotropin.
RESULTS thyroidism associated with a diffuse enlargement of the thyroid

[A] Background
gland (9). Autonomous hormone production may progress from
subclinical to overt hyperthyroidism, and the administration of
[A1] Causes of thyrotoxicosis pharmacologic amounts of iodine to such patients may result in
In general, thyrotoxicosis can occur if (i) the thyroid is iodine-induced hyperthyroidism (10). GD is the most common
excessively stimulated by trophic factors; (ii) constitutive cause of hyperthyroidism in the United States (11,12). Although
activation of thyroid hormone synthesis and secretion occurs, toxic nodular goiter is less common than GD, its prevalence
leading to autonomous release of excess thyroid hormone; increases with age and in the presence of dietary iodine
(iii) thyroid stores of preformed hormone are passively re- deficiency. Therefore, toxic nodular goiter may actually be more
leased in excessive amounts owing to autoimmune, infec- common than GD in older patients, especially in regions of
tious, chemical, or mechanical insult; or (iv) there is exposure iodine deficiency (13,14). Unlike toxic nodular goiter, which is
to extrathyroidal sources of thyroid hormone, which may be progressive (unless triggered by excessive iodine intake), re-
either endogenous (struma ovarii, metastatic differentiated mission of mild GD has been reported in up to 30% of patients
thyroid cancer) or exogenous (factitious thyrotoxicosis). without treatment (15).
Hyperthyroidism is generally considered overt or subclinical, Less common causes of thyrotoxicosis include the enti-
depending on the biochemical severity of the hyperthyroidism, ties of painless and subacute thyroiditis, which occur due to
although in reality the disease represents a continuum of over- inflammation of thyroid tissue with release of preformed
active thyroid function. Overt hyperthyroidism is defined as a hormone into the circulation. Painless thyroiditis caused by
subnormal (usually undetectable) serum thyrotropin (TSH) with lymphocytic inflammation appears to occur with a different
elevated serum levels of triiodothyronine (T3) and/or free thy- frequency depending on the population studied: in Denmark it
roxine estimates (free T4). Subclinical hyperthyroidism is de- accounted for only 0.5% of thyrotoxic patients, but it was 6% of
fined as a low or undetectable serum TSH with values within the patients in Toronto and 22% of patients in Wisconsin (16–18).
normal reference range for both T3 and free T4. Both overt and Painless thyroiditis may occur during lithium (19), cyto-
subclinical disease may lead to characteristic signs and symp- kine (e.g., interferon-a) (20), or tyrosine kinase inhibitor
toms, although subclinical hyperthyroidism is usually considered therapy (21), and in the postpartum period it is referred to as
milder. Overzealous or suppressive thyroid hormone adminis- postpartum thyroiditis (22). A painless destructive thyroiditis
tration may cause either type of thyrotoxicosis, particularly (not usually lymphocytic) occurs in 5%–10% of amiodarone-
subclinical thyrotoxicosis. Endogenous overt or subclinical thy- treated patients (23). Subacute thyroiditis is thought to be
rotoxicosis is caused by excess thyroid hormone production and caused by viral infection and is characterized by fever and
release or by inflammation and release of hormone by the gland. thyroid pain (24).
Endogenous hyperthyroidism is most commonly due to GD
or nodular thyroid disease. GD is an autoimmune disorder in [A2] Clinical consequences of thyrotoxicosis
which thyrotropin receptor antibodies (TRAb) stimulate the The cellular actions of thyroid hormone are mediated by
TSH receptor, increasing thyroid hormone production and re- T3, the active form of thyroid hormone. T3 binds to two
lease. The development of nodular thyroid disease includes specific nuclear receptors (thyroid hormone receptor a and b)
growth of established nodules, new nodule formation, and de- that regulate the expression of many genes. Nongenomic
velopment of autonomy over time (8). In TAs, autonomous actions of thyroid hormone include regulation of numerous
hormone production can be caused by somatic activating mu- important physiologic functions.
tations of genes regulating thyroid growth and hormone syn- Thyroid hormone influences almost every tissue and organ
thesis. Germline mutations in the gene encoding the TSH system. It increases tissue thermogenesis and basal meta-
receptor can cause sporadic or familial nonautoimmune hyper- bolic rate and reduces serum cholesterol levels and systemic
1348 ROSS ET AL.
vascular resistance. Some of the most profound effects of in- the pituitary–thyroid axis is intact is an inverse log-linear
creased thyroid hormone levels occur within the cardiovascular relationship; therefore, small changes in free T4 result in large
system (25). Untreated or partially treated thyrotoxicosis is changes in serum TSH concentrations. Serum TSH levels are
associated with weight loss, osteoporosis, atrial fibrillation, considerably more sensitive than direct thyroid hormone
embolic events, muscle weakness, tremor, neuropsychiatric measurements for assessing thyroid hormone excess (35).
symptoms, and rarely cardiovascular collapse and death (26,27). In overt hyperthyroidism, serum free T4, T3, or both are
Only moderate correlation exists between the degree of thyroid elevated, and serum TSH is subnormal (usually <0.01 mU/L in
hormone elevation and clinical signs and symptoms. Symptoms a third-generation assay). In mild hyperthyroidism, serum T4
and signs that result from increased adrenergic stimulation in- and free T4 can be normal, only serum T3 may be elevated, and
clude tachycardia and anxiety and may be more pronounced in serum TSH will be low or undetectable. These laboratory
younger patients and those with larger goiters (28). The signs findings have been called ‘‘T3-toxicosis’’ and may represent the
and symptoms of mild, or subclinical, thyrotoxicosis are similar earliest stages of hyperthyroidism caused by GD or an auton-
to those of overt thyrotoxicosis but differ in magnitude. Mea- omously functioning thyroid nodule. As with T4, total T3
surable changes in basal metabolic rate, cardiovascular hemo- measurements are affected by protein binding. Assays for es-
dynamics, and psychiatric and neuropsychological function can timating free T3 are less widely validated and less robust than
be present in mild thyrotoxicosis (29). those for free T4. Therefore, measurement of total T3 is fre-
quently preferred over free T3 in clinical practice. Subclinical
[B] How should clinically or incidentally hyperthyroidism is defined as a normal serum free T4 and
discovered thyrotoxicosis be evaluated normal total T3 or free T3, with subnormal serum TSH con-
and initially managed? centration. Laboratory protocols that store sera and automati-
cally retrieve the sample and add on free T4 and total T3
[B1] Assessment of disease severity measurements when the initial screening serum TSH concen-
Assessment of thyrotoxic manifestations, and especially trations are low avoid the need for subsequent blood draws.
potential cardiovascular and neuromuscular complications, is In the absence of a TSH-producing pituitary adenoma or
essential in formulating an appropriate treatment plan. Al- thyroid hormone resistance, or in the presence of spurious
though it might be anticipated that the severity of thyrotoxic assay results due to interfering antibodies, a normal serum
symptoms is proportional to the elevation in the serum levels TSH level precludes the diagnosis of thyrotoxicosis. The
of free T4 and T3, in one small study of 25 patients with GD, term ‘‘euthyroid hyperthyroxinemia’’ has been used to de-
the Hyperthyroid Symptom Scale did not strongly correlate scribe a number of entities, primarily thyroid hormone–
with free T4 or T3 and was inversely correlated with age (28). binding protein disorders, which cause elevated total serum
The importance of age as a determinant of the prevalence and T4 concentrations (and frequently elevated total serum T3
severity of hyperthyroid symptoms has recently been con- concentrations) in the absence of hyperthyroidism (36).
firmed (30). Cardiac evaluation may be necessary, especially These conditions include elevations in T4 binding globulin
in the older patient, and may require an echocardiogram, (TBG) or transthyretin (37); the presence of an abnormal
electrocardiogram, Holter monitor, or myocardial perfusion albumin which binds T4 with high capacity (familial dysal-
studies (31). The need for evaluation should not postpone buminemic hyperthyroxinemia); a similarly abnormal trans-
therapy of the thyrotoxicosis. In addition to the administra- thyretin; and, rarely, immunoglobulins that directly bind T4
tion of b-blockers (31), treatment may be needed for con- or T3. TBG excess may occur as a hereditary X-linked trait, or
comitant myocardial ischemia, congestive heart failure, or it may be acquired as a result of pregnancy or estrogen ad-
atrial arrhythmias (25). Anticoagulation may be necessary in ministration, hepatitis, acute intermittent porphyuria or dur-
patients in atrial fibrillation (32). Goiter size, obstructive ing treatment with 5-fluorouracil, perphenazine, or some
symptoms, and the severity of Graves’ orbitopathy (GO), the narcotics. Other causes of euthyroid hyperthyroxinemia in-
inflammatory disease that develops in the orbit in association clude drugs that inhibit T4 to T3 conversion, such as amio-
with autoimmune thyroid disorders, can be discordant with darone (23) or high-dose propranolol (31), acute psychosis
the degree of hyperthyroidism or hyperthyroid symptoms. (38), extreme high altitude (39), and amphetamine abuse
All patients with known or suspected hyperthyroidism (40). Estimates of free thyroid hormone concentrations fre-
should undergo a comprehensive history and physical exam- quently also give erroneous results in these disorders. Spur-
ination, including measurement of pulse rate, blood pressure, ious free T4 elevations may occur from heterophilic
respiratory rate, and body weight. Thyroid size, tenderness, antibodies or in the setting of heparin therapy, due to in vitro
symmetry, and nodularity should also be assessed along with activation of lipoprotein lipase and release of free fatty acids
pulmonary, cardiac, and neuromuscular function (29,31,33) that displace T4 from its binding proteins.
and the presence or absence of peripheral edema, eye signs, or Heterophilic antibodies can also cause spurious high TSH
pretibial myxedema. values, and this should be ruled out by repeating the TSH
in another assay, measurement of TSH in serial dilution, or
[B2] Biochemical evaluation direct measurement of human anti-mouse antibodies.
Serum TSH measurement has the highest sensitivity and Ingestion of high doses of biotin may cause spurious re-
specificity of any single blood test used in the evaluation sults in assays that utilize a streptavidin–biotin separation
of suspected thyrotoxicosis and should be used as an ini- technique (41,42). In immunometric assays, frequently used
tial screening test (34). However, when thyrotoxicosis is to measure TSH, excess biotin displaces biotinylated anti-
strongly suspected, diagnostic accuracy improves when a bodies and causes spuriously low results, while in competitive
serum TSH, free T4, and total T3 are assessed at the initial binding assays, frequently used to measure free T4, excess
evaluation. The relationship between free T4 and TSH when biotin competes with biotinylated analogue and results in
falsely high results. Patients taking high doses of biotin or Table 3. Causes of Thyrotoxicosis
supplements containing biotin, who have elevated T4 and Thyrotoxicosis associated with a normal or elevated RAI
suppressed TSH, should stop taking biotin and have repeat uptake over the necka
measurements at least 2 days later. GD
After excluding euthyroid hyperthyroxinemia, TSH-mediated TA or TMNG
hyperthyroidism should be considered when thyroid hormone Trophoblastic disease
concentrations are elevated and TSH is normal or elevated. A TSH-producing pituitary adenomas
pituitary lesion on magnetic resonance imaging (MRI) and a Resistance to thyroid hormone (T3 receptor b mutation,
disproportionately high ratio of the serum level of the a-subunit THRB)b
of the pituitary glycoprotein hormones to TSH supports the di- Thyrotoxicosis associated with a near-absent RAI uptake
agnosis of a TSH-producing pituitary adenoma (43). A family over the neck
history and genetic testing for mutations in the thyroid hormone Painless (silent) thyroiditis
receptor b (THRB) gene supports the diagnosis of resistance to Amiodarone-induced thyroiditis
thyroid hormone (44). Subacute (granulomatous, de Quervain’s) thyroiditis
Palpation thyroiditis
Iatrogenic thyrotoxicosis
[B3] Determination of etiology Factitious ingestion of thyroid hormone
Struma ovarii
& RECOMMENDATION 1 Acute thyroiditis
The etiology of thyrotoxicosis should be determined. If the Extensive metastases from follicular thyroid cancer
diagnosis is not apparent based on the clinical presentation a
and initial biochemical evaluation, diagnostic testing is In iodine-induced or iodine-exposed hyperthyroidism (including
amiodarone type 1), the uptake may be low.
indicated and can include, depending on available exper- b
Patients are not uniformly clinically hyperthyroid. T3, triiodo-
tise and resources, (1) measurement of TRAb, (2) deter- thyronine.
mination of the radioactive iodine uptake (RAIU), or (3)
measurement of thyroidal blood flow on ultrasonography.
A 123I or 99mTc pertechnetate scan should be obtained kelp. However, RAIU is rarely <1% unless the iodine expo-
when the clinical presentation suggests a TA or TMNG. sure is reoccurring, such as during treatment with amiodar-
one. When exposure to excess iodine is suspected (e.g., when
Strong recommendation, moderate-quality evidence.
the RAIU is lower than expected from the clinical history),
assessment of urinary iodine concentration (spot urine iodine
In a patient with a symmetrically enlarged thyroid, recent adjusted for urine creatinine concentration or a 24-hour urine
onset of orbitopathy, and moderate to severe hyperthyroid- iodine concentration) may be helpful. The uptake over the
ism, the diagnosis of GD is likely and further evaluation of neck will also be absent in a patient with struma ovarii, where
hyperthyroidism causation is unnecessary. In a thyrotoxic the abnormal thyroid tissue is located in an ovarian teratoma.
patient with a nonnodular thyroid and no definite orbitopathy, Thyroid scans provide a planar image of the thyroid gland
measurement of TRAb or RAIU can be used to distinguish using a gamma camera to assess potential variability in the
GD from other etiologies. In a study using a model of a concentration of the radioisotope within thyroid tissue. RAI
theoretical population of 100,000 enrollees in a managed care scans may be obtained coincident with the RAIU and tech-
organization in the United States, the use of TRAb mea- netium scans may be obtained coincident with the technetium
surements to diagnose GD compared to RAIU measurements uptake. While technetium scans result in a low range of
reduced costs by 47% and resulted in a 46% quicker diag- normal uptake and high background activity, total body ra-
nosis (45). diation exposure is less than for 123I scans; either type of scan
RAIU measures the percentage of administered RAI that is can be useful in determining the etiology of hyperthyroidism
concentrated into thyroid tissue after a fixed interval, usually in the presence of thyroid nodularity.
24 hours. Technetium uptake measurements utilize pertech- A thyroid scan should be obtained if the clinical presen-
netate that is trapped by the thyroid, but not organified. A tation suggests a TA or TMNG. The pattern of RAIU in GD is
technetium (TcO4) uptake measures the percentage of ad- diffuse unless coexistent nodules or fibrosis is present. The
ministered technetium that is trapped by the thyroid after a pattern of uptake in a patient with a single TA generally
fixed interval, usually 20 minutes. shows focal uptake in the adenoma with suppressed uptake in
Uptake measurements are indicated when the diagnosis is the surrounding and contralateral thyroid tissue. The image in
in question (except during pregnancy and usually during TMNG demonstrates multiple areas of focal increased and
lactation (see Section [T4]) and distinguishes causes of thy- suppressed uptake. If autonomy is extensive, the image may
rotoxicosis having elevated or normal uptake over the thyroid be difficult to distinguish from that of GD (46). Additionally,
gland from those with near-absent uptake (Table 3). Uptake is GD and nontoxic nodular goiter may coincide, resulting in
usually elevated in patients with GD and normal or high in positive TRAb levels and a nodular ultrasound or heteroge-
toxic nodular goiter, unless there has been a recent exposure neous uptake images (47).
to iodine (e.g., radiocontrast). The RAIU will be near zero in Where expertise is available, ultrasonography with color
patients with painless, postpartum, or subacute thyroiditis; flow Doppler can distinguish thyroid hyperactivity (increased
factitious ingestion of thyroid hormone; or recent excess io- flow) from destructive thyroiditis (48). Quantitative Doppler
dine intake. The RAIU may be low after exposure to iodin- evaluation requires careful adjustments to prevent artifacts
ated contrast in the preceding 1–2 months or with ingestion of and measures the peak systolic velocity from intrathyroidal
a diet unusually rich in iodine such as seaweed soup or arteries or the inferior thyroidal artery (49). This test may
1350 ROSS ET AL.
be particularly useful when radioactive iodine (RAI) is con- assays are unable to distinguish the TSH-R antibody types.
traindicated, such as during pregnancy or breastfeeding. Bioassays for the Thyroid Stimulating Immunoglobulin
Doppler flow has also been used to distinguish between (TSI) measure the ability of TSI to increase the intracellular
subtypes of amiodarone-induced thyrotoxicosis (see Section level of cAMP directly or indirectly, e.g. from engineered
[V2]) and between GD and destructive thyroiditis (see Sec- Chinese Hamster Ovary (CHO) cells transfected with
tion [W2]). hTSH-R reported through increased luciferase production.
The ratio of total T3 to total T4 can also be useful in as- Such assays specifically detect simulating antibodies (TSI)
sessing the etiology of thyrotoxicosis when scintigraphy is and can differentiate between the TSH-R antibody types. In
contraindicated. Because a hyperactive gland produces more the setting of overt thyrotoxicosis, newer TRAb binding and
T3 than T4, T3 will be elevated above the upper limit of bioassays have a sensitivity of 96–97% and a specificity of
normal more than T4 in thyrotoxicosis caused by hyperthy- 99% for GD (56,57).
roidism, whereas T4 is elevated more than T3 in thyrotoxi-
cosis caused by thyroiditis (50); in one study the ratio of total [B4] Symptomatic management
T3 to total T4 (ng/lg) was >20 in GD and toxic nodular goiter,
and <20 in painless or postpartum thyroiditis (51). A high & RECOMMENDATION 2
T4 to T3 ratio may be seen in thyrotoxicosis factitia (from Beta-adrenergic blockade is recommended in all patients
exogenous levothyroxine). with symptomatic thyrotoxicosis, especially elderly pa-
The choice of initial diagnostic testing depends on cost, tients and thyrotoxic patients with resting heart rates in
availability, and local expertise. TRAb is cost effective be- excess of 90 beats per minute or coexistent cardiovascular
cause if it is positive it confirms the diagnosis of the most disease.
common cause of thyrotoxicosis. If negative it does not dis-
tinguish among other etiologies, however, and it can be
negative in very mild GD. If third-generation TRAb assays
are not readily available, RAIU is preferred for initial testing. In a randomized controlled trial of MMI alone versus MMI
Diagnostic testing may be influenced by the choice of and a b-adrenergic blocking agent, after 4 weeks, patients
therapy (see Section [C]). For example, measuring TRAb in a taking b-adrenergic blockers had lower heart rates, less
patient with GD who plans on taking methimazole (MMI) shortness of breath and fatigue, and improved ‘‘physical
with the hope of achieving a remission will provide a baseline functioning’’ on the SF-36 health questionnaire (58).
measurement for disease activity. Obtaining a RAIU in a Technical remarks: Since there is not sufficient b-1 se-
patient who prefers RAI treatment will provide both diag- lectivity of the available b-blockers at the recommended
nostic information and facilitate the calculation of the RAI doses, these drugs are generally contraindicated in patients
dose (see Section [D2]). with bronchospastic asthma. In patients with quiescent bron-
In most patients, distinction between subacute and painless chospastic asthma in whom heart rate control is essential, or in
thyroiditis is not difficult. Subacute thyroiditis is generally patients with mild obstructive airway disease or symptomatic
painful, the gland is firm to hard on palpation, and the Raynaud’s phenomenon, a relative b-1 selective agent can be
erythrocyte sedimentation rate is usually >50 mm/h and used cautiously, with careful monitoring of pulmonary status
sometimes over 100 mm/h. Patients with painless thyroiditis (Table 4). Occasionally, very high doses of b-blockers are
presenting within the first year after childbirth (postpartum required to manage symptoms of thyrotoxicosis and to reduce
thyroiditis) often have a personal or family history of auto- the heart rate to near the upper limit of normal (31), but most
immune thyroid disease and typically have measurable serum often low to moderate doses (Table 4) give sufficient symp-
concentrations of anti–thyroid peroxidase antibodies (52). tom relief. Oral administration of calcium channel blockers,
Thyroglobulin is released along with thyroid hormone both verapamil and diltiazem, have been shown to affect rate
in subacute, painless, and palpation thyroiditis (following control in patients who do not tolerate or are not candidates for
manipulation of the thyroid gland during surgery), whereas b-adrenergic blocking agents.
its release is suppressed in the setting of exogenous thyroid
hormone administration. If not elucidated by the history, [C] How should overt hyperthyroidism
factitious ingestion of thyroid hormone can be distinguished due to GD be managed?
from other causes of thyrotoxicosis by a low serum thyro- & RECOMMENDATION 3
globulin level, a near-zero RAIU, and a T3 to T4 ratio (ng/lg) Patients with overt Graves’ hyperthyroidism should be
<20 if due to exogenous levothyroxine (53). In patients with treated with any of the following modalities: RAI therapy,
antithyroglobulin antibodies, which interfere with thyro- ATDs, or thyroidectomy.
globulin measurement, an alternative but not widely avail-
able approach is measurement of fecal T4 (54); mean values Strong recommendation, moderate-quality evidence.
were 1.03 nmol/g in euthyroid patients, 1.93 nmol/g in
Graves’ hyperthyroidism, and 12–24 nmol/g in factitious Once it has been established that the patient is hyperthy-
thyrotoxicosis. roid and the cause is GD, the patient and physician must
Technical remarks: There are two methods for measuring choose between three effective and relatively safe initial
Thyroid Receptor Antibodies (TRAb) (55). Third generation treatment options: RAI therapy, ATDs, or thyroidectomy
TSH Binding Inhibition Immunoglobulin (TBII) assays are (59). In the United States, RAI has been the therapy most
competition assays which measure inhibition of binding of preferred by physicians, but a trend has been present in recent
either a labeled monoclonal anti-human TSH-R antibody or years to increase use of ATDs and reduce the use of RAI. A
labeled TSH to a recombinant TSH-R. These TRAb or TBII 2011 survey of clinical endocrinologists showed that 59.7%
Table 4. Beta-Adrenergic Receptor Blockade in the Treatment of Thyrotoxicosis

Druga Dosage Frequency Considerations
b
Propanolol 10–40 mg 3–4 times per day Nonselective b-adrenergic receptor blockade
Longest experience
May block T4 to T3 conversion at high doses
Preferred agent for nursing and pregnant mothers
Atenolol 25–100 mg 1–2 times per day Relative b-1 selectivity
Increased compliance
Avoid during pregnancy
Metoprololb 25–50 mg 2–3 times per day Relative b-1 selectivity
Nadolol 40–160 mg 1 time per day Nonselective b-adrenergic receptor blockade
Once daily
Least experience to date
May block T4 to T3 conversion at high doses
Esmolol IV pump 50–100 lg/kg/min In intensive care unit setting of severe
thyrotoxicosis or storm
a
Each of these drugs has been approved for treatment of cardiovascular diseases, but to date none has been approved for the treatment of
thyrotoxicosis.
bAlso available in once daily preparations.
T4, thyroxine.
of respondents from the United States selected RAI as pri- hypertension, or congestive heart failure should also be
mary therapy for an uncomplicated case of GD, compared considered good candidates for RAI therapy.
with 69% in a similar survey performed 20 years earlier (60). b. ATDs: Patients with high likelihood of remission (pa-
In Europe, Latin America, and Japan, there has been a greater tients, especially women, with mild disease, small goi-
physician preference for ATDs (61). The long-term quality of ters, and negative or low-titer TRAb); pregnancy; the
life (QoL) following treatment for GD was found to be the elderly or others with comorbidities increasing surgi-
same in patients randomly allocated to one of the three cal risk or with limited life expectancy; individuals in
treatment options (62). Currently, no scientific evidence ex- nursing homes or other care facilities who may have
ists to support the recommendation of alternative therapies limited longevity and are unable to follow radiation
for the treatment of hyperthyroidism (63). safety regulations; patients with previously operated
Technical remarks: Once the diagnosis has been made, the or irradiated necks; patients with lack of access to a
treating physician and patient should discuss each of the high-volume thyroid surgeon; patients with moderate
treatment options, including the logistics, benefits, expected to severe active GO; and patients who need more rapid
speed of recovery, drawbacks, potential side effects, and biochemical disease control.
costs (64). This sets the stage for the physician to make c. Surgery: Women planning a pregnancy in <6 months
recommendations based on best clinical judgment and allows provided thyroid hormone levels are normal (i.e., pos-
the final decision to incorporate the personal values and sibly before thyroid hormone levels would be normal if
preferences of the patient. The treatment selection should RAI were chosen as therapy); symptomatic compres-
also take into account the local availability and the associated sion or large goiters (‡80 g); relatively low uptake of
costs. Whenever surgery is selected as treatment one should RAI; when thyroid malignancy is documented or sus-
consider the use of expert high-volume thyroid surgeons with pected (e.g., suspicious or indeterminate cytology);
on average lower risk of complications; lack of that expertise large thyroid nodules especially if greater than 4 cm or
should be considered against the known risk of alternative if nonfunctioning, or hypofunctioning on 123I or 99mTc
choices. Long-term continuous treatment of hyperthyroidism pertechnetate scanning; coexisting hyperparathyroid-
with ATDs may be considered in selected cases (65,66). ism requiring surgery; especially if TRAb levels are
particularly high; and patients with moderate to severe
Clinical situations that favor a particular modality as active GO.
treatment for Graves’ hyperthyroidism (Table 5):
Contraindications to a particular modality as treat-
a. RAI therapy: Women planning a pregnancy in the fu-
ment for Graves’ hyperthyroidism:
ture (in more than 6 months following RAI adminis-
tration, provided thyroid hormone levels are normal), a. RAI therapy: Definite contraindications include preg-
individuals with comorbidities increasing surgical risk, nancy, lactation, coexisting thyroid cancer, or suspi-
and patients with previously operated or externally ir- cion of thyroid cancer, individuals unable to comply
radiated necks, or lack of access to a high-volume with radiation safety guidelines and used with informed
thyroid surgeon, and patients with contraindications to caution in women planning a pregnancy within 4–6
ATD use or failure to achieve euthyroidism during months.
treatment with ATDs. Patients with periodic thyrotoxic b. ATDs: Definite contraindications to ATD therapy in-
hypokalemic paralysis, right heart failure pulmonary clude previous known major adverse reactions to ATDs.
1352 ROSS ET AL.
Table 5. Clinical Situations That Favor a Particular Modality as Treatment

for Graves’ Hyperthyroidism
Clinical situations RAI ATD Surgery
Pregnancya x OO / ! O/!
Comorbidities with increased surgical risk and/or limited OO O x
life expectancy
Inactive GO O O O
Active GO b
OO OO
Liver disease OO ! O
Major adverse reactions to ATDs OO x O
Patients with previously operated or externally irradiated necks OO O !
Lack of access to a high-volume thyroid surgeon OO O !
Patients with high likelihood of remission (especially women, O OO O
with mild disease, small goiters, and negative or low-titer TRAb)
Patients with periodic paralysis OO O OO
Patients with right pulmonary hypertension, or congestive heart failure OO O !
Elderly with comorbidities O O !
Thyroid malignancy confirmed or suspected x - OO
One of more large thyroid nodules - O OO
Coexisting primary hyperparathyroidism requiring surgery - - OO
OO = preferred therapy; O = acceptable therapy; ! = cautious use; - = not first-line therapy but may be acceptable depending on the clinical
circumstances; X = contraindication.
a
For women considering a pregnancy within 6 months, see discussion in Section [T2].
b
Table 14 describes the use of RAI in GO in detail, considering disease activity, severity, and other risk factors for GO progression.
c. Surgery: Factors that may mitigate against the choice of avoidance of ATD side effects (see Section [E]), and
surgery include substantial comorbidity such as cardio- the possibility of disease recurrence.
pulmonary disease, end-stage cancer, or other debilitat- c. Surgery: Patients choosing surgery as treatment for GD
ing disorders, or lack of access to a high-volume thyroid would likely place a relatively higher value on prompt
surgeon. Pregnancy is a relative contraindication, and and definitive control of hyperthyroidism, avoidance of
surgery should only be used in the circumstance when exposure to radioactivity, and the potential side effects
rapid control of hyperthyroidism is required and anti- of ATDs and a relatively lower value on potential
thyroid medications cannot be used. Thyroidectomy is surgical risks, and need for lifelong thyroid hormone
best avoided in the first and third trimesters of pregnancy replacement.
because of teratogenic effects associated with anesthetic
agents and increased risk of fetal loss in the first tri-
mester and increased risk of preterm labor in the third. [D] If RAI therapy is chosen, how should
Optimally, thyroidectomy is performed in the second it be accomplished?
trimester; however, although it is the safest time, it is not [D1] Preparation of patients with GD for RAI therapy
without risk (4.5%–5.5% risk of preterm labor) (67,68).
Thyroid surgery in pregnancy is also associated with a & RECOMMENDATION 4
higher rate of complications, including hypoparathy- Because RAI treatment of GD can cause a transient ex-
roidism and recurrent laryngeal nerve (RLN) injury (68). acerbation of hyperthyroidism, b-adrenergic blockade
should be considered even in asymptomatic patients who
Patient values that may impact choice of therapy:
are at increased risk for complications due to worsening of
a. RAI therapy: Patients choosing RAI therapy as treat- hyperthyroidism (i.e., elderly patients and patients with
ment for GD would likely place relatively higher value comorbidities).
on definitive control of hyperthyroidism, the avoidance
Weak recommendation, low-quality evidence.
of surgery, and the potential side effects of ATDs, as
well as a relatively lower value on the need for lifelong & RECOMMENDATION 5
thyroid hormone replacement, rapid resolution of hy-
In addition to b-adrenergic blockade (see Recommenda-
perthyroidism, and potential worsening or development
tions 2 and 4), pretreatment with MMI prior to RAI therapy
of GO (69).
for GD should be considered in patients who are at in-
b. ATDs: Patients choosing ATD as treatment for GD
creased risk for complications due to worsening of hy-
would place relatively higher value on the possibility of
perthyroidism. MMI should be discontinued 2–3 days
remission and the avoidance of lifelong thyroid hor-
prior to RAI.
mone treatment, the avoidance of surgery, and exposure
to radioactivity and a relatively lower value on the Weak recommendation, moderate-quality evidence.
& RECOMMENDATION 6 cardiovascular disease, resuming MMI or carbimazole 3–

In patients who are at increased risk for complications due 7 days after RAI administration should be considered and
to worsening of hyperthyroidism, resuming MMI 3–7 days generally tapered as thyroid function normalizes. In one
after RAI administration should be considered. study, if MMI was restarted 7 days after RAI, the free T4
Weak recommendation, low-quality evidence. measured 3 weeks after RAI was 6% lower than the values at
the time of RAI administration, and if MMI was not restarted
& RECOMMENDATION 7
after RAI, the free T4 values were 36% higher than the values
Medical therapy of any comorbid conditions should be at the time of RAI administration (80). Over several decades,
optimized prior to RAI therapy. there have been reports that pretreatment with lithium
reduces the activity of RAI necessary for cure of Graves’
Strong recommendation, low-quality evidence. hyperthyroidism and may prevent the thyroid hormone in-
crease seen upon ATD withdrawal (81–83). However, this
RAI has been used to treat hyperthyroidism for more than approach is not used widely, and insufficient evidence exists
seven decades. It is well tolerated and complications are rare, to recommend the practice. In selected patients with Graves’
except for those related to orbitopathy (see Section [U]). hyperthyroidism who would have been candidates for pre-
Thyroid storm occurs only rarely following the administra- treatment with ATDs because of comorbidities or excessive
tion of RAI (70–72). In one study of patients with thyrotoxic symptoms, but who are allergic to ATDs, the duration of
cardiac disease treated with RAI as the sole modality, no hyperthyroidism may be shortened by administering iodine
clinical worsening in any of the cardinal symptoms of thy- (e.g., saturated solution of potassium iodide [SSKI]) begin-
rotoxicosis was seen (73). However, RAI can induce a short- ning 1 week after RAI administration (84).
term increase of thyroid hormone levels (74,75). To prevent a
clinical exacerbation of hyperthyroidism, the use of MMI or [D2] Administration of RAI in the treatment of GD
carbimazole, the latter of which is not marketed in the United
States, before and after RAI treatment may be considered in & RECOMMENDATION 8
patients with severe hyperthyroidism, the elderly, and indi- Sufficient activity of RAI should be administered in a
viduals with substantial comorbidity that puts them at greater single application, typically a mean dose of 10–15 mCi
risk for complications of worsening thyrotoxicosis (75,76). (370–555 MBq), to render the patient with GD hypothy-
The latter includes patients with cardiovascular complica- roid.
tions such as atrial fibrillation, heart failure, or pulmonary
hypertension and those with renal failure, infection, trauma,
poorly controlled diabetes mellitus, and cerebrovascular or & RECOMMENDATION 9
pulmonary disease (70). These comorbid conditions should
A pregnancy test should be obtained within 48 hours prior
be addressed with standard medical care and the patient
to treatment in any woman with childbearing potential who
rendered medically stable before the administration of RAI if
is to be treated with RAI. The treating physician should
possible. If possible iodinated radiocontrast should be avoi-
obtain this test and verify a negative result prior to ad-
ded. In addition, b-adrenergic blocking drugs should be used
ministering RAI.
judiciously in these patients in preparation for RAI therapy
(25,77). MMI (75) and carbimazole (78) have shown to re- Strong recommendation, low-quality evidence.
duce thyroid hormone levels after RAI treatment in ran-
domized controlled trials. However, a recent meta-analysis of The goal of RAI therapy in GD is to control hyperthy-
randomized controlled trials also found that MMI, carbima- roidism by rendering the patient hypothyroid; this treatment
zole, and propylthiouracil (PTU) reduce the success rate if is very effective, provided a sufficient radiation dose is de-
given in the week before or after RAI treatment (71). Use of posited in the thyroid. This outcome can be accomplished
higher activities of RAI may offset the reduced effectiveness equally well by either administering a fixed activity or by
of RAI therapy following antithyroid medication (75,76). calculating the activity based on the size of the thyroid and its
A special diet is not required before RAI therapy, but nu- ability to trap RAI (85).
tritional supplements that may contain excess iodine and The first method is simple, while the second method re-
seaweeds should be avoided for at least 7 days. A low-iodine quires two unknowns to be determined: the uptake of RAI
diet may be useful for those with relatively low RAIU to and the size of the thyroid. The therapeutic RAI activity can
increase the proportion of RAI trapped. then be calculated using these two factors and the quantity of
Technical remarks: Patients that might benefit from ad- radiation (lCi or Bq) to be deposited per gram (or cc) of
junctive MMI or carbimazole may be those who tolerate thyroid (e.g., activity [lCi] = gland weight [g] · 50–200 lCi/
hyperthyroid symptoms poorly. Such patients frequently g · [1/24 hour uptake in % of administered activity]). The
have free T4 at 2–3 times the upper limit of normal. Young activity in microcuries or becquerels is converted to milli-
and middle-aged patients who are otherwise healthy and curies or megabecquerel by dividing the result by 1000. The
clinically well compensated despite significant biochemical most frequently used uptake is calculated at 24 hours, and the
hyperthyroidism can generally receive RAI without pre- size of the thyroid is determined by palpation or ultrasound.
treatment. If given as pretreatment, MMI and carbimazole One study found that this estimate by experienced physicians
should be discontinued before the administration of RAI. is accurate compared with anatomic imaging (86); however,
Discontinuation of ATDs for 2–3 days prevents a short-term other investigators have not confirmed this observation (87).
increase of thyroid hormone levels (79), which is found after Alternately, a more detailed calculation can be made to
6 days (75,76). In elderly patients or in those with underlying deposit a specific radiation dose (in rad or Gy) to the thyroid.
1354 ROSS ET AL.
Using this approach, it is also necessary to know the effective United States, the treating physician must ensure and docu-
half-life of RAI (88). This requires additional time and ment that no adult member of the public is exposed to
computation, and because the outcome has not shown to be 0.5 mSv (500 milli-roentgen equivalent in man [mrem])
better, this method is seldom used in the United States. when the patient is discharged with a retained activity of
Evidence shows that to achieve a hypothyroid state, 33 mCi (1.22 GBq) or greater, or emits ‡7 mrem/h (70 lSv/h)
>150 lCi/g (5.55 MBq/g) needs to be delivered (88–90). at 1 m.
Patients who are on dialysis or who have jejunostomy or Technical remarks: Continuity of follow-up should be
gastric feeding tubes require special care and management provided and can be facilitated by communication between
when being administered RAI treatment (91). the referring physician and the treating physician, including a
The success of RAI therapy in GD strongly depends on the request for therapy from the former and a statement from the
administered activities. In patients without adjunctive ATD, latter that the treatment has been administered.
randomized controlled trials found 61% success with 5.4 mCi
(200 MBq) (92), 69% with 8.2 mCi (302 MBq) (93), 74% [D3] Patient follow-up after RAI therapy for GD
with 10 mCi (370 MBq) (94), 81% with 15 mCi (555 MBq)
(94), and 86% with 15.7 mCi (580 MBq) (95) RAI. Because & RECOMMENDATION 11
of the high proportion of patients requiring retreatment, RAI Follow-up within the first 1–2 months after RAI therapy
therapy with low activities is generally not recommended. for GD should include an assessment of free T4, total T3,
A long-term increase in cardiovascular and cerebrovas- and TSH. Biochemical monitoring should be continued at
cular deaths has been reported after RAI therapy not resulting 4- to 6-week intervals for 6 months, or until the patient
in hypothyroidism as opposed to unchanged mortality in becomes hypothyroid and is stable on thyroid hormone
RAI-treated patients on levothyroxine therapy, reflecting the replacement.
role of persistent hyperthyroidism as opposed to that of RAI
Strong recommendation, low-quality evidence.
therapy on mortality (96,97). A recent meta-analysis found
no increase in the overall cancer risk after RAI treatment for
hyperthyroidism; however, a trend towards increased risk of Most patients respond to RAI therapy with a normalization
thyroid, stomach, and kidney cancer was seen, requiring fur- of thyroid function tests and improvement of clinical symp-
ther research (98). In some men, a modest fall in the testos- toms within 4–8 weeks. Hypothyroidism may occur from 4
terone to luteinizing hormone (LH) ratio occurs after RAI weeks on, with 40% of patients being hypothyroid by 8 weeks
therapy that is subclinical and reversible (99). Conception and >80% by 16 weeks (106). This transition can occur
should be delayed in women until stable euthyroidism is es- rapidly but more commonly between 2 and 6 months, and the
tablished (on thyroid hormone replacement following suc- timing of thyroid hormone replacement therapy should be
cessful thyroid ablation). This typically takes 4–6 months or determined by results of thyroid function tests, clinical
longer. Conception should be delayed 3–4 months in men to symptoms, and physical examination. Transient hypothy-
allow for turnover of sperm production. However, once the roidism following RAI therapy can rarely occur, with sub-
patient (either sex) is euthyroid, there is no evidence of reduced sequent complete recovery of thyroid function or recurrent
fertility, and offspring of treated patients show no congenital hyperthyroidism (107). In such patients the thyroid gland
anomalies compared to the population at large (100). often remains palpable.
Technical remarks: Rendering the patient hypothyroid can Beta-blockers that were instituted prior to RAI treatment
be accomplished equally well by administering either a suf- should be tapered when free T4 and total T3 have returned to
ficient fixed activity or calculating an activity based on the the reference range. As free T4 and total T3 improve, MMI
size of the thyroid and its ability to trap iodine. Fetuses ex- can usually be tapered, which allows an assessment of the
posed to RAI after the 10th to 11th week of gestation may be response to RAI.
born athyreotic (101,102) and are also at a theoretical in- Most patients eventually develop hypothyroidism fol-
creased risk for reduced intelligence and/or cancer. In lowing RAI, which is indicated by a free T4 below normal
breastfeeding women, RAI therapy should not be adminis- range. At this point, levothyroxine should be instituted.
tered for at least 6 weeks after lactation stops to ensure that TSH levels may not rise immediately with the develop-
RAI will no longer be actively concentrated in the breast ment of hypothyroidism and should not be used initially to
tissues. A delay of 3 months will more reliably ensure that determine the need for levothyroxine. When thyroid hor-
lactation-associated increase in breast sodium iodide sym- mone replacement is initiated, the dose should be adjusted
porter activity has returned to normal (103). Breastfeeding based on an assessment of free T4. The required dose may
should not be resumed after RAI therapy. be less than the typical full replacement, and careful ti-
tration is necessary owing to nonsuppressible residual
& RECOMMENDATION 10 thyroid function. Overt hypothyroidism should be avoided,
The physician administering RAI should provide written especially in patients with active GO (see Section [U2]).
advice concerning radiation safety precautions following Once euthyroidism is achieved, lifelong annual thyroid
treatment. If the precautions cannot be followed, alterna- function testing is recommended at least annually, or if
tive therapy should be selected. the patient experiences symptoms of hypothyroidism or
hyperthyroidism.
Technical remarks: Since TSH levels may remain sup-
pressed for a month or longer after hyperthyroidism resolves,
All national and regional radiation protection rules re- the levels should be interpreted cautiously and only in concert
garding RAI treatment should be followed (104,105). In the with free T4 and total T3.
[D4] Treatment of persistent Graves’ hyperthyroidism & RECOMMENDATION 15

following RAI therapy Prior to initiating ATD therapy for GD, we suggest that
patients have a baseline complete blood count, including
& RECOMMENDATION 12 white blood cell (WBC) count with differential, and a liver
When hyperthyroidism due to GD persists after 6 months profile including bilirubin and transaminases.
following RAI therapy, retreatment with RAI is suggested.
In selected patients with minimal response 3 months after
therapy additional RAI may be considered.
Weak recommendation, low-quality evidence. In the United States, MMI and PTU are available, and in
some countries, carbimazole, a precursor of MMI, is widely
used. Carbimazole is rapidly converted to MMI in the serum
Technical remarks: Response to RAI therapy can be as-
(10 mg of carbimazole is metabolized to approximately 6 mg
sessed by monitoring the size of the gland, thyroid function,
of MMI). They work in an identical fashion and both will be
and clinical signs and symptoms. The goal of retreatment is to
referred to as MMI in this text. Both are effective as a single
control hyperthyroidism with certainty by rendering the pa-
daily dose. At the start of MMI therapy, initial doses of 10–
tient hypothyroid. Patients who have persistent, suppressed
30 mg daily are used to restore euthyroidism, and the dose can
TSH with normal total T3 and free T4 may not require im-
then be titrated down to a maintenance level (generally 5–
mediate retreatment but should be monitored closely for ei-
10 mg daily) (109,114). The dose of MMI should be targeted
ther relapse or development of hypothyroidism. In the small
to the degree of thyroid dysfunction because too low a dose
percentage of patients with hyperthyroidism refractory to
will not restore a euthyroid state in patients with severe dis-
several applications of RAI, surgery should be considered
ease (115) and an excessive dose can cause iatrogenic hy-
(108).
pothyroidism in patients with mild disease (116). In addition,
adverse drug reactions are more frequent with higher MMI
[E] If ATDs are chosen as initial management
doses. Thus, it is important to use an MMI dose that will
of GD, how should the therapy be managed?
achieve the clinical goal of normalization of thyroid function
ATDs have been employed for seven decades (109). The reasonably rapidly, while minimizing adverse drug effects.
goal of the therapy is to render the patient euthyroid as The task force suggests the following as a rough guide to
quickly and safely as possible. These medications do not initial MMI daily dosing: 5–10 mg if free T4 is 1–1.5 times
cure Graves’ hyperthyroidism; however, when given in the upper limit of normal; 10–20 mg for free T4 1.5–2 times
adequate doses, they are very effective in controlling the the upper limit of normal; and 30–40 mg for free T4 2–3 times
hyperthyroidism. When they fail to achieve euthyroidism, the upper limit of normal. These rough guidelines should be
the usual cause is nonadherence (110). The treatment itself tailored to the individual patient, incorporating additional
might have a beneficial immunosuppressive role, either to information on symptoms, gland size, and total T3 levels
primarily decrease thyroid specific autoimmunity, or sec- where relevant. Serum T3 levels are important to monitor
ondarily, by ameliorating the hyperthyroid state, which may initially because some patients normalize their free T4 levels
restore the dysregulated immune system back to normal with MMI but have persistently elevated serum T3, indicating
(111). In fact, the rate of remission with ATD therapy is continuing thyrotoxicosis (117).
much higher (112) than the historical rates of spontaneous MMI has the benefit of once-a-day administration and a
remission (113). reduced risk of major side effects compared to PTU. PTU has
a shorter duration of action and is usually administered two or
[E1] Initiation of ATD therapy for the treatment of GD three times daily, starting with 50–150 mg three times daily,
depending on the severity of the hyperthyroidism. As the
& RECOMMENDATION 13 clinical findings and thyroid function tests return to normal,
MMI should be used in virtually every patient who chooses reduction to a maintenance PTU dose of 50 mg two or three
ATD therapy for GD, except during the first trimester of times daily is usually possible. When more rapid biochemical
pregnancy when PTU is preferred, in the treatment of control is needed in patients with severe thyrotoxicosis, an
thyroid storm, and in patients with minor reactions to MMI initial split dose of MMI (e.g., 15 or 20 mg twice a day) may
who refuse RAI therapy or surgery. be more effective than a single daily dose because the dura-
tion of action of MMI may be less than 24 hours (118). Higher
doses of antithyroid medication are sometimes administered
&
continuously and combined with L-thyroxine in doses to
RECOMMENDATION 14
maintain euthyroid levels (so-called block and replace ther-
Patients should be informed of side effects of ATDs and
apy). However, this approach is not generally recommended
the necessity of informing the physician promptly if they
because it has been shown to result in a higher rate of ATD
should develop pruritic rash, jaundice, acolic stools or dark
side effects (109,119).
urine, arthralgias, abdominal pain, nausea, fatigue, fever,
The use of potassium iodide (KI) as a beneficial adjunct to
or pharyngitis. Preferably, this information should be in
ATD therapy for GD has been investigated in previous
writing. Before starting ATDs and at each subsequent visit,
studies (120). Indeed, a recent randomized controlled trial
the patient should be alerted to stop the medication im-
described the administration of 38 mg of KI together with
mediately and call their physician if there are symptoms
15 mg of MMI daily, which resulted in better control of hy-
suggestive of agranulocytosis or hepatic injury.
perthyroidism and fewer adverse reactions compared to
Strong recommendation, low-quality evidence. 30 mg of MMI given alone (121).
1356 ROSS ET AL.
[E2] Adverse effects of ATDs periods of time and developed agranulocytosis after a
In general, adverse effects of ATDs can be divided into second or subsequent exposure. Thirty of the events (4%)
common, minor allergic side effects and rare but serious were fatal. In the third study from Denmark, the frequency
allergic/toxic events such as agranulocytosis, vasculitis, or of agranulocytosis was 0.27% with PTU and 0.11% with
hepatic damage. In a recent systematic review of eight studies MMI (129). As in prior studies, the median duration of
that included 667 GD patients receiving MMI or PTU, 13% therapy prior to the development of agranulocytosis was 36
of patients experienced adverse events (122). The minor al- and 38 days for MMI and PTU, respectively.
lergic reactions included pruritus or a limited, minor rash in
6% of patients taking MMI and 3% of patients taking PTU [E4] Hepatotoxicity
(122). Hepatocellular injury occurred in 2.7% of patients Hepatotoxicity is another major adverse effect of ATD
taking PTU and 0.4% of patients taking MMI. In a separate therapy. MMI hepatotoxicity has been described as typi-
study of 449 GD patients receiving MMI or PTU, 24% de- cally cholestatic, but hepatocellular disease may be seen
veloped a cutaneous reaction, 3.8% developed transaminase (130,131). In contrast, PTU can cause fulminant hepatic ne-
elevations more than 3-fold above normal, and 0.7% devel- crosis that may be fatal; liver transplantation has been nec-
oped agranulocytosis (absolute neutrophil count <500) essary in some patients taking PTU (132). It is for this reason
(123). Cutaneous reactions were more common with PTU or that the Food and Drug Administration (FDA) issued a safety
higher dose MMI (30 mg/d) compared with lower dose MMI alert in 2010 regarding the use of PTU, and an analysis of
(15 mg/d). Hepatotoxicity was more common with PTU. FDA Medwatch data (133) concluded that children are more
Cutaneous reactions appeared after a median of 18–22 days susceptible to hepatotoxic reactions from PTU than are
of treatment, significantly earlier than transaminase eleva- adults.
tions (median 28 days). The percentage of patients dis- A recent pharmacoepidemiologic study from Taiwan chal-
continuing ATD therapy was 17% in the low-dose MMI lenges the concept that MMI hepatotoxicity is usually chole-
group, 29% in the high-dose MMI group, and 34% in the PTU static, while PTU hepatotoxicity is most often hepatocellular
group (123). (134). Among 71,379 new users of ATDs with a median
follow-up of 196 days, MMI was associated with a higher rate
[E3] Agranulocytosis of a diagnosis of noninfectious hepatitis than PTU (0.25% vs.
Although ATD-associated agranulocytosis is uncom- 0.08%, respectively), whereas cholestasis was not different
mon, it is life-threatening. PTU at any dose appears to be (0.019% vs. 0.016%). A diagnosis of liver failure was more
more likely to cause agranulocytosis compared with low common after PTU (0.048% vs. 0.026% in MMI-treated pa-
doses of MMI (124–126). Three recent reports of large tients). Similar findings were also recently reported from
numbers of ATD-treated patients who developed hemato- China (135). These surprising results from Asia, which are in
logic complications provide information on risk factors, contrast to other data from the United States (133,136), sug-
treatment, and outcomes (127–129). Two studies were from gest that prior data on MMI-related hepatotoxicity from small
Japan and one was from Denmark. In both countries the case series may need to be reconsidered. In the study from
majority of patients are treated with MMI, so data are more Denmark (129), hepatotoxic reactions were not classified as
limited for PTU-associated agranulocytosis. In the first cholestatic or hepatocellular, but the frequency of ‘‘liver
study, a retrospective cohort analysis of over 50,000 GD failure’’ was similar for MMI (0.03%) and PTU (0.03%).
patients, 55 developed agranulocytosis, of whom five had
pancytopenia, for an estimated cumulative incidence of [E5] Vasculitis
0.3% in 100 days (127), with a median interval to onset of Aside from hematologic and hepatic adverse effects,
69 days. All 50 patients with agranulocytosis alone were other rare side effects are associated with ATDs. PTU and
successfully treated with granulocyte colony stimulating rarely MMI can cause antineutrophil cytoplasmic antibody
factor, steroids, or supportive care, but one of five patients (pANCA)-positive small vessel vasculitis (137,138) as well
with pancytopenia died. No predictive risk factors for the as drug-induced lupus (139). The risk appears to increase
development of agranulocytosis could be identified. The with duration of therapy as opposed to other adverse effects
second study was based on a national database for adverse seen with ATDs that typically occur early in the course
drug reactions, which may have included some patients of treatment (140,141). Typically, granulocyte myeloperox-
reported in the first study (128). A total of 754 GD patients idase is the targeted antigen of the ANCA, but antibodies to
who developed ATD-induced hematologic complications many other proteins are seen as well (142). ANCA-positive
were reported, for an estimated incidence of 0.1%–0.15%. vasculitis is more common in patients of Asian ethnicity, and
Of them, 725 patients received MMI, 28 received PTU, the majority of reports come from Asia (143). While up to
and one received both drugs. Eighty-nine percent devel- 40% of patients taking PTU develop ANCA positivity, the
oped agranulocytosis, and 11% developed pancytopenia or vast majority of such individuals do not develop clinical
aplastic anemia. At the onset of agranulocytosis, the aver- vasculitis (144). When the drug is discontinued, the ANCA
age MMI dose was 25 mg/d and the average PTU dose was slowly disappear in most individuals (144). Children seem to
217 mg/d. The average age of patients developing agranu- be more likely to develop PTU-related ANCA-positive vas-
locytosis was slightly older (45 vs. 40 years), an observa- culitis (133). In most cases, the vasculitis resolves with drug
tion that has been made by others. Seventy-two percent discontinuation, although immunosuppressive therapy may
developed agranulocytosis within 60 days of starting ATD, be necessary (145).
and 85% within 90 days. In 7% of patients, agranulocytosis Rare cases of insulin autoimmune syndrome with symp-
occurred later than 4 months after starting ATD, but some tomatic hypoglycemia have been reported in patients treated
of these patients had discontinued the medication for long with MMI (146,147).
Technical remarks: Baseline blood tests to aid in the in- had a normal WBC count within a week and 53% within 2
terpretation of future laboratory values should be considered weeks before developing agranulocytosis (128). However,
before initiating ATD therapy. This suggestion is made in other patients did display a gradual decline in WBC count
part because low WBC counts are common in patients with prior to developing agranulocytosis, suggesting that moni-
GD and in African Americans [10% of whom have a neu- toring might have been useful in some affected patients (152).
trophil count under 2000 (148)], and abnormal liver enzymes Because patients are typically symptomatic, measuring WBC
are frequently seen in patients with thyrotoxicosis (149). counts during febrile illnesses and at the onset of pharyngitis
While there is no evidence that neutropenia or liver disease has been the standard approach to monitoring. If monitoring
increases the risk of complications from ATDs, the opinion of is employed, the maximum benefit would be for the first
the task force is that a baseline absolute neutrophil count 90 days of therapy, when the vast majority of agranulocytosis
<1000/mm3 or liver transaminase enzyme levels elevated occurs. In a patient developing agranulocytosis or other seri-
more than 5-fold above the upper limit of normal should ous side effects while taking either MMI or PTU, use of the
prompt serious reconsideration of initiating ATD therapy. It other medication is contraindicated owing to risk of cross-
is advisable to provide information concerning side effects of reactivity between the two medications (153). The contrain-
ATDs to the patient both verbally and in writing to ensure dication to use PTU might be reconsidered in life-threatening
their comprehension, and document that it has been done. thyrotoxicosis (i.e., thyroid storm) in a MMI-treated patient
This information can be found online (150,151). who has developed agranulocytosis, especially if the duration
of therapy is brief (154).
[E6] Monitoring of patients taking ATDs
Periodic clinical and biochemical evaluation of thyroid & RECOMMENDATION 18
status in patients taking ATDs is necessary, and it is essential Liver function and hepatocellular integrity should be as-
that patients understand its importance. An assessment of sessed in patients taking MMI or PTU who experience
serum free T4 and total T3 should be obtained about 2–6 pruritic rash, jaundice, light-colored stool or dark urine,
weeks after initiation of therapy, depending on the severity of joint pain, abdominal pain or bloating, anorexia, nausea, or
the thyrotoxicosis, and the dose of medication should be fatigue.
adjusted accordingly. Serum T3 should be monitored because
the serum free T4 levels may normalize despite persistent
elevation of serum total T3. Serum TSH may remain sup-
pressed for several months after starting therapy, and it is Hyperthyroidism can itself cause mildly abnormal liver
therefore not a good parameter for monitoring therapy early function tests in up to 30% of patients (149). PTU may cause
in the course. transient elevations of serum transaminases in up to one-third
Once the patient is euthyroid, the dose of MMI can usually of patients. Significant elevations to 3-fold above the upper
be decreased by 30%–50%, and biochemical testing repeated limit of normal are seen in up to 4% of patients taking PTU
in 4–6 weeks. Once euthyroid levels are achieved with the (155), a prevalence higher than with MMI. As previously
minimal dose of medication, clinical and laboratory evalua- noted, PTU can also cause fatal hepatic necrosis, leading to
tion can be undertaken at intervals of 2–3 months. If a patient the suggestion by some that patients taking this ATD have
is receiving long-term MMI (>18 months), this interval can routine monitoring of their liver function, especially during
be increased to 6 months (see below). the first 6 months of therapy. A 2009 review of the literature
(136) found that PTU hepatotoxicity occurred after a median
& RECOMMENDATION 16 of 120 days after initiation of therapy. Distinguishing these
A differential WBC count should be obtained during fe- abnormalities from the effect of persistent thyrotoxicosis is
brile illness and at the onset of pharyngitis in all patients difficult unless they are followed prospectively. In patients
taking antithyroid medication. with improving thyrotoxicosis, a rising alkaline phosphatase
with normalization of other liver function does not indicate
worsening hepatic toxicity (156) because the origin of the
& alkaline phosphatase is from bone, not liver. The onset of
RECOMMENDATION 17
PTU-induced hepatotoxicity may be acute, difficult to ap-
There is insufficient evidence to recommend for or against
preciate clinically, and rapidly progressive. If not recognized,
routine monitoring of WBC counts in patients taking
it can lead to liver failure and death (115,157–159). Routine
ATDs.
monitoring of liver function in all patients taking ATDs has
No recommendation; insufficient evidence to assess not been found to prevent severe hepatotoxicity. If monitor-
benefits and risks. ing is employed, the maximum benefit would be for the first
120 days of therapy, when the vast majority of instances of
No consensus exists concerning the utility of periodic hepatotoxicity occur.
monitoring of WBC counts and liver function tests in pre- Technical remarks: PTU should be discontinued if trans-
dicting early onset of adverse reaction to the medication aminase levels (found incidentally or measured as clinically
(152). Although routine monitoring of WBC counts may indicated) reach >3 times the upper limit of normal or if
detect early agranulocytosis, this practice is not likely to levels elevated at the onset of therapy increase further. After
identify cases because the frequency is quite low (0.2%– discontinuing the drug, liver function tests should be moni-
0.5%) and the condition is usually sudden in onset. In a recent tored weekly until there is evidence of resolution. If resolu-
analysis of 211 patients with ATD-induced agranulocytosis tion is not evident, prompt referral to a gastroenterologist or
who had at least one prior granulocyte count measured, 21% hepatologist for specialty care is warranted. Except in cases
1358 ROSS ET AL.
of severe PTU-induced hepatotoxicity, MMI can be used to treatment with RAI or thyroidectomy. Continued low-dose
control the thyrotoxicosis without ill effect (160,161). MMI treatment for longer than 12–18 months may be
considered in patients not in remission who prefer this
& RECOMMENDATION 19 approach.
There is insufficient information to recommend for or
against routine monitoring of liver function tests in pa-
tients taking ATDs.
A patient is considered to be in remission if they have had a
No recommendation; insufficient evidence to assess
normal serum TSH, free T4, and total T3 for 1 year after
benefits and risks.
discontinuation of ATD therapy. The remission rate varies
considerably between geographical areas. In earlier studies in
[E7] Management of allergic reactions
the United States, about 20%–30% of patients were reported
& to have a lasting remission after 12–18 months of medication
RECOMMENDATION 20
(59), but more recent data are not available. The remission
Minor cutaneous reactions may be managed with concur-
rate may be higher in Europe and Japan; a long-term Euro-
rent antihistamine therapy without stopping the ATD.
pean study indicated a 50%–60% remission rate after 5–6
Persistent symptomatic minor side effects of antithyroid
years of treatment (163), and a study in Japan reported a 68%
medication should be managed by cessation of the medi-
remission rate after 2 years of treatment (164). A meta-
cation and changing to RAI or surgery, or switching to the
analysis shows the remission rate in adults is not improved by
other ATD when RAI or surgery are not options. In the
a course of ATDs longer than 18 months (119). A lower
case of a serious allergic reaction, prescribing the alter-
remission rate has been described in men, smokers (espe-
native drug is not recommended.
cially men), and those with large goiters (‡80 g) (165–169).
Strong recommendation, low-quality evidence. Higher initial doses of MMI (60–80 mg/d) do not improve
remission rates; they increase the risk of side effects and are
A recent study provided evidence that switching from one not recommended (170).
ATD to the other is safe in the case of minor side effects, TRAb assessment at the end of the course of ATD therapy
although patients may develop similar side effects with the is a useful method of dividing patients into two groups: one
second ATD (123). In this study, 71 patients with an adverse with persistent elevations who are unlikely to be in remission,
event from either MMI or PTU switched to the other ATD, and another group with low or undetectable TRAb, who
with doses individually determined. Median dose of the have a higher probability of permanent remission (171,172).
second ATD was 15 mg/d for MMI (range 10–30) and In the group with elevated TRAb, relapse rates approach
300 mg/d for PTU (range 150–450). Thirty-four percent of 80%–100%, while in the latter group, relapse rates are in the
patients switched to PTU and 30% of patients switched to 20%–30% range (171,172).
MMI developed side effects, generally the same type as oc-
curred on the original ATD, while the remaining patients [E9] Persistently elevated TRAb
tolerated the second ATD without complications (123). One Patients with persistently high TRAb could continue ATD
recent case report described a more severe reaction to MMI therapy (and repeat TRAb after an additional 12–18 months)
consisting of rash, pruritis, and tongue and throat swelling or opt for alternate definitive therapy with RAI or surgery.
that was successfully managed with antihistamine therapy, In selected patients (i.e., younger patients with mild stable
but this is not generally recommended because of the risk of disease on a low dose of MMI), long-term MMI is a rea-
anaphylaxis (162). sonable alternative approach (65,173). Another study re-
ported that MMI doses of 2.5–10 mg/d for a mean of 14 years
[E8] Duration of ATD therapy for GD were safe and effective for the control of GD in 59 patients
(174). A recent retrospective analysis compared long-term
& RECOMMENDATION 21 outcomes (mean follow-up period of 6–7 years) of patients
Measurement of TRAb levels prior to stopping ATD who had relapsed after a course of ATDs, who were treated
therapy is suggested because it aids in predicting which with either RAI and levothyroxine or long-term ATD therapy
patients can be weaned from the medication, with normal (175). Those patients treated with RAI (n = 114) more often
levels indicating greater chance for remission. had persistent thyroid eye disease, continuing thyroid dys-
function, and experienced more weight gain compared with
patients receiving long-term ATD treatment (n = 124).
&
If continued MMI therapy is chosen, TRAb levels might be
RECOMMENDATION 22
monitored every 1–2 years, with consideration of MMI dis-
If MMI is chosen as the primary therapy for GD, the
continuation if TRAb levels become negative over long-term
medication should be continued for approximately 12–18
follow-up. For patients choosing long-term MMI therapy,
months, then discontinued if the TSH and TRAb levels are
monitoring of thyroid function every 4–6 months is reason-
normal at that time.
able, and patients can be seen for follow-up visits every 6–12
Strong recommendation, high-quality evidence. months.
& RECOMMENDATION 23 [E10] Negative TRAb
If a patient with GD becomes hyperthyroid after com- If TRAb is negative and thyroid function is normal at the
pleting a course of MMI, consideration should be given to end of 12–18 months of MMI therapy, it is reasonable to
discontinue the drug. If a patient experiences a relapse in Preoperative KI, SSKI, or Lugol’s solution should be used
follow-up, RAI therapy or surgery can be considered. before surgery in most patients with GD. This treatment is
Technical remarks: In patients with negative TRAb, re- beneficial because it decreases thyroid blood flow, vascu-
lapses tend to occur relatively later than those that develop in larity, and intraoperative blood loss during thyroidectomy
patients whose MMI is stopped when TRAb is still positive (181,182). In a recent series of 162 patients with GD and 102
(171,176), although 5% occurred within the first 2 months in patients with TMNG, none of whom received SSKI preop-
one study (167). Therefore, in this population, thyroid func- eratively, no significant differences were observed in opera-
tion testing should be monitored at 2- to 3-month intervals for tive times, blood loss, or postoperative complications
the first 6 months, then at 4- to 6-month intervals for the next between the two groups; the authors concluded that omitting
6 months, and then every 6–12 months in order to detect preoperative SSKI for GD patients does not impair patient
relapses as early as possible. The patient should be counseled outcomes (183). Given that this study was performed at a
to contact the treating physician if symptoms of hyperthy- single high-volume institution, its findings may not be gen-
roidism are recognized. Should a relapse occur, patients eralizable; comparison was made between two different pa-
should be counseled about alternatives for therapy, which thologies, and there was no comparison group of patients
would include another course of MMI, RAI, or surgery. If with GD who received SSKI. It is also unclear whether it was
ATD therapy is chosen, patients should be aware that adequately powered to detect a significant difference, if one
agranulocytosis can occur with a second exposure to a drug, existed. However, this study mitigates concern when thy-
even many years later, despite an earlier uneventful course of roidectomy is scheduled and SSKI is not given because of
therapy (177,178). If the patient remains euthyroid for more shortages, scheduling issues, patient allergy, or patient in-
than 1 year (i.e., they are in remission), thyroid function tolerance. In addition, rapid preparation for emergent surgery
should be monitored at least annually because relapses can can be facilitated by the use of corticosteroids (184) and
occur years later (171), and some patients eventually become potentially cholestyramine (185–187).
hypothyroid (179). Technical remarks: KI can be given as 5–7 drops (0.25–
0.35 mL) of Lugol’s solution (8 mg iodide/drop) or 1–2 drops
[F] If thyroidectomy is chosen for treatment of GD, (0.05–0.1 mL) of SSKI (50 mg iodide/drop) three times daily
how should it be accomplished? mixed in water or juice for 10 days before surgery.
Recent data suggest that supplementing oral calcium, vi-
[F1] Preparation of patients with GD for thyroidectomy
tamin D, or both preoperatively may reduce the risk of
& postoperative hypocalcemia due to parathyroid injury or in-
RECOMMENDATION 24
creased bone turnover (188). Oltmann et al. (189) compared
If surgery is chosen as treatment for GD, patients should be
45 Graves’ patients treated with 1 g oral calcium carbonate
rendered euthyroid prior to the procedure with ATD pre-
three times a day for 2 weeks prior to surgery to 38 Graves’
treatment, with or without b-adrenergic blockade. A KI-
patients who underwent thyroidectomy without treatment
containing preparation should be given in the immediate
as well as to 38 euthyroid controls; rates of biochemical
preoperative period.
and symptomatic hypocalcemia were significantly higher
Strong recommendation, low-quality evidence. in nontreated Graves’ patients compared to the two other
treatment groups. Another study that focused on postopera-
& RECOMMENDATION 25 tive hypocalcemia after thyroid surgery for thyroid cancer,
Calcium and 25-hydroxy vitamin D should be assessed not hyperthyroidism, identified a reduction in postoperative
preoperatively and repleted if necessary, or given pro- symptomatic hypocalcemia when patients have preoperative
phylactically. Calcitriol supplementation should be con- serum 25-hydroxy vitamin D levels >20 ng/mL (> 8 nmol/L)
sidered preoperatively in patients at increased risk for prior to the operating room (190). A meta-analysis of risk
transient or permanent hypoparathyroidism. factors for postoperative hypocalcemia identified preopera-
tive vitamin D deficiency as a risk factor for postoperative
hypocalcemia, as well as GD itself (188). In two studies in-
&
cluded in another meta-analysis, supplementing calcitriol for
RECOMMENDATION 26
a brief period preoperatively helped reduce transient post-
In exceptional circumstances, when it is not possible to
thyroidectomy hypocalcemia (191–193).
render a patient with GD euthyroid prior to thyroidectomy,
the need for thyroidectomy is urgent, or when the patient is
[F2] The surgical procedure and choice of surgeon
allergic to ATDs, the patient should be adequately treated
with b-adrenergic blockade, KI, glucocorticoids, and po- & RECOMMENDATION 27
tentially cholestyramine in the immediate preoperative
If surgery is chosen as the primary therapy for GD, near-
period. The surgeon and anesthesiologist should have ex-
total or total thyroidectomy is the procedure of choice.
perience in this situation.
Thyroid storm may be precipitated by the stress of surgery, Thyroidectomy has a high cure rate for the hyperthyroid-
anesthesia, or thyroid manipulation and may be prevented by ism of GD. Total thyroidectomy has a nearly 0% risk of
pretreatment with ATDs. Whenever possible, thyrotoxic recurrence, whereas subtotal thyroidectomy may have an 8%
patients who are undergoing thyroidectomy should be ren- chance of persistence or recurrence of hyperthyroidism at 5
dered euthyroid by MMI before undergoing surgery (180). years (194–197). The most common complications following
1360 ROSS ET AL.
near-total or total thyroidectomy are hypocalcemia due to may not predict eucalcemia for GD patients (214). Vitamin D
hypoparathyroidism (which can be transient or permanent), insufficiency may serve as an underlying cause.
recurrent or superior laryngeal nerve injury (which can be Patients can be discharged if they are asymptomatic and
temporary or permanent), postoperative bleeding, and com- their serum calcium levels corrected for albumin are 8.0 mg/
plications related to general anesthesia. dL (2.0 mmol/L) or above and are not falling over a 24-hour
period. The use of ionized calcium measurements are pre-
& RECOMMENDATION 28 ferred by some and are helpful if the patient has abnormal
If surgery is chosen as the primary therapy for GD, levels of serum proteins. Intravenous calcium gluconate
the patient should be referred to a high-volume thyroid should be readily available and may be administered if pa-
surgeon. tients have worsening hypocalcemic symptoms despite oral
supplementation and/or their concomitant serum calcium
levels are falling despite oral repletion. In patients with se-
vere hypocalcemia, teriparatide administration has yielded
Improved patient outcome has been shown to be inde- encouraging preliminary results (elimination of symptoms
pendently associated with high thyroidectomy surgeon and earlier hospital discharge), but more data are needed
volume; specifically, average complication rates, length before it can be considered for clinical practice (215). Per-
of hospital stay, and cost are reduced when the operation sistent hypocalcemia in the postoperative period should
is performed by a surgeon who conducts many thyroid- prompt measurement of serum magnesium and possible
ectomies. A significant association is seen between in- magnesium repletion (216,217). In addition to reduced
creasing thyroidectomy volume and improved patient serum calcium levels, reduced serum phosphate and increased
outcome; the association is robust and is more pronounced serum potassium levels may be observed in hungry bone
with an increasing number of thyroidectomies (198,199). syndrome. Following discharge, serum iPTH levels should be
Data show that surgeons who perform more than 25 thy- measured in the setting of persistent hypocalcemia to deter-
roid surgeries per year have superior patient clinical mine if permanent hypoparathyroidism is truly present or
and economic outcomes compared to those who perform whether ‘‘bone hunger’’ is ongoing. As the patient reaches
fewer; complication rates are 51% higher on average eucalcemia, calcium and calcitriol therapy can be tapered.
when surgery is performed by low-volume surgeons Technical remarks: Calcium supplementation can be ac-
(62,199,200). complished with oral calcium (usually calcium carbonate,
The surgeon should be thoroughly trained in the procedure, 1250–2500 mg, equivalent to 500–1000 mg of elemental
have an active practice in thyroid surgery, and have con- calcium) four times daily, tapered by 500 mg of elemental
ducted a significant number of thyroidectomies with a low calcium every 2 days, or 1000 mg every 4 days as tolerated. In
frequency of complications. Following thyroidectomy for addition, calcitriol may be started at a dose of 0.5 lg daily and
GD in the hands of high-volume thyroid surgeons, the rate of continued for 1–2 weeks (218) and increased or tapered ac-
permanent hypoparathyroidism has been determined to be cording to the calcium and/or iPTH level. Patients can be
<2%, and permanent RLN injury occurs in <1% (201). The discharged if they are asymptomatic and have stable serum
frequency of bleeding necessitating reoperation is 0.3%– calcium levels. Postoperative evaluation is generally con-
0.7% (202). Mortality following thyroidectomy is between 1 ducted 1–2 weeks following discharge with continuation of
in 10,000 and 5 in 1,000,000 (203). supplementation based on clinical parameters.
[F3] Postoperative care & RECOMMENDATION 30

ATD should be stopped at the time of thyroidectomy for
& RECOMMENDATION 29 GD, and b-adrenergic blockers should be weaned follow-
Following thyroidectomy for GD, alternative strategies ing surgery.
may be undertaken for management of calcium levels:
serum calcium with or without intact parathyroid hormone
(iPTH) levels can be measured, and oral calcium and & RECOMMENDATION 31
calcitriol supplementation administered based on these
Following thyroidectomy for GD, L-thyroxine should be
results, or prophylactic calcium with or without calcitriol
started at a daily dose appropriate for the patient’s weight
prescribed empirically.
(0.8 lg/lb or 1.6 lg/kg), with elderly patients needing
Weak recommendation, low-quality evidence. somewhat less, and serum TSH measured 6–8 weeks
postoperatively.
Successful prediction of calcium status after total thyroid- Strong recommendation, low-quality evidence.
ectomy can be achieved using the slope of 6- and 12-hour
postoperative calcium levels (204–210). Postoperative routine Technical remarks: If TSH was suppressed preoperatively,
supplementation with oral calcium and calcitriol decreases free T4 and TSH should be measured 6–8 weeks postopera-
development of hypocalcemic symptoms and intravenous tively, since recovery of the pituitary–thyroid axis is occa-
calcium requirement, allowing for safer early discharge (211). sionally delayed. The appropriate dosing of L-thyroxine will
Low iPTH levels (<10–15 pg/mL) in the immediate postop- vary with patient body mass index (219), and the percentage
erative setting appear to predict symptomatic hypocalcemia of levothyroxine absorbed from the gut. Once stable and
and need for calcium and calcitriol (1,25 vitamin D) supple- normal, TSH should be measured annually or more fre-
mentation (212,213). However, normal levels of serum iPTH quently if clinically indicated.
& RECOMMENDATION 32 or thyroid storm 2 (TS2) with evidence of systemic de-

Communication among different members of the multi- compensation require aggressive therapy. The decision to
disciplinary team is essential, particularly during transi- use aggressive therapy in patients with a BWPS of 25–44
tions of care in the pre- and postoperative settings. should be based on clinical judgment.
Strong recommendation, low-quality evidence. Strong recommendation, moderate-quality evidence.
& RECOMMENDATION 35
It is important to ensure that adequate communication
occurs between the medical team and the treating surgeon to A multimodality treatment approach to patients with thy-
ensure that euthyroidism is achievable prior to surgical in- roid storm should be used, including b-adrenergic block-
tervention; in addition, if the patient is noted to have signif- ade, ATD therapy, inorganic iodide, corticosteroid therapy,
icant vitamin D deficiency, preoperative vitamin D repletion cooling with acetaminophen and cooling blankets, volume
could be performed and surgery scheduled to permit it. Im- resuscitation, nutritional support, and respiratory care and
portant intraoperative findings and details of postoperative monitoring in an intensive care unit, as appropriate for an
care, including calcium supplementation needs and man- individual patient.
agement of surgical hypothyroidism, should be communi- Strong recommendation, low-quality evidence.
cated by the surgeon to the patient and the other physicians
who will be important in the patient’s postoperative care Life-threatening thyrotoxicosis or thyroid storm is a rare
(220). disorder characterized by multisystem involvement and
mortality rates in the range of 8%–25% in modern series
[G] How should thyroid nodules be managed (25,72,226,227). A high index of suspicion for thyroid storm
in patients with GD? should be maintained in patients with thyrotoxicosis asso-
& ciated with any evidence of systemic decompensation. Di-
RECOMMENDATION 33
agnostic criteria for thyroid storm in patients with severe
If a thyroid nodule is discovered in a patient with GD, the
thyrotoxicosis were first proposed in 1993 and subsequently
nodule should be evaluated and managed according to
widely adopted as the BWPS for thyroid storm (26,72,186,
recently published guidelines regarding thyroid nodules in
226,228). These criteria (Table 6) include hyperpyrexia,
euthyroid individuals.
tachycardia, arrhythmias, congestive heart failure, agitation,
Strong recommendation, moderate-quality evidence. delirium, psychosis, stupor, and coma, as well as nausea,
vomiting, diarrhea, hepatic failure, and the presence of an
Thyroid cancer occurs in GD with a frequency of 2% or identified precipitant (26). Points in the BWPS system are
less (221). Thyroid nodules larger than 1–1.5 cm should be based on the severity of individual manifestations, with a
evaluated before RAI therapy. If a RAI scan is performed, point total of ‡45 consistent with thyroid storm, 25–44 points
any nonfunctioning or hypofunctioning nodules should be classified as impending thyroid storm, and <25 points mak-
considered for fine-needle aspiration because they may have ing thyroid storm unlikely. Recently, an additional empiri-
a higher probability of being malignant (62). If the cyto- cally defined diagnostic system has been proposed by the
pathology is suspicious or diagnostic of malignancy, surgery JTA (72). The JTA system uses combinations of similar
is advised after normalization of thyroid function with ATDs. clinical features to assign patients to the diagnostic cate-
Surgery should also be considered for indeterminate cytol- gories TS1 or TS2.
ogy. Disease-free survival at 20 years is reported to be 99% Data comparing these two diagnostic systems suggest an
after thyroidectomy for GD in patients with small (£1 cm) overall agreement, but a tendency toward underdiagnosis
coexisting thyroid cancers (222). using the JTA categories of TS1 and TS2, compared to a
The use of thyroid ultrasonography in all patients with GD BWPS ‡45 (72,186,226,227). In a recent study including 25
has been shown to identify more nodules and cancer than patients with a clinical diagnosis of thyroid storm, the BWPS
does palpation and 123I scintigraphy. However, since most of was ‡45 in 20 patients and 25–44 in the remaining five, but
these cancers are papillary microcarcinomas with minimal these latter five patients (20%) were not identified using the
clinical impact, further study is required before routine ul- JTA system (226).
trasound (which may lead to surgery) can be recommended Importantly, in the same series, among 125 patients hos-
(223,224). pitalized with a clinical diagnosis of compensated thyrotox-
Technical remarks: The ATA recently published updated icosis but not in thyroid storm, 27 (21.6%) had a BWPS ‡45,
management guidelines for patients with thyroid nodules and and 21 (16.8%) had a diagnosis category of either TS1 or
differentiated thyroid cancer (225). TS2, suggesting similar rates of overdiagnosis with these two
systems. However, an additional 50 patients (40%) hospi-
[H] How should thyroid storm be managed? talized with a clinical diagnosis of thyrotoxicosis without
thyroid storm would have been diagnosed as having im-
& RECOMMENDATION 34 pending thyroid storm by the BWPS, which reinforces that a
The diagnosis of thyroid storm should be made clinically BWPS in the 25–44 range does not supplant clinical judg-
in a severely thyrotoxic patient with evidence of systemic ment in the selection of patients for aggressive therapy.
decompensation. Adjunctive use of a sensitive diagnostic In summary, the diagnosis of thyroid storm remains a
system should be considered. Patients with a Burch– clinical one that is augmented by current diagnostic systems.
Wartofsky Point Scale (BWPS) of ‡45 or Japanese Thy- A BWPS ‡45 appears more sensitive than a JTA classifica-
roid Association ( JTA) categories of thyroid storm 1 (TS1) tion of TS1 or TS2 in detecting patients with a clinical
1362 ROSS ET AL.
Table 6. Point Scale for the Diagnosis of Thyroid Storma

Criteria Points Criteria Points
Thermoregulatory dysfunction Gastrointestinal–hepatic dysfunction
Temperature (F)b Manifestation
99.0–99.9 5 Absent 0
100.0–100.9 10 Moderate (diarrhea, abdominal 10
pain, nausea/vomiting)
101.0–101.9 15 Severe (jaundice) 20
102.0–102.9 20
103.0–103.9 25
‡104.0 30
Cardiovascular Central nervous system disturbance
Tachycardia (beats per minute) Manifestation
100–109 5 Absent 0
110–119 10 Mild (agitation) 10
120–129 15 Moderate (delirium, psychosis, 20
extreme lethargy)
130–139 20 Severe (seizure, coma) 30
‡140 25
Atrial fibrillation
Absent 0
Present 10
Congestive heart failure Precipitant history
Absent 0 Status
Mild 5 Positive 0
Moderate 10 Negative 10
Severe 20
Scores totaled
>45 Thyroid storm
Impending storm
<25 Storm unlikely
a
Source: Burch and Wartofsky (26). Printed with permission.
b
Celsius 37.2–37.7 (5), 37.8–38.3 (10), 38.3–38.8 (15), 38.9–39.4 (20), 39.4–39.9 (25), ‡40 (30 points).
diagnosis of thyroid storm, but patients with a BWPS of 25– of thyroid hormone at the tissue level; (iii) reversal of sys-
44 represent a group in whom the decision to use aggressive temic decompensation; (iv) treatment of the precipitating
therapy should be based on sound clinical judgment and not event or intercurrent illness; and (v) definitive therapy (26). A
based solely on diagnostic category in order to avoid over- number of therapeutic measures are specifically intended to
treatment and the resultant risk of drug toxicity. At a mini- decrease T4-to-T3 conversion, such as the preferential use of
mum, patients in this intermediate category should be PTU over MMI (229,230), glucocorticoid therapy (231), and
observed closely for deterioration. Care should be taken with the use of b-adrenergic blocking agents such as propranolol,
either system to avoid inappropriate application to patients with selective ability to inhibit type 1 deiodinase (232). For
without severe thyrotoxicosis because each of the manifes- example, an early article comparing acute changes in thyroid
tations of thyroid storm, with the possible exception of severe hormone level after initiation of PTU or MMI found that T3
hyperpyrexia, may also be seen in the presence of any major levels dropped by approximately 45% in the first 24 hours
illness, many of which are also known precipitants of thyroid of PTU therapy compared to an approximately 10%–15%
storm (186). decrease after starting MMI (229). Both plasmapheresis/
Precipitants of thyroid storm in a patient with previously plasma exchange and emergency surgery have been used to
compensated thyrotoxicosis include abrupt cessation of treat thyroid storm in patients who respond poorly to tradi-
ATDs, thyroidectomy, or nonthyroidal surgery in a patient tional therapeutic measures (233,234).
with unrecognized or inadequately treated thyrotoxicosis, Prevention of thyroid storm involves recognizing and ac-
and a number of acute illnesses unrelated to thyroid disease tively avoiding common precipitants, educating patients
(72,186,228). Thyroid storm occasionally occurs following about avoiding abrupt discontinuation of ATD therapy, and
RAI therapy. ensuring that patients are euthyroid prior to elective surgery,
Aggressive treatment for thyroid storm involves the early labor and delivery, or other acute stressors.
targeting of each pharmacologically accessible step in thy- Technical remarks: Treatment with inorganic iodine
roid hormone production and action (Table 7). The treatment (SSKI/Lugol’s solution) or oral cholecystographic agents
strategy for thyroid storm can be broadly divided into (i) (235) leads to rapid decreases in both T4 and T3 levels.
therapy directed against thyroid hormone secretion and Combined with ATDs in patients with severe thyrotoxi-
synthesis; (ii) measures directed against the peripheral action cosis, these agents result in rapid clinical improvement
Table 7. Thyroid Storm: Drugs and Doses

Drug Dosing Comment
a
Propylthiouracil 500–1000 mg load, then Blocks new hormone synthesis
250 mg every 4 hours
Blocks T4-to-T3 conversion
Methimazole 60–80 mg/d Blocks new hormone synthesis
Propranolol 60–80 mg every 4 hours Consider invasive monitoring in congestive
heart failure patients
Blocks T4-to-T3 conversion in high doses
Alternate drug: esmolol infusion
Iodine (saturated solution 5 drops (0.25 mL or 250 mg) Do not start until 1 hour after antithyroid drugs
of potassium iodide) orally every 6 hours
Blocks new hormone synthesis
Blocks thyroid hormone release
Alternative drug: Lugol’s solution
Hydrocortisone 300 mg intravenous load, May block T4-to-T3 conversion
then 100 mg every 8 hours
Prophylaxis against relative adrenal insufficiency
Alternative drug: dexamethasone
a
May be given intravenously.
(120). Unfortunately, the oral radiographic contrast agents patients) escaped the inhibitory effects of iodine and four
ipodate and iopanoic acid are not currently available in patients did not respond at all to KI. None of the patients had
many countries. side effects. Initial free T4 concentration and goiter size did
not predict a response to therapy. Among 20 Japanese pa-
[I] Is there a role for iodine as primary therapy tients with mild hyperthyroidism initially treated with KI
in the treatment of GD? alone and matched using propensity score analysis with
patients treated with MMI alone, 85% of the patients treated
Prior to the introduction of ATDs, iodine was commonly
with KI alone had normal thyroid function at 6 months and 1
reported to ameliorate the hyperthyroidism associated with
year, comparable to that of the matched controls treated
GD (236,237). Iodine acutely lowers thyroid hormone con-
with MMI (244). Most patients were treated with 50 mg
centrations by reducing hormone secretion (238,239), and
KI daily.
inhibits its own organification (the Wolff–Chaikoff effect)
The inhibitory effects of iodine are greater in patients with
(240). However, reports of escape from these beneficial ef-
a prior history of RAI exposure (245) suggesting a role for KI
fects of iodine (241) as well as reports of iodine-induced
in patients who remain hyperthyroid after one dose of RAI
hyperthyroidism in patients with nodular goiter (242) dis-
and prefer to avoid a second dose. The use of KI prior to
couraged the use of iodine in GD. Recent studies have sug-
thyroidectomy for GD is discussed in Section [F1], the use
gested a potential role for iodine in patients who have had
of KI as adjunctive therapy following RAI is discussed in
adverse reactions to ATD and who also have a contraindi-
Section [D1], the use of KI in combination with MMI for
cation or aversion to RAI or surgery (243,244).
treating GD is discussed in Section [E1], and the use of KI
&
in hyperthyroidism complicating pregnancy is discussed in
RECOMMENDATION 36
Section [T].
Potassium iodide may be of benefit in select patients with
hyperthyroidism due to GD, those who have adverse re-
[J] How should overt hyperthyroidism due
actions to ATDs, and those who have a contraindication
to TMNG or TA be managed?
or aversion to RAI therapy (or aversion to repeat RAI
therapy) or surgery. Treatment may be more suitable for & RECOMMENDATION 37
patients with mild hyperthyroidism or a prior history of We suggest that patients with overtly TMNG or TA
RAI therapy. be treated with RAI therapy or thyroidectomy. On occa-
No recommendation; insufficient evidence to assess sion, long-term, low-dose treatment with MMI may be
benefits or risks. appropriate.
Weak recommendation, moderate-quality evidence.
Among 44 Japanese patients who had adverse reactions to
ATD and who were treated with KI alone, 66% were well Two effective and relatively safe definitive treatment op-
controlled for an average of 18 years (range 9–28 years), and tions exist for TMNG and TA: RAI therapy and thyroid
39% achieved a remission after 7 years (range 2–23 years) surgery. The decision regarding treatment should take into
(243). Among the responders, the doses used were between consideration several clinical and demographic factors as
13 and 100 mg and were adjusted depending upon bio- well as patient preference. The goal of therapy is the rapid
chemical response. Among 15 nonresponders, 11 (25% of all and durable elimination of the hyperthyroid state.
1364 ROSS ET AL.
For patients with TMNG, the risk of treatment failure or and 60% at 20 years. They observed a faster progression to
need for repeat treatment is <1% following near-total and/ hypothyroidism among patients who were older and who had
total thyroidectomy (246,247), compared with a 20% risk of incomplete TSH suppression (correlating with only partial
the need for retreatment following RAI therapy (246,248). extranodular parenchymal suppression) due to prior therapy
Euthyroidism is achieved within days after surgery (246,247). with ATDs. The nodule is rarely eradicated in patients with TA
However, the risk of hypothyroidism and the requirement for undergoing RAI therapy, which can lead to the need for con-
exogenous thyroid hormone therapy is 100% after near-total/ tinued surveillance (225,257,260).
total thyroidectomy. For patients with TMNG who receive RAI Potential complications following near-total/total thyroid-
therapy, the response is 50%–60% by 3 months and 80% by 6 ectomy include the risk of permanent hypoparathyroidism
months (246,248,249). In a large study of patients with TMNG (<2.0%) or RLN injury (<2.0%) (261,262). A small risk of
treated with RAI, the prevalence of hypothyroidism was 3% at permanent RLN injury exists with surgery for TA (254). Fol-
1 year and 64% at 24 years (250). Hypothyroidism was more lowing RAI therapy, there have been reports of new-onset GD
common among patients under 50 years of age, compared with (up to 4% prevalence) (263) as well as concern for thyroid
those over 70 years (61% vs. 36% after 16 years). In a more malignancy (254,264,265) and a very minimal increase in late
recent study, the prevalence of hypothyroidism was 4% at 1 nonthyroid malignancy (265). Overall, the success rate of RAI
year and 16% at 5 years (251). (definitive hypothyroidism or euthyroidism) is high: 93.7% in
In a large retrospective series of patients with TMNG pre- TA and 81.1% in TMNG patients (266).
senting with compressive symptoms, all patients undergoing Technical remarks: Once the diagnosis has been made, the
total thyroidectomy had resolution of these symptoms after treating physician and patient should discuss each of the treat-
treatment, whereas only 46% of patients undergoing RAI had ment options, including the logistics, benefits, expected speed of
improvement in such symptoms (252). This outcome may be recovery, drawbacks, side effects, and costs. This discussion sets
due in part to the fact that very large goiters treated with high- the stage for the physician to make a recommendation based
activity RAI only decrease in size by 30%–50% (253). upon best clinical judgment and for the final decision to incor-
For patients with TA, the risk of treatment failure is <1% porate the personal values and preferences of the patient.
after surgical resection (ipsilateral thyroid lobectomy or isth- TMNG and TA are an uncommon cause of hyperthyroidism in
musectomy) (254). Typically, euthyroidism is achieved within pregnancy and there is a lack of studies in this setting. However,
days after surgery. The prevalence of hypothyroidism varies considering the theoretical risks associated with surgery or ATD
from 2% to 3% following lobectomy for TA, although rates of therapy (has to be used throughout pregnancy and there is a
hypothyroidism after lobectomy for nontoxic nodules have tendency to overtreat the fetus), the optimal therapy might be
been reported to be as high as 20% (254–256), and lower after definitive therapy with RAI or surgery in advance of a planned
isthmusectomy in the unique circumstance in which the TA is pregnancy. Most experts prefer to avoid the use of RAI within 6
confined to the thyroid isthmus. For patients with TA who months of a pregnancy; it should be used with caution if at all.
receive RAI therapy there is a 6%–18% risk of persistent hy- The panel agreed that TMNG and TA with high nodular
perthyroidism and a 3%– 5.5% risk of recurrent hyperthy- RAIU and widely suppressed RAIU in the perinodular thy-
roidism (254,257). There is a 75% response rate by 3 months roid tissue are especially suitable for RAI therapy. However,
and 89% rate by 1 year following RAI therapy for TA there are insufficient data to make a recommendation based
(225,257,258). The prevalence of hypothyroidism after RAI is on these findings.
progressive and hastened by the presence of antithyroid anti-
bodies or a nonsuppressed TSH at the time of treatment
Factors that favor a particular modality as treatment
(257,259,260). A study following 684 patients with TA treated
for TMNG or TA (Table 8):
with RAI reported a progressive increase in overt and sub-
clinical hypothyroidism (259). At 1 year, the investigators a. RAI therapy: Advanced patient age, significant co-
noted a 7.6% prevalence, with 28% at 5 years, 46% at 10 years, morbidity, prior surgery or scarring in the anterior neck,
Table 8. Clinical Situations That Favor a Particular Modality as Treatment

for Toxic Multinodular Goiter or Toxic Adenoma
Clinical situations RAI ATD Surgery
TMNG
Pregnancya x OO / ! O/!
Advanced age, comorbidities with increased surgical risk and/or OO O x
limited life expectancy
Patients with previously operated or externally irradiated necks OO O !
Lack of access to a high-volume thyroid surgeon OO O !
Symptoms or signs of compression within the neck O - OO
Thyroid malignancy confirmed or suspected x - OO
Large goiter/nodule O - OO
Goiter/nodule with substernal or retrosternal extension O - OO
Coexisting hyperparathyroidism requiring surgery - - OO
OO = preferred therapy; O = acceptable therapy; ! = cautious use; - = not usually first line therapy but may be acceptable depending on the
clinical circumstances; X = contraindication.
a
For women considering a pregnancy within 6 months, see discussion in Section [T2].
small goiter size, RAIU sufficient to allow therapy, and [K] If RAI therapy is chosen as treatment for TMNG
lack of access to a high-volume thyroid surgeon (the or TA, how should it be accomplished?
latter factor is more important for TMNG than for TA). [K1] Preparation of patients with TMNG or TA for RAI
b. Surgery: Presence of symptoms or signs of compression therapy
within the neck, concern for coexisting thyroid cancer,
coexisting hyperparathyroidism requiring surgery, large & RECOMMENDATION 38
goiter size (>80 g), substernal or retrosternal extension, Because RAI treatment of TMNG or TA can cause a
RAIU insufficient for therapy, or need for rapid cor- transient exacerbation of hyperthyroidism, b-adrenergic
rection of the thyrotoxic state (252). blockade should be considered even in asymptomatic pa-
c. ATDs: Advanced age, comorbidities with increased sur- tients who are at increased risk for complications due to
gical risk or associated with decreased life-expectancy, worsening of hyperthyroidism (i.e., elderly patients and
and poor candidates for ablative therapy. patients with comorbidities).
Contraindications to a particular modality as treat- Weak recommendation, low-quality evidence.
ment for TMNG or TA:
Medical management before RAI therapy should be tai-
a. RAI therapy: Definite contraindications to the use of lored to the patient’s risk for complications if hyperthyroid-
RAI include pregnancy, lactation, coexisting thyroid ism worsens, based on the severity of the hyperthyroidism,
cancer, individuals unable to comply with radiation patient age, and comorbid conditions. Worsened chemical
safety guidelines and used with caution in women hyperthyroidism with increased heart rate and rare cases of
planning a pregnancy within 4–6 months. supraventricular tachycardia, including atrial fibrillation and
b. Surgery: Factors weighing against the choice of surgery atrial flutter, have been observed in patients treated with RAI
include significant comorbidity, such as cardiopulmo- for either TMNG or nontoxic multinodular goiter (MNG)
nary disease, end-stage cancer, or other debilitating (267–269). In susceptible patients with pre-existing cardiac
disorders, or lack of access to a high-volume thyroid disease or in the elderly, RAI treatment may produce sig-
surgeon. Pregnancy is a relative contraindication, and nificant clinical worsening (268). Therefore, the use of b-
surgery should only be used in this circumstance when blockers to prevent posttreatment tachyarrhythmias should
rapid control of hyperthyroidism is required and ATDs be considered in all patients with TMNG or TA who are older
cannot be used. Thyroidectomy is best avoided in the first than 60 years of age and those with cardiovascular disease
and third trimesters of pregnancy because of teratogenic or severe hyperthyroidism (31). The decision regarding the
effects associated with anesthetic agents and increased use of MMI pretreatment is more complex and is discussed
risk of fetal loss in the first trimester and preterm labor in below.
the third. Optimally, thyroidectomy should be performed
in the latter portion of the second trimester. Although it is & RECOMMENDATION 39
the safest time, it is not without risk (4.5%–5.5% risk of In addition to b-adrenergic blockade (see Recommenda-
preterm labor) (67,68). tions 2 and 38) pretreatment with MMI prior to RAI
c. ATDs: Definite contraindications to ATD therapy in- therapy for TMNG or TA should be considered in patients
clude previous known major adverse reactions to ATDs. who are at increased risk for complications due to wors-
ening of hyperthyroidism, including the elderly and those
Factors that may impact patient preference:
with cardiovascular disease or severe hyperthyroidism.
a. RAI therapy: Patients with either TMNG or TA
choosing RAI therapy would likely place relatively
higher value on the avoidance of surgery and attendant & RECOMMENDATION 40
hospitalization or complications arising from either
In patients who are at increased risk for complications
surgery or anesthesia; also, patients with TMNG would
due to worsening of hyperthyroidism, resuming ATDs
place greater value on the possibility of remaining eu-
3–7 days after RAI administration should be considered.
thyroid after RAI treatment.
b. Surgery: Patients choosing surgery would likely place a Weak recommendation, low-quality evidence.
relatively higher value on definitive control of hyper-
thyroid symptoms, avoidance of exposure to radioac- Young and middle-aged patients with TMNG or TA gen-
tivity and a lower value on potential surgical and erally do not require pretreatment with ATDs (MMI) before
anesthetic risks; patients with TMNG choosing surgery receiving RAI, but may benefit from b-blockade if symptoms
would place a lower value on the certain need for warrant and contraindications do not exist.
lifelong thyroid hormone replacement, whereas patients Technical remarks: If an ATD is used in preparation for
with TA who choose surgery would place greater value RAI therapy in patients with TMNG or TA, caution should be
on the possibility of achieving euthyroidism without taken to avoid RAI therapy when the TSH is normal or ele-
hormone replacement. vated to prevent direct RAI treatment of perinodular and
c. ATDs: Patients choosing ATDs would likely place a contralateral normal thyroid tissue, which increases the risk
relatively higher value on avoidance of exposure to of developing hypothyroidism. However, if volume reduc-
radioactivity and on potential surgical and anesthetic tion is a goal, at the expense of an increased risk of hypo-
risks and a lower value on the certain need for lifelong thyroidism, pretreatment with MMI, allowing the TSH to rise
thyroid ATD therapy. slightly prior to RAI administration, results in greater volume
1366 ROSS ET AL.
reduction after fixed doses of RAI (270). Similarly, a recent be onerous if high activities of RAI are needed for large
meta-analysis indicated that the application of recombinant goiters. Both pretreatment with MMI allowing the TSH to
human TSH (rhTSH) before RAI therapy in nontoxic MNG rise slightly (270) and the off-label use of rhTSH (271) may
or TMNG results in greater thyroid volume reduction but reduce the total activity of RAI needed, but they increase the
higher hypothyroidism rates than RAI therapy alone (271). risk of hypothyroidism (see prior discussion Section [K1]).
Unless volume reduction is an important goal, rhTSH ad- Technical remarks: Enlargement of the thyroid is very rare
ministration before RAI therapy of TMNG is not generally after RAI treatment. However, patients should be advised
recommended as it could possibly exacerbate hyperthyroid- to immediately report any tightening of the neck, difficulty
ism (272), it represents an off-label use, and mainly stimu- breathing, or stridor following the administration of RAI.
lates RAIU in TSH-sensitive perinodular tissues (273). Any compressive symptoms, such as discomfort, swelling,
dysphagia, or hoarseness, which develop following RAI
[K2] Evaluation of thyroid nodules before RAI therapy therapy, should be carefully assessed and monitored, and if
clinically necessary, corticosteroids can be administered.
& RECOMMENDATION 41 Respiratory compromise in this setting is extremely rare and
Nonfunctioning nodules on radionuclide scintigraphy or requires management as any other cause of acute tracheal
nodules with suspicious ultrasound characteristics should compression.
be managed according to published guidelines regarding
thyroid nodules in euthyroid individuals. & RECOMMENDATION 43
Sufficient activity of RAI should be administered in a
single application to alleviate hyperthyroidism in patients
with TA.
Thorough assessment of suspicious nodules within a
TMNG, according to the published guidelines (225,274), Strong recommendation, moderate-quality evidence.
should be completed before selection of RAI as the treatment
of choice. The prevalence of thyroid cancer in TMNG his- RAI administered to treat TA can be given either as a fixed
torically has been estimated to be about 3% (247). More activity of approximately 10–20 mCi (370–740 MBq) or an
recently, it has been estimated to be as high as 9%, which is activity calculated on the basis of nodule size using 150–
similar to the 10.6% prevalence noted in nontoxic MNG 200 lCi (5.5–7.4 MBq) RAI per gram corrected for 24-hour
(275). RAIU (278). A long-term follow-up study of patients with
Technical remarks: Both the ATA and AACE, the latter in TA, in which patients with nodules <4 cm were administered
conjunction with the European Thyroid Association and an average of 13 mCi (481 MBq) and those with larger nod-
Associazione Medici Endocrinologi, and the Latin American ules an average of 17 mCi (629 MBq), showed a progressive
Thyroid Society have published management guidelines for increase in hypothyroidism over time in both groups, sug-
patients with thyroid nodules (225,274,276,277). gesting that hypothyroidism develops over time regardless
of activity adjustment for nodule size (259). A randomized
[K3] Administration of RAI in the treatment of TMNG or TA trial of 97 patients with TA compared the effects of high
(22.5 mCi or 833 MBq) or low (13 mCi or 481 MBq) fixed
& RECOMMENDATION 42 activity RAI, with a calculated activity that was either high
Sufficient activity of RAI should be administered in a (180–200 lCi/g or 6.7–7.4 Bq) or low (90–100 lCi/g or 3.3–
single application to alleviate hyperthyroidism in patients 3.7 Bq) and corrected for 24-hour RAIU (279). This study
with TMNG. confirmed previous reports showing an earlier disappear-
ance of hyperthyroidism and earlier appearance of hypothy-
roidism with higher RAI activity. Use of a calculated activity
allowed for a lower RAI activity to be administered for a
The goal of RAI therapy, especially in older patients, is the
similar efficacy in the cure of hyperthyroidism.
elimination of the hyperthyroid state. Higher activities of
RAI, even when appropriately calculated for the specific
[K4] Patient follow-up after RAI therapy for TMNG or TA
volume or mass of hyperthyroid tissue, result in more rapid
resolution of hyperthyroidism and less need for retreatment, & RECOMMENDATION 44
but a higher risk for early hypothyroidism. One study showed
Follow-up within the first 1–2 months after RAI therapy
a 64% prevalence of hypothyroidism 24 years after RAI
for TMNG or TA should include an assessment of free T4,
therapy for TMNG, with a higher prevalence among patients
total T3, and TSH. Biochemical monitoring should be
who required more than one treatment (250). The prevalence
continued at 4- to 6-week intervals for 6 months, or until
of hypothyroidism following RAI therapy is increased by
the patient becomes hypothyroid and is stable on thyroid
normalization or elevation of TSH at the time of treatment
hormone replacement.
resulting from ATD pretreatment or use of rhTSH and by the
presence of antithyroid antibodies (278). Strong recommendation, low-quality evidence.
The activity of RAI used to treat TMNG, calculated on the
basis of goiter size to deliver 150–200 lCi (5.55–7.4 MBq) RAI therapy for TMNG results in resolution of hyperthy-
per gram of tissue corrected for 24-hour RAIU, is usually roidism in approximately 55% of patients at 3 months and
higher than that needed to treat GD. In addition, the RAIU 80% of patients at 6 months, with an average failure rate of
values for TMNG may be lower, necessitating an increase in 15% (246–248). Goiter volume is decreased by 3 months,
the applied activity of RAI. Radiation safety precautions may with further reduction observed over 24 months, for a total
size reduction of 40% (248). For TA, 75% of patients were no [L2] The surgical procedure and choice of surgeon
longer hyperthyroid at 3 months, with nodule volume de-
& RECOMMENDATION 47
creased by 35% at 3 months and by 45% at 2 years (257). Risk
of persistent or recurrent hyperthyroidism ranged from 0% to If surgery is chosen as treatment for TMNG, near-total or
30%, depending on the series (246–248,257). Long-term total thyroidectomy should be performed.
follow-up studies show a progressive risk of clinical or sub- Strong recommendation, moderate-quality evidence.
clinical hypothyroidism of about 8% by 1 year and 60% by 20
years for TA (259), and an average of 3% by 1 year and 64%
by 24 years for TMNG (250). Recurrence can be avoided in TMNG if a near-total or total
GD might develop after RAI for TMNG in up to 4% of thyroidectomy is performed initially (285). This procedure
patients (280). Such patients develop worsening hyperthy- can be performed with the same low rate of complications as
roidism within a few months of RAI therapy. Treatment with a subtotal thyroidectomy (286–289). Reoperation for recur-
additional RAI is effective. rent or persistent goiter results in a 3- to 10-fold increase in
Technical remarks: If thyroid hormone therapy is neces- the risk of permanent vocal cord paralysis or hypoparathy-
sary, the dose required may be less than full replace- roidism (290,291).
ment because of underlying persistent autonomous thyroid &
function. RECOMMENDATION 48
Surgery for TMNG should be performed by a high-volume
[K5] Treatment of persistent or recurrent hyperthyroidism thyroid surgeon.
following RAI therapy for TMNG or TA Strong recommendation, moderate-quality evidence.
& RECOMMENDATION 45 TMNG is more common in older patients. Data regarding
If hyperthyroidism persists beyond 6 months following outcomes following thyroidectomy in elderly patients have
RAI therapy for TMNG or TA, retreatment with RAI is shown conflicting results. Overall, however, studies con-
suggested. In selected patients with minimal response 3 ducted at the population level have demonstrated signifi-
months after therapy additional RAI may be considered. cantly higher rates of postoperative complications, longer
Weak recommendation, low-quality evidence. length of hospital stay, and higher costs among elderly pa-
tients (198). Data showing equivalent outcomes among the
Technical remarks: In severe or refractory cases of per- elderly usually have come from high-volume centers (292).
sistent hyperthyroidism due to TMNG or TA, following Robust data demonstrate that surgeon volume of thyroidec-
treatment with RAI, surgery may be considered. Because tomies is an independent predictor of patient clinical and
some patients with mild hyperthyroidism following RAI economic outcomes (i.e., in-hospital complications, length of
administration will continue to improve over time, use of stay, and total hospital charges) following thyroid surgery
MMI with close monitoring may be considered to allow (198,199,293). The recommendation for referral to a high-
control of the hyperthyroidism until the RAI is effective. volume surgeon is essentially the same as that described in
Section [F2] for the choice of surgeon in GD.
[L] If surgery is chosen, how should & RECOMMENDATION 49
it be accomplished?
If surgery is chosen as the treatment for TA, a thyroid
[L1] Preparation of patients with TMNG or TA for surgery ultrasound should be done to evaluate the entire thyroid
gland. An ipsilateral thyroid lobectomy, or isthmusectomy
& RECOMMENDATION 46 if the adenoma is in the thyroid isthmus, should be per-
If surgery is chosen as treatment for TMNG or TA, patients formed for isolated TAs.
with overt hyperthyroidism should be rendered euthyroid
prior to the procedure with MMI pretreatment, with or Strong recommendation, moderate-quality evidence.
without b-adrenergic blockade. Preoperative iodine should
not be used in this setting. A preoperative thyroid ultrasound is useful because it
will detect the presence of contralateral nodularity that is
Strong recommendation, low-quality evidence. suspicious in appearance or that will necessitate future
surveillance, both circumstances in which a total thyroid-
Risks of surgery are increased in the presence of thyro- ectomy may be more appropriate. Lobectomy removes the
toxicosis. Thyrotoxic crisis during or after the operation, can TA while leaving normal thyroid tissue, allowing residual
result in extreme hypermetabolism, hyperthermia, tachycar- normal thyroid function in the majority of patients. One
dia, hypertension, coma, or death. Therefore, prevention with large clinical series for TA demonstrated no surgical deaths
careful preparation of the patient is of paramount importance and low complication rates (254). In patients who wish
(281,282). The literature reports a very low risk of anesthesia- to avoid general anesthesia or who have significant co-
related mortality associated with thyroidectomy (254,283). morbidities, the risk of anesthesia can be lowered further
Preoperative iodine therapy is not indicated because of the when cervical block analgesia with sedation is employed by
risk of exacerbating the hyperthyroidism (284). Usually hy- thyroid surgeons and anesthesiologists experienced in this
perthyroidism is less severe in patients with TMNG, so that in approach (294). Patients with positive antithyroid anti-
most cases, patients with allergy to ATDs can be prepared for bodies preoperatively have a higher risk of postoperative
surgery, when necessary, with b-blockers alone. hypothyroidism (256,278).
1368 ROSS ET AL.
& RECOMMENDATION 50 & RECOMMENDATION 54

We suggest that surgery for TA be performed by a high- Following lobectomy for TA, TSH and estimated free T4
volume surgeon. levels should be obtained 4–6 weeks after surgery and
thyroid hormone supplementation started if there is a
persistent rise in TSH above the reference range.
While surgeon experience in the setting of TA is of some- Strong recommendation, low-quality evidence.
what less importance than in TMNG, it remains a factor to
consider in deciding between surgery and RAI therapy. High- Technical remarks: After lobectomy for TA, serum cal-
volume thyroid surgeons tend to have better outcomes follow- cium levels do not need to be obtained, and calcium and
ing lobectomy than low-volume surgeons, but the differences calcitriol supplements do not need to be administered. Thy-
are not statistically significant (198). High-volume surgeons roid hormone replacement is required in about 15%–20% of
may be more comfortable with performing the thyroid lobec- patients following thyroid lobectomy (295). Serum TSH
tomy under cervical block analgesia with sedation. levels may have been suppressed or normal prior to lobec-
tomy, depending on the degree of preoperative preparation
[L3] Postoperative care
with ATDs. TSH levels may remain in the high normal range
&
for 3–6 months following lobectomy; therefore, continued
RECOMMENDATION 51
monitoring in an asymptomatic patient for 4–6 months
Following thyroidectomy for TMNG, serum calcium with
postoperatively is reasonable, since there may be eventual
or without iPTH levels should be measured, and oral cal-
recovery of normal thyroid function (296).
cium and calcitriol supplementation administered based on
the results.
[L4] Treatment of persistent or recurrent disease following
Weak recommendation, low-quality evidence. surgery for TMNG or TA
Technical remarks: The management of hypocalcemia & RECOMMENDATION 55

following thyroidectomy for TMNG is essentially the same RAI therapy should be used for retreatment of persistent or
as that described in Section [F3] for postoperative manage- recurrent hyperthyroidism following inadequate surgery
ment in GD. Severe or prolonged preoperative hyperthy- for TMNG or TA.
roidism and larger size and greater vascularity of the goiter
(more typically seen in GD) increase the risk of postoperative Strong recommendation, low-quality evidence.
hypocalcemia.
Persistent or recurrent hyperthyroidism following surgery is
& RECOMMENDATION 52 indicative of inadequate surgery. As remedial thyroid surgery
MMI should be stopped at the time of surgery for TMNG comes at significantly increased risk of hypoparathyroidism
or TA. Beta-adrenergic blockade should be slowly dis- and RLN injury, it should be avoided, if possible, in favor of
continued following surgery. RAI therapy (290,291). If this is not an option, it is essential that
the surgery be performed by a high-volume thyroid surgeon.
[M] If ATDs are chosen as treatment of TMNG
Technical remarks: The duration over which b-adrenergic or TA, how should the therapy be managed?
blockade should be tapered should take into account the
preoperative free T4 concentration, the heart rate, and the ATDs do not induce remission in patients with nodular
week-long half-life of T4. Additionally, patients taking thyroid disease. Therefore, discontinuation of treatment results
higher doses of b-blockers will require a longer taper. in relapse (262,297). However, prolonged (lifelong) ATD
therapy may be the best choice for some individuals with
& RECOMMENDATION 53 limited life expectancy and increased surgical risk, including
Following thyroidectomy for TMNG, thyroid hormone residents of nursing homes or other care facilities where
replacement should be started at a dose appropriate for compliance with radiation safety regulations may be difficult.
the patient’s weight (0.8 lg/lb or 1.6 lg/kg) and age,
& RECOMMENDATION 56
with elderly patients needing somewhat less. TSH should
be measured every 1–2 months until stable, and then Long-term MMI treatment of TMNG or TA might be in-
annually. dicated in some elderly or otherwise ill patients with
limited life expectancy, in patients who are not good
Strong recommendation, low-quality evidence. candidates for surgery or ablative therapy, and in patients
who prefer this option.
Technical remarks: The appropriate dosing of L-thyroxine
will vary with patient body mass index (219). If a significant Weak recommendation, low-quality evidence.
thyroid remnant, which may demonstrate autonomous pro-
duction of thyroid hormone, remains following thyroidec- Technical remarks: The required dose of MMI to restore
tomy, immediate postoperative doses of thyroid hormone the euthyroid state in TMNG or TA patients is usually low
should be initiated at somewhat less than full replacement (5–10 mg/d). Because long-term, low-dose ATD treatment in
doses and subsequently adjusted based on thyroid function nodular hyperthyroidism can be difficult to regulate, frequent
testing. (every 3 months) monitoring is recommended initially,
especially in the elderly (298), until stability has been argue that it preserves normal thyroid function compared to
documented, after which testing frequency can be decreased. surgery or RAI (307). However, additional data are needed to
determine the success at correcting hyperthyroidism in pa-
tients with TA and TMNG. The use of RFA should be limited
[N] Is there a role for ethanol or radiofrequency
to centers where clinicians have received adequate training in
ablation in the management of TA or TMNG?
the technique.
& RECOMMENDATION 57
Alternative therapies such as ethanol or radiofrequency [O] How should GD be managed in children
ablation of TA and TMNG can be considered in select and adolescents?
patients in whom RAI, surgery, and long-term ATD are [O1] General approach
inappropriate, contraindicated, or refused, and expertise in
these procedures is available. & RECOMMENDATION 58
No recommendation; insufficient evidence to assess Children with GD should be treated with MMI, RAI
benefits and risks. therapy, or thyroidectomy. RAI therapy should be avoided
in very young children (<5 years). RAI therapy in children
[N1] Ethanol ablation is acceptable if the activity is >150 lCi/g (5.55 MBq/g) of
Reports that support the efficacy of percutaneous ethanol thyroid tissue, and for children between 5 and 10 years of
injection under sonographic guidance to treat TA and TMNG age if the calculated RAI administered activity is <10 mCi
come largely from Europe (299–301). Experience in the (<370 MBq). Thyroidectomy should be chosen when de-
United States is limited. A typical protocol involves the in- finitive therapy is required, the child is too young for RAI,
jection of ethanol (average dose 10 mL, depending on size of and surgery can be performed by a high-volume thyroid
the area to be ablated) into the TA or autonomous area of a surgeon.
TMNG. In one study, the average patient required four ses- Strong recommendation, moderate-quality evidence.
sions at 2-week intervals (299). One hundred twenty-five
patients with TA were followed for an average of 5 years; The treatment of pediatric patients with GD varies con-
2.4% refused further treatment because of pain, and 3.2% had siderably among institutions and practitioners. It is important
complications including transient RLN palsy, abscess, or to recognize that lasting remission after ATD therapy occurs
hematoma (299). Ninety-three percent of patients achieved a in only a minority of pediatric patients with GD, including
functional cure (no uptake on RAI scintigraphy), and 92% children treated with ATDs for many years. In determining
had a >50% reduction in nodule size (299). In another study the initial treatment approach, the patient’s age, clinical
of both TA and TMNG, 78% of cases achieved a functional status, and likelihood of remission should be considered.
cure, all nodules regressed, and there was no recurrent hy- Patient and parent values and preferences should also be
perthyroidism during 5 years of follow-up (300). Ethanol strongly considered when choosing one of the three treatment
ablation also has been used following RAI to reduce nodule modalities.
size (301). However, its use has been limited due to pain Because some children will go into remission, MMI
associated with extravasation of the ethanol to extranodular therapy for 1 year is still considered first-line treatment for
locations, and other adverse effects, which have included most children. However, the majority of pediatric patients
transient thyrotoxicosis, permanent ipsilateral facial dys- with GD will eventually require either RAI or surgery.
esthesia, paranodular fibrosis interfering with subsequent When ATDs are used in children, only MMI should be used,
surgery (302), and toxic necrosis of the larynx and adjacent except in exceptional circumstances. If clinical character-
skin (303). istics suggest a low chance of remission at initial presen-
tation (see Section [P6] below), MMI, RAI, or surgery may
[N2] Radiofrequency ablation be considered initially. If remission is not achieved after a
Both radiofrequency ablation (RFA) and laser therapy course of therapy with ATDs, RAI or surgery should be
have been used to treat thyroid nodules. A meta-analysis considered. Alternatively, MMI therapy may be continued
demonstrated that RFA resulted in larger reductions in nodule long term or until the child is considered old enough for
size with fewer sessions than laser therapy (304). A retro- surgery or RAI.
spective multicenter report of RFA for TA in 44 patients Properly administered, RAI is an effective treatment for GD
utilized an 18-gauge electrode under ultrasound guidance in the pediatric population (308–310). RAI is widely used in
with a mean follow-up of 20 months (305). An 82% reduction children but still viewed as controversial by some practitioners
in nodule volume was achieved, but 20% of nodules re- owing primarily to concern over cancer risks (311,312). Al-
mained autonomous on scintigraphy, and 18% of patients though there are sparse clinical data relating to RAI use in
remained hyperthyroid. All patients complained of pain children with GD and subsequent thyroid cancer (313), it is
during the procedure, but there were no complications (305). known that risks of thyroid cancer after external irradiation
A Korean study compared the use of RFA to surgery for are highest in children <5 years of age, and they decline
nontoxic nodules (306). RFA was associated with an 85% with advancing age (314,315); see discussion of RAI ther-
reduction in nodule size, the cost was similar to surgery, there apy and cancer risk in Section [P3] below. In comparison,
were fewer complications (RLN injury or hypoparathyroid- activities of RAI used with contemporary therapy are not
ism: 6% for surgery and 1% for RFA), and no patient who known to be associated with an increased risk of thyroid
received RFA became hypothyroid (306). Advocates of RFA neoplasm in children.
1370 ROSS ET AL.
Thyroidectomy is an effective treatment for GD, but it is counseled about this possibility and nutrition consultation
associated with a higher complication rate in children than in considered if excessive weight gain occurs.
adults (316–318). Thyroidectomy should be performed in
those children who are too young for RAI, provided that & RECOMMENDATION 60
surgery can be performed by a high-volume thyroid surgeon, Pediatric patients and their caretakers should be informed
preferably with experience in conducting thyroidectomies in of side effects of ATD preferably in writing, and the ne-
children. cessity of stopping the medication immediately and in-
Technical remarks: There may be circumstances in which forming their physician if they develop pruritic rash,
RAI therapy is indicated in young children, such as when a jaundice, acolic stools or dark urine, arthralgias, abdomi-
child has developed a reaction to ATDs, proper surgical ex- nal pain, nausea, fatigue, fever, or pharyngitis.
pertise is not available, or the patient is not a suitable surgical
candidate.
& RECOMMENDATION 61
[P] If ATDs are chosen as initial management of GD
Prior to initiating ATD therapy, we suggest that pediatric
in children, how should the therapy be managed?
patients have, as a baseline, complete blood cell count,
[P1] Initiation of ATD therapy for the treatment of GD including WBC count with differential, and a liver pro-
in children file including bilirubin, transaminases, and alkaline
phosphatase.
& RECOMMENDATION 59
MMI should be used in children who are treated with ATD
therapy.
PTU is associated with an unacceptable risk of hepato-
Strong recommendation, moderate-quality evidence. toxicity in children, with a risk of liver failure of 1 in 2000–
4000 children taking the medication (326,327). PTU can
Technical remarks: MMI comes in 5- or 10-mg tablets and cause fulminant hepatic necrosis that may be fatal; liver
can be given once daily, even in patients with severe hy- transplantation has been necessary in some patients taking
perthyroidism. Although many practitioners give MMI in PTU (326). For this reason, the FDA issued a black box
divided doses, data in adults do not support a need for such warning regarding the use of PTU (328), noting that 32 (22
and show that compliance with once-daily MMI therapy is adult and 10 pediatric) cases of serious liver injury have been
superior to multiple daily doses of PTU (83% vs. 53%) (319). associated with PTU use (326,328). Furthermore, since the
The MMI dose typically used is 0.2–0.5 mg/kg daily, with a recommendation to avoid PTU use in children was issued, we
range from 0.1–1.0 mg/kg daily (320–322). One approach is are unaware of any published cases of PTU-related liver
to prescribe the following whole tablet or quarter to half- failure (327).
tablet doses: infants, 1.25 mg/d; 1–5 years, 2.5–5.0 mg/d; 5– Because PTU-induced liver injury is of rapid onset and can
10 years, 5–10 mg/d; and 10–18 years, 10–20 mg/d. With be rapidly progressive, biochemical monitoring of liver
severe clinical or biochemical hyperthyroidism, doses that function tests and transaminase levels has not been shown to
are 50%–100% higher than the above can be used. be useful in surveillance for PTU-related liver injury. When
Although there may be a tendency to use higher rather than neither prompt surgery nor RAI therapy are options, and
lower doses of MMI at treatment onset, data in adults show ATD therapy is necessary in a patient who has developed a
only modest benefit of higher doses and only in severe thy- minor toxic reaction to MMI, a short course of PTU use can
rotoxicosis (free T4 > 7 ng/dL [0.554 pmol/L]) (115). Be- be considered. When surgery is the planned therapy and
cause most side effects of MMI are dose-related and occur MMI cannot be administered, if the patient is not too
within the first 3 months of treatment (128), high doses of thyrotoxic (and the hyperthyroidism is due to GD), the
MMI (e.g., >30 mg for an adolescent or adult) should rarely hyperthyroid state can be controlled before surgery with b-
be used initially. blockade and SSKI (50 mg iodide/drop) 3–7 drops (0.15–
When thyroid hormone levels normalize, MMI doses can 0.35 mL) by mouth, given three times a day for 10 days
be reduced by 50% or more to maintain a euthyroid state before surgery. Prior to surgery it is desirable to have the
(112). Alternatively, some physicians elect not to reduce free T4 level or total T4 and total T3 levels in the normal or
the MMI dose and add levothyroxine to make the patient subnormal range. Alternatively, if the surgery cannot be
euthyroid, a practice referred to as ‘‘block and replace.’’ performed within a few weeks, a short course of PTU may
However, because meta-analyses suggest a higher prevalence be administered with the child closely monitored clinically
of adverse events using block-and-replace regimens than for signs of hepatic dysfunction including nausea, anorexia,
dose titration (119,323), likely due to higher doses of MMI malaise, and abdominal pain.
and the dose-related complications associated with MMI MMI may also be associated with hepatotoxicity in chil-
(324), we suggest that this practice be avoided. However, it dren, but this tends to be milder and is typically cholestatic
may have utility in rare patients, after addressing compliance, rather than hepatocellular (326). At least one case of chole-
who are inadequately controlled on one dose of MMI, then static jaundice has been reported in a child (326). However,
become hypothyroid after a minimal dose increase. there have been reports of hepatocellular toxicity with MMI
Practitioners should also monitor the weight of children in adults (134).
treated with ATDs. Excessive weight gain within 6 months of MMI may also be associated with ANCA-positive vascu-
treatment is seen in children treated for GD, and the gain in litis (329), although this occurs far less frequently than with
weight can persist (325). Parents and patients should be PTU. Patients of Asian origin seem to be more susceptible to
this adverse reaction, and it can develop after months to years cellular injury appear to be much less than those observed in
of therapy. Many PTU-treated patients also develop ANCA adults (326).
positivity on treatment but remain asymptomatic (330). Agranulocytosis has been reported in about 0.3% of adult
Typical manifestations of ANCA-positive vasculitis are patients taking MMI or PTU (128,324,335). Data on the
polyarthritis, purpuric skin lesions, and occasionally pul- prevalence of agranulocytosis in children are unavailable, but
monary and/or renal involvement. Discontinuation of the it is estimated to be very low. In adults, agranulocytosis is
drug generally results in resolution of the symptoms, but in dose dependent with MMI and rarely occurs at low doses
more severe cases, glucocorticoids or other immunosup- (e.g., 5–10 mg/d) (128,324,335). When agranulocytosis de-
pressive therapy may be needed. velops, 95% of the time it occurs in the first 100 days of
Technical remarks: It is advisable to provide information therapy (128,324,335). The overall rate of side effects from
concerning side effects of ATDs to the patient or caretaker in ATDs (both major and minor) in children has been reported
writing. See Recommendation 14 Technical remarks for a to be 6%–35% (332,334,336,337).
discussion regarding the utility of obtaining complete blood Technical remarks: While routine monitoring of WBC
count and liver profile before initiating MMI therapy. counts may occasionally detect early agranulocytosis, it is not
recommended because of the rarity of the condition and its
[P2] Symptomatic management of Graves’ hyperthyroid- sudden onset, which is generally symptomatic. For this rea-
ism in children son, measuring WBC counts during febrile illnesses and at
the onset of pharyngitis has become the standard approach for
& RECOMMENDATION 62 monitoring.
Beta-adrenergic blockade is recommended for children
experiencing symptoms of hyperthyroidism, especially [P4] Monitoring of children taking PTU
those with heart rates in excess of 100 beats per minute.
& RECOMMENDATION 64
In general, PTU should not be used in children. But if it is
used, the medication should be stopped immediately and
In children in whom the diagnosis of Graves’ hyperthy-
liver function and hepatocellular integrity assessed in chil-
roidism is strongly suspected or confirmed, and who are
dren who experience anorexia, pruritus, rash, jaundice, light-
showing significant symptoms, including, but not limited to,
colored stool or dark urine, joint pain, right upper quadrant
tachycardia, muscle weakness, tremor, or neuropsychologi-
pain or abdominal bloating, nausea, or malaise.
cal changes, treatment with atenolol, propranolol, metopro-
lol, or other b-blockers leads to a decrease in heart rate and Strong recommendation, low-quality evidence.
symptoms of GD. In those with reactive airway disease,
cardio-selective b-blockers such as atenolol or metoprolol
Technical remarks: PTU should be discontinued if trans-
can be used cautiously (331), with the patient monitored for
aminase levels (obtained in symptomatic patients or found
exacerbation of asthma.
incidentally) reach 2–3 times the upper limit of normal. After
discontinuing the drug, liver function tests (i.e., bilirubin,
[P3] Monitoring of children taking MMI
alkaline phosphatase, and transaminases) should be moni-
After initiation of MMI therapy, thyroid function tests
tored weekly until there is evidence of resolution. If there is
(free T4, total T3, TSH) are obtained at 2–6 weeks, the dose is
no evidence of resolution, referral to a gastroenterologist or
adjusted if indicated, and thyroid function tests are measured
hepatologist is warranted.
again at 4–6 weeks, and then every 2–3 months once the dose
is stabilized. Depending on the severity of hyperthyroidism
[P5] Management of allergic reactions in children taking
and the MMI dose, it can take several months for elevated
MMI
thyroid hormone levels to fall into the normal range. Serum
TSH may remain suppressed for several months after starting & RECOMMENDATION 65
therapy and is therefore not a good parameter for monitoring
Persistent minor cutaneous reactions to MMI therapy in
therapy early in the course.
children should be managed by concurrent antihistamine
&
treatment or cessation of the medication and changing to
RECOMMENDATION 63
therapy with RAI or surgery. In the case of a serious ad-
ATDs should be stopped immediately and WBC counts
verse reaction to an ATD, prescribing the other ATD is not
measured in children who develop fever, arthralgias, mouth
recommended.
sores, pharyngitis, or malaise.
Although MMI has a better overall safety profile than PTU, If children develop serious adverse reactions to MMI, RAI
MMI is associated with minor adverse events that may affect or surgery should be considered because the risks of PTU are
up to 20% of children (332). MMI-related adverse events considered greater than the risks of RAI or surgery. In special
include allergic reactions, rashes, myalgias, and arthralgias circumstances, in which the patient appears to be at risk for
(333,334), as well as hypothyroidism from overtreatment. thyroid storm and ATD therapy is needed in a child with a
Side effects from MMI usually occur within the first 3 months serious adverse reaction to MMI, PTU may be considered for
of starting therapy, but adverse events can occur later. In short-term therapy to control hyperthyroidism. In this setting,
children, the risks of MMI-related cholestasis and hepato- families should be informed of the risks of PTU.
1372 ROSS ET AL.
[P6] Duration of MMI therapy in children with GD curred in only 17% of prepubertal children treated 5.9 – 2.8
years, compared with 30% of pubertal individuals treated
& RECOMMENDATION 66 2.8 – 1.1 years (340). In another report, the course of GD was
If MMI is chosen as the first-line treatment for GD in compared in 7 prepubertal, 21 pubertal, and 12 postpubertal
children, it may be tapered in those children requiring low children (336). Remission was achieved in 10 patients (28%)
doses after 1–2 years to determine if a spontaneous re- with similar rates among the three groups, whereas the time
mission has occurred, or it may be continued until the child to remission tended to be longer in the small proportion of
and caretakers are ready to consider definitive therapy, if prepubertal children (median age, 6 years) (336).
needed. Persistence of GD in children is correlated with the persis-
Strong recommendation, moderate-quality evidence. tence of TRAb. A recent study found that TRAb levels nor-
malized after 24 months in only 18% of pediatric patients on
ATDs (346). There were no data showing that there was nor-
The issue of how long ATDs should be used in children malization of TRAb levels when patients were on ATDs for a
before considering either RAI or surgery is a topic of con- longer time. Therefore, it appears that TRAb levels persist
troversy and warrants further study. Prospective studies in longer in children than in adults (346). Whereas monitoring of
adults show that if remission does not occur after 12–18 TRAb levels while on ATDs has been shown to be useful in
months of therapy, there is a lower chance of remission oc- adult patients for predicting the likelihood of remission or re-
curring with prolonged therapy (338). In children, when lapse of GD after stopping the medication (172), this approach
ATDs are used for 1–2 years, remission rates are generally has yet to be validated in children.
20%–30%, with remission defined as being euthyroid for 1 Whereas most studies, including recent large database
year after cessation of therapy (333,339,340). Retrospective reports (343), show that the vast majority of patients treated
studies have suggested that the chance of remission after 2 for GD with ATDs do not go into remission, a recent pro-
years of ATDs is low if the thyroid gland is large (more than spective report from France shows that with prolonged ATD
2.5 times normal size for age), the child is young (<12 years) or use, remission rates of up to 49% could be achieved. This
not Caucasian, serum TRAb levels are above normal on ther- study reported remission rates of 20%, 37%, 45%, and 49%
apy, or free T4 levels are substantially elevated at diagnosis after 4, 6, 8, and 10 years follow-up of 154 children treated
(>4 ng/dL, 50 pmol/L) (339). One prospective study suggested with ATDs (337). The use of MMI in this group of children
that likelihood of remission could best be predicted by the was associated with a very low rate of medication side effects
initial response to ATDs, with achievement of euthyroid state (337). Thus, whereas many practitioners will treat for 1–2
within 3 months, suggesting higher likelihood. Younger chil- years with MMI, these data suggest that treatment for longer
dren and those with high initial thyroid hormone levels were periods is also reasonable, as long as side effects to medi-
also found to be less likely to achieve remission within 2 years cation do not occur.
in the prospective studies (334,337).
Remission rates in children treated with ATDs for longer & RECOMMENDATION 67
than 2 years have been reported. Although two decades ago it Pediatric patients with GD who are not in remission fol-
was suggested that 25% of children with GD go into remission lowing at least 1–2 years of MMI therapy should be consid-
with every 2 years of continued treatment (341), other studies ered for treatment with RAI or thyroidectomy. Alternatively,
of larger cohorts of pediatric patients with GD treated with if children are tolerating ATD therapy, ATDs may be used for
ATDs for extended periods have not revealed similar remis- extended periods. This approach may be especially useful for
sion rates (333,339,342). Of 120 pediatric patients treated the child not considered to be a candidate for either surgery
with ATDs at one center, after 1 year of therapy with ATDs, or RAI. Individuals on prolonged ATD therapy (>2 years)
25% were in remission; after 2 years, 26%; after 4 years, 37%; should be reevaluated every 6–12 months and when transi-
and after 4–10 years, 15%. Importantly, 30% of the children tioning to adulthood.
who went into remission eventually relapsed (333). In another
large cohort of 184 medically treated children, after 1 year of
therapy with ATDs, 10% were in remission; after 2 years,
If remission is not achieved upon stopping MMI after at
14%; after 3 years, 20%; and after 4 years, 23% (339,342).
least 1 or 2 years of therapy, RAI or surgery should be con-
More recently, in a retrospective analysis from Japan of
sidered, depending on the age of the child. Alternatively,
1138 children, 723 were continued on long-term ATD treat-
practitioners can continue MMI for extended periods, as long
ment, 271 underwent surgery or RAI, and 144 dropped out. Of
as adverse drug effects do not occur and the hyperthyroid
the 639 patients of the 723 who discontinued ATD treatment
state is controlled. As already noted, adverse reactions typi-
after a mean of 3.8 years (range 0.3 to 24.8 years), 46.2%
cally occur within the first few months of therapy.
achieved remission, and 34.2% relapsed. The prevalence of
adverse events associated with MMI and PTU were 21.4%
[Q] If RAI is chosen as treatment for GD in children,
and 18.8%, respectively (343).
how should it be accomplished?
In comparison, other recent studies of long-term remission
rates of pediatric GD treated with ATDs are very low (<20%), [Q1] Preparation of pediatric patients with GD for RAI
especially with longer follow-up, in cohorts from Germany therapy
(344) and Denmark (345).
Data also suggest that age-related differences exist in re- & RECOMMENDATION 68
sponsiveness to ATDs. In one study that compared outcomes We suggest that children with GD having total T4 levels of
of 32 prepubertal and 68 pubertal children, remission oc- >20 lg/dL (260 nmol/L) or free T4 >5 ng/dL (60 pmol/L)
who are to receive RAI therapy be pretreated with MMI Calculated dosing also will help assure that an adequate ad-
and b-adrenergic blockade until total T4 and/or free T4 ministered activity is given.
normalize before proceeding with RAI treatment. When RAI activities >150 lCi/g (>5.55 MBq/g) are ad-
ministered, hypothyroidism rates are about 95% (88,339,
349). While there are reports that hyperthyroidism can re-
lapse in pediatric patients rendered hypothyroid with RAI,
Although the frequency of short-term worsening of hy-
this is very infrequent.
perthyroidism following pretreatment with ATD therapy is
Technical remarks: RAI is excreted by saliva, urine, per-
not known, there are rare reports of pediatric patients with
spiration, tears, and stool. Significant radioactivity is retained
severe hyperthyroidism who have developed thyroid storm
within the thyroid for several days. It is therefore important
after receiving RAI (347,348).
that patients and families be informed of and adhere to local
Technical remarks: When children receiving MMI are to
radiation safety recommendations following RAI therapy.
be treated with RAI, the medication should be stopped 2–
After RAI therapy, T3, T4, and/or free T4 levels should be
3 days before treatment (349). At that time patients should be
obtained every month. Because TSH levels may remain
placed on b-blockers (if not already taking) until total T4 and/
suppressed for several months after correction of the hyper-
or free T4 levels normalize following RAI therapy, which
thyroid state, TSH determinations may not be useful in this
generally takes 2–4 months. Although some physicians re-
setting for assessing hypothyroidism. Hypothyroidism typi-
start ATDs after treatment with RAI (80), this practice is
cally develops by 2–3 months posttreatment (333,349,350),
seldom required in children (309,310,350). Thyroid hormone
at which time levothyroxine should be prescribed.
levels in children begin to fall within the first week following
RAI therapy. ATDs can complicate assessment of posttreat-
[Q3] Side effects of RAI therapy in children
ment hypothyroidism since it could be the result of the MMI
Side effects of RAI therapy in children are uncommon
rather than the RAI therapy.
apart from the lifelong hypothyroidism that is the goal of
therapy. Fewer than 10% of children complain of mild ten-
[Q2] Administration of RAI in the treatment of GD
derness over the thyroid in the first week after therapy; it can
in children
be treated effectively with acetaminophen or nonsteroidal
&
anti-inflammatory agents for 24–48 hours (310,349).
RECOMMENDATION 69
If residual thyroid tissue remains in young children after
If RAI therapy is chosen as treatment for GD in children,
RAI treatment, a theoretical risk of development of thyroid
sufficient RAI should be administered in a single dose to
cancer exists. Detractors of the use of RAI therapy in children
render the patient hypothyroid.
point to the increased rates of thyroid cancer and thyroid
Strong recommendation, moderate-quality evidence. nodules observed in young children exposed to radiation
from nuclear fallout at Hiroshima or after the Chernobyl
The goal of RAI therapy for GD is to induce hypothy- nuclear reactor explosion. However, these data do not apply
roidism, rather than euthyroidism, because lower adminis- directly when assessing risks of RAI therapy. The risk of
tered activities of RAI result in residual, partially irradiated thyroid neoplasia is greatest with exposure to low-level
thyroid tissue that is at increased risk for thyroid neoplasm external radiation (0.1–25 Gy; *0.09–30 lCi/g or 3.33–
development (351). Because of an increased risk of thyroid 1110 Bq/g) (314,315,352,354,357), not with the higher
nodules and cancer associated with low-level thyroid irradi- administered activities used to treat GD. It is also important
ation in children (314,352–354) and poor remission rates to note that iodine deficiency and exposure to radionuclides
with low-administered activities of RAI (88–90), it is im- other than RAI may have contributed to the increased risk
portant that RAI activities >150 lCi (>5.55 MBq/g) rather of thyroid cancer in young children after the Chernobyl
than smaller activities of RAI be administered to achieve reactor explosion (315). Notably, thyroid cancer rates were
hypothyroidism (312). With large glands (50–80 g), RAI not increased among 3000 children exposed to RAI from
activities of 131I 200–300 lCi/g (7.4–11.1 MBq/g) may be the Hanford nuclear reactor site in an iodine-replete region
needed (349). The administered activity of RAI to patients (358). Increased thyroid cancer rates also were not seen in
with very large goiters is high, and a tendency exists to un- 6000 children who received RAI for the purpose of diag-
derestimate the size of the gland (and thereby administer nostic scanning (359).
insufficient RAI activities to these patients) (90). Therefore, No evidence suggests that children or adults treated for GD
surgery may be preferable to RAI in children with goiters with more than 150 lCi/g (5.55 MBq/g) of RAI have an in-
larger than 80 g. creased risk of thyroid cancer directly attributable to RAI.
Physicians at some centers administer a fixed dose of about While there are several studies of this issue in adults treated
15 mCi RAI to all children (350), whereas others calculate the with RAI for GD (see Section [D2]), few studies have fo-
activity from estimation or direct measurement of gland size cused on populations exposed to RAI for the treatment of GD
and 123I uptake (349). To assess thyroid size, particularly in in childhood or adolescence.
the setting of a large gland, ultrasonography is recommended In one study, an analysis was carried out of 602 individuals
(355). There are no data comparing outcomes of fixed versus exposed to RAI below 20 years of age in Swedish and U.S.
calculated activities in children; in adults, similar outcomes populations (360). The average follow-up period was 10
have been reported with the two approaches (356). One po- years, and the mean administered activity of RAI to the
tential advantage of calculated versus fixed dosing is that it thyroid was 88 Gy (approximately 80 lCi/g or 2.96 MBq/g
may be possible to use lower administered activities of RAI, equivalent), an activity known to be associated with thyroid
especially when uptake is high and the thyroid is small. neoplasia and below that recommended for treatment of GD.
1374 ROSS ET AL.
Two cases of thyroid cancer were reported compared to 0.1 needed. The theoretical risks of RAI use must therefore be
cases expected over that period of time. Effects on the de- weighed against the known risks inherent in thyroidectomy or
velopment of nonthyroid cancers were not examined. prolonged ATD use when choosing among the three different
The pediatric study with the longest follow-up reported 36- treatment options for GD in the pediatric age group.
year outcomes of 116 patients, treated with RAI between The activity of RAI administered should be based on thy-
1953 and 1973 (100). The patients ranged in age at treatment roid size and uptake and not arbitrarily reduced because of age
from 3 to 19 years. No patient developed thyroid cancer or in young individuals. Attempts to minimize the RAI activity
leukemia. There was no increase in the rate of spontaneous will result in undertreatment and the possible need for addi-
abortion or in the number of congenital anomalies in offspring. tional RAI therapy and radiation exposure.
It is important to note that the sample size was small; thus, the
statistical power was inadequate to address this issue fully. [R] If thyroidectomy is chosen as treatment for GD
Total-body radiation dose after RAI varies with age, and in children, how should it be accomplished?
the same absolute activities of RAI will result in more radi-
[R1] Preparation of children with GD for thyroidectomy
ation exposure to a young child than to an adolescent or adult
(361). At present, we do not have dosimetry information & RECOMMENDATION 70
regarding RAI use in children with GD to assess total body
Children with GD undergoing thyroidectomy should be
exposure in children. Using phantom modeling, it has been
rendered euthyroid with the use of MMI. A KI-containing
estimated that at 0, 1, 5, 10, and 15 years of age, and adult-
preparation should be given in the immediate preoperative
hood, respective total-body radiation activities are 11.1, 4.6,
period.
2.4, 1.45, 0.90, and 0.85 rem (1 rem = 0.1 Sv) per millicurie
of RAI administered (361). Based on the Biological Effects Strong recommendation, low-quality evidence.
of Ionizing Radiation Committee VII analysis of acute,
low-level radiation exposure (362), the theoretical lifetime
attributable risk of all-cancer incidence and all-cancer Surgery is an acceptable form of therapy for GD in chil-
dren. Thyroidectomy is the preferred treatment for GD in
mortality for a large population of treated children can be
young children (<5 years) when definitive therapy is re-
estimated (Table 9).
quired, and the surgery can be performed by a high-volume
To date, long-term studies of children treated with RAI for
GD have not revealed an increased risk of nonthyroid ma- thyroid surgeon. In individuals with large thyroid glands
(>80 g), the response to RAI may be poor (88,90) and surgery
lignancies. If a small risk exists, a sample size of more than
also may be preferable for these patients. When performed,
10,000 children who were treated at <10 years of age would
be needed to identify the risk, likely exceeding the number of near-total or total thyroidectomy is the recommended pro-
cedure (363).
such treated children. Based on cancer risk projections from
Technical remarks: MMI is typically given for 1–2 months
estimated whole-body, low-level radiation exposure as re-
lated to age, it is theoretically possible that there may be a low in preparation for thyroidectomy. KI (50 mg iodide/drop) can
be given as 1–2 drops (i.e., 0.05–0.1 mL) three times daily for
risk of malignancies in very young children treated with RAI.
10 days before surgery. SSKI can be mixed in juice or milk.
Thus, we recommend that RAI therapy be avoided in very
young children (<5 years) and that RAI be considered in & RECOMMENDATION 71
those children between 5 and 10 years of age when the re-
If surgery is chosen as therapy for GD in children, total or
quired activity for treatment is <10 mCi (<370 MBq). It is
near-total thyroidectomy should be performed.
important to emphasize that these recommendations are based
on theoretical concerns and further direct study of this issue is Strong recommendation, moderate-quality evidence.
Table 9. Theoretical Projections of Cancer Incidence or Cancer Mortality Related

to 131I Therapy for Hyperthyroidism as Related to Age
Lifetime attributable risk of cancer mortality
131
Total-body I dose Per 100,000 per Per 100,000 per Lifetime cancer
Age at (rem or rad) 0.1 Gy or Sv rad or rem risk for 15 mCi 131I Relative lifetime
exposure cancer risk for
(year) Per mCi Per 15 mCi Males Females Average Males Females Average Cases per 100,000 % 15 mCi 131I a
0 11.1 167 1099 1770 1435 110 177 143 23,884 23.9 1.96
1 4.6 69.0 1099 1770 1435 110 177 143 9898 9.9 1.40
5 2.4 36.0 852 1347 1100 85 135 110 3958 3.96 1.16
10 1.45 21.8 712 1104 908 71 110 91 1975 1.97 1.08
15 0.9 13.5 603 914 759 60 91 76 1024 1.02 1.04
20 0.85 12.8 511 762 637 51 76 64 812 0.81 1.03
40 0.85 12.8 377 507 442 38 51 44 564 0.56 1.02
60 0.85 12.8 319 409 364 32 41 36 464 0.46 1.02
a
Using a gross average of dying from a spontaneous cancer of 25% data analysis by Dr. Patrick Zanzonico, Memorial Sloan Kettering
Cancer Center (New York, NY).
& RECOMMENDATION 72 gression from SH to overt hyperthyroidism appears more

Thyroidectomy in children should be performed by high- likely if the TSH is suppressed (<0.01 mU/L), rather than low
volume thyroid surgeons. but detectable (0.01–0.4 mU/L) (375–377). Patients with GD
Strong recommendation, moderate-quality evidence. rather than a TMNG as the cause of SH may be more likely to
spontaneously remit (367,378). In patients at high risk of
complications from SH, TSH and free T4 should be repeated
Surgical complication rates are higher in children than in
within 2–6 weeks. For all other patients, it is important to
adults, with higher rates in younger than in older children
document that SH is a persistent problem by repeating the
(316,318). Postoperatively, younger children also appear to
serum TSH at 3–6 months, prior to initiating therapy. In
be at higher risk for transient hypoparathyroidism than ado-
clinical series, TMNG is the most common cause of SH,
lescents or adults (316,318).
especially in older persons (367,376,377). The second most
Postoperative hypocalcemia requiring intravenous cal-
common cause of SH is GD, which is more prevalent in
cium infusions appears to occur more frequently than in in
younger persons and is also common in patients who previ-
adults. Data from one center suggest that if calcitriol is started
ously received ATD therapy. Other unusual causes include
3 days before surgery (0.25 or 0.5 lg, twice daily), the need
solitary autonomously functioning nodules and various forms
for postoperative calcium infusions is markedly reduced,
of thyroiditis, the latter of which would be more strictly
leading to reduction in the length of stay (318). The calcitriol
termed ‘‘subclinical thyrotoxicosis.’’
is then weaned over the first two postoperative weeks (318).
In addition, complication rates are 2-fold higher when
[S2] Clinical significance of SH
thyroidectomy is performed by pediatric or general surgeons
Since SH is a mild form of hyperthyroidism, it is not sur-
who do not have extensive current experience in this proce-
prising that deleterious effects seen in overt hyperthyroidism
dure than when performed by high-volume thyroid surgeons
might also occur in SH. A large number of recent studies have
(316). Further support for the notion that thyroidectomy
elucidated these effects.
for GD in children should be performed by experienced
thyroid surgeons comes from reports of institutional ex-
Overall mortality. Several longitudinal studies have ex-
perience showing low complication rates at high-volume
amined correlations between SH and overall mortality, with
centers (318,364). In circumstances in which local pediatric
variable results. Some studies report increased overall mor-
thyroid surgery expertise is not available, referral of a child
tality rates in SH subjects (374,379–383), especially older
with GD to a high-volume thyroid surgery center that also
subjects, while others indicate no relation (384–387). Lim-
has pediatric experience is indicated, especially for young
itations of some of these studies include sample sizes, age
children. A multidisciplinary health-care team that includes
ranges, length of follow-up, and diagnosis of SH by a single
pediatric endocrinologists and experienced thyroid sur-
TSH measurement. A recent meta-analysis of individual-
geons and anesthesiologists is optimal.
level data from 52,674 participants, pooled from 10 cohorts
and providing greater power, concluded that SH confers a
[S] How should subclinical hyperthyroidism
24% increased risk of overall mortality (388).
be managed?
[S1] Prevalence and causes of SH Cardiovascular disease. A recent large study of 26,707
The prevalence of subclinical hyperthyroidism (SH) in an people followed for 12 years reported increased cardiovas-
adult population depends on age, sex, and iodine intake. In a cular mortality with SH (389). Some other, smaller studies
representative sample of U.S. subjects without known thy- have reached similar conclusions (374,383), although other
roid disease, 0.7% had suppressed TSH levels (<0.1 mU/L), smaller studies have failed to find a correlation (380,381,
and 1.8% had low TSH levels (<0.4 mU/L) (365). Similar 384,386). There have been two recent meta-analyses that
rates have been reported in studies from Europe, with higher examined this question, one of study-level data of 17 co-
levels in women and older subjects (366,367). The differ- horts (390) and the other of individual-level data in 52,674
ential diagnosis of an isolated low or suppressed TSH level participants (388). Both analyses concluded that SH confers
includes exogenous thyroid hormone use, nonthyroidal ill- an increased risk of cardiovascular mortality, with hazard
ness, drug effects, and pituitary/hypothalamic disease, all of ratios of 1.52 (390) and 1.29 (388). In the individual-level
which need to be ruled out before the diagnosis of SH can be meta-analysis, relative risks did not differ based on age, sex,
established in a patient with an isolated low or suppressed pre-existing cardiovascular disease, or the presence of car-
TSH level. In addition, mean serum TSH levels are lower in diovascular risk factors. However, the risk was greater in
black non-Hispanic Americans, some of whom may have subjects with TSH levels <0.1 mU/L compared to those with
slightly low TSH levels without thyroid disease (365). Finally, TSH levels 0.1–0.4 mU/L.
some otherwise healthy older persons may have low serum Some of these studies, including the meta-analyses, have
TSH levels, low-normal serum levels of free T4 and total T3, also examined nonfatal cardiovascular events in SH, with
and no evidence of thyroid or pituitary disease, suggesting an similar increased risks (383,388,390,391). The most recent
altered set point of the pituitary–thyroid axis (368,369). data indicate that SH subjects appear to be at particular risk
The natural history of SH is variable (367,370–377), with for the development of heart failure (381,388,392), especially
annualized rates of 0.5%–7% progression to overt hyper- older subjects (381,392) and those with lower TSH levels
thyroidism and 5%–12% reversion to normal TSH levels. In (392). Mechanistic correlates of these findings include in-
one study (372), 51.2% of patients had spontaneously decreased left ventricular mass and impaired left ventricular
veloped a normal TSH when first checked at some time function in SH that improve with treatment (393–396). In
within 5 years (mean time to repeat TSH, 13 months). Pro- addition, two studies have shown impaired glucose tolerance
1376 ROSS ET AL.
and decreased insulin sensitivity in SH, suggesting this may cluded that SH subjects had significantly elevated hazard
contribute to increased cardiovascular risk (397,398). ratios of 1.36 for hip fractures (6 vs. 4.9 fractures per 1000
Arrhythmias are another concern in SH. Sawin et al. (399) person-years) and 1.28 for any fractures (14.4 vs. 11.2 frac-
first reported a 2.8-fold increased risk of atrial fibrillation in tures per 1000 person-years) (413). Risks were further in-
SH subjects over age 60 years in 1994, and subsequent creased if TSH levels were <0.1 mU/L compared to 0.1–
studies have confirmed that the risk of arrhythmias, particu- 0.44 mU/L, and if SH was due to endogenous etiologies, ra-
larly atrial fibrillation, is increased in SH (381,384,388, ther than thyroid hormone administration. Risks did not differ
391,400,401). In the largest study to date (586,460 people when stratified by age, although absolute fracture rates were
followed for a median of 5.5 years), the highest relative risk lower in younger subjects. There are smaller, nonrandomized
for atrial fibrillation occurred in younger subjects, possibly trials that have shown improvement in bone mineral density
because other causes predominate with age, and in subjects with therapy of SH with ATDs or RAI (414–417).
with lower TSH levels (401). However, absolute incidence
rates of atrial fibrillation were much lower in younger sub- Mood and cognition. A large body of literature has in-
jects; for example, women under the age of 65 years had atrial vestigated possible correlations between SH and cognitive
fibrillation incidence rates of 2.3 events per 1000 person- decline [reviewed by Gan and Pearce (418), with more recent
years (relative risk of 1.89 compared to age-matched euthy- studies by others (419,420)]. Approximately equal numbers
roid women), while women 65 years and older had incidence of studies report significant associations between SH and
rates of 22.7 per 1000 person-years (relative risk of 1.27 measures of cognitive decline and the development of de-
compared to age-matched euthyroid women). Similar trends mentia, versus no associations. Therefore, at this time,
were seen for men. A further population-based study found no conclusions regarding this issue can be reached. There
that SH increased the risk for stroke in subjects over age appears to be no correlation between SH and depression
50 years with a hazard ratio of 3.39 (402), although a re- (421–423).
cent meta-analysis of stroke risk in SH found insufficient
number of events to draw definitive conclusions (403). Physical functioning. Four studies have investigated
Complementing these epidemiologic studies, investigations whether SH is associated with self-reported functional ca-
of smaller numbers of subjects with SH have revealed in- pacity or objective measures of physical functioning (420,
creased heart rate at rest and during exercise, decreased heart 423–425). Three could find no correlation, while the fourth
rate variability, and increased frequency of atrial and ven- found a correlation between SH and lower physical perfor-
tricular premature beats, which improve with treatment of SH mance in men only (425). Another uncontrolled study
(393,394,404,405). showed an increase in muscle mass and muscle strength in
Taken together, these data provide a strong argument for middle-aged women with SH after treatment with RAI or
the treatment of SH in older subjects to avoid dysrhythmias thyroidectomy (426).
and possible subsequent stroke. Whether younger patients
should be treated for the same preventive indications is less [S3] When to treat SH
clear. The most recent data provide evidence that relative
risks of cardiovascular mortality and atrial fibrillation are & RECOMMENDATION 73
elevated in younger, as well as older, patients with SH. When TSH is persistently <0.1 mU/L, treatment of SH is
However, the absolute risks of these events are very low in recommended in all individuals ‡65 years of age; in pa-
younger patients, so the risk/benefit ratio of treating younger tients with cardiac risk factors, heart disease or osteopo-
SH patients is not clear. Clinical judgement should be used in rosis; in postmenopausal women who are not on estrogens
these cases, and treatment decisions individualized. or bisphosphonates; and in individuals with hyperthyroid
symptoms.
Osteoporosis and fractures. Most studies of endogenous
SH show decreased bone mineral density in postmenopausal
women, but not in men or premenopausal women (406). & RECOMMENDATION 74
However, it is not clear that this finding translates to in-
When TSH is persistently <0.1 mU/L, treatment of
creased fracture risk. A number of population-based studies
SH should be considered in asymptomatic individuals
have reported that certain groups of subjects with SH
<65 years of age without the risk factors listed in Re-
have increased fracture rates, including all adults (407),
commendation 73.
postmenopausal women (408), men (409), or subjects who
progress to overt hyperthyroidism over time (391). The most Weak recommendation, moderate-quality evidence.
recent and by far the largest individual study to date (231,355
subjects) reported a hazard rate for all major osteoporotic Treatment of SH is controversial, since few intervention
fractures combined (hip, humerus, forearm, spine) of 1.13 studies showing benefit have been performed, especially for
[confidence intervals 1.014–1.26]. Risk increased with du- clinically important endpoints such as cardiovascular events,
ration of SH, such that after a median follow-up of 7.5 years, atrial fibrillation, and fractures. Additionally, none of these
13.5% of subjects with a low TSH level had experienced at studies included a control arm. Thus, the evidence rests only
least one major osteoporotic fracture, compared to 6.9% of with small uncontrolled studies that have shown improve-
subjects with a normal TSH level (407). Other studies have ments in cardiac structure and function, heart rate and the
not found increased fracture rates in SH subjects (410–412). frequency of premature atrial and ventricular beats, bone
A recent participant-level meta-analysis of 13 cohorts mineral density, and muscle strength (393–396,405,414–
(70,298 participants, median follow-up of 12.1 years) con- 417,426). In 2004, a panel of experts determined that the
evidence for benefit was sufficient to warrant therapy of SH ported increased risks of overall mortality in older subjects
in older individuals whose serum TSH level was <0.1 mU/L (380,429), cardiovascular events (391), heart failure (381),
(427). This recommendation was based primarily on the and atrial fibrillation in all subjects (401) or in older subjects
studies showing an increased rate of atrial fibrillation and (384), and vertebral fractures in older women (408). How-
altered skeletal health with a suppressed level of TSH de- ever, there are no interventional data for or against treatment
scribed above. Emerging epidemiologic data since then on of individuals with serum TSH levels between 0.1 mU/L and
risks for overall and cardiovascular-specific mortality, sum- the lower limit of the reference range. Therefore, treatment
marized above, have strengthened this argument, even in decisions must be individualized, based on the limited epi-
the absence of interventional data. The European Thyroid demiologic evidence and patient risk factors. The task force
Association recently reviewed these data and published felt that the limited data are stronger for older subjects, and
guidelines for the treatment of subclinical hyperthyroidism, therefore treatment should be considered for older subjects, but
which are largely concordant with recommendations pre- it is not recommended for subjects <65 years of age. However,
sented here (428). younger subjects should be monitored at regular 6- to 12-month
There are insufficient data for or against treatment of SH in intervals, and treatment should be considered if the TSH per-
younger persons or premenopausal women with SH and serum sistently decreases to <0.1 mU/L. In patients with symptoms of
TSH <0.1 mU/L. One uncontrolled study of middle-aged hyperthyroidism, a trial of b-adrenergic blockers may be useful
patients showed an improvement in hyperthyroid symptoms to determine whether symptomatic therapy might suffice.
with therapy (393). Although this study did not include Technical remarks: A TSH level between 0.1 and 0.4 mU/
younger individuals, the task force elected to recommend L on repeated measurement over a 3- to 6-month period is
treatment of SH patients younger than 65 years of age with considered persistent, effectively ruling out transient thy-
persistent TSH <0.1 mU/L and hyperthyroid symptoms. In roiditis as a cause. The thyroid disorder underlying SH with
the absence of symptoms or risk factors, treatment decisions TSH persistently within this range should be diagnosed be-
must be individualized. fore considering treatment to avoid treating patients with
Technical remarks: A TSH level of <0.1 mU/L on repeated transient, functional disorders related to acute illness, drugs,
measurement over a 3- to 6-month period is considered to be and other causes of low TSH. A summary of factors to con-
persistent, effectively ruling out transient thyroiditis as a sider when deciding whether or not to treat a patient with SH
cause. The thyroid disorder underlying SH should be diag- is provided (Table 10).
nosed, and is most commonly TMNG, GD, or TA.
[S4] How to treat SH
& RECOMMENDATION 75
When TSH is persistently below the lower limit of normal & RECOMMENDATION 77
but ‡0.1 mU/L, treatment of SH should be considered in If SH is to be treated, the treatment should be based on the
individuals ‡65 years of age and in patients with cardiac etiology of the thyroid dysfunction and follow the same
disease, osteoporosis, or symptoms of hyperthyroidism. principles as outlined for the treatment of overt hyper-
thyroidism.
& RECOMMENDATION 76
When TSH is persistently below the lower limit of nor-
mal but ‡0.1 mU/L, asymptomatic patients under age 65 The treatment of SH is similar to the treatment of overt
without cardiac disease or osteoporosis can be observed hyperthyroidism. RAI is appropriate for most patients, es-
without further investigation of the etiology of the sub- pecially in older patients when TMNG is a frequent cause of
normal TSH or treatment. SH. There are no data to inform whether elderly patients with
SH would benefit from pretreatment with ATDs to normalize
Weak recommendation, low-quality evidence. thyroid function before RAI therapy. Given the low risk of
exacerbation (71), the risks of ATD therapy may outweigh
A number of the epidemiologic studies listed above per- any potential small benefit.
formed analyses for SH subjects with low but detectable TSH A course of ATD therapy is a reasonable alternative to
levels (generally 0.1–0.4 mU/L). Some of these studies re- RAI in patients with GD and SH, especially in younger
Table 10. Subclinical Hyperthyroidism: When to Treat

Factor TSH (<0.1 mU/L) TSH (0.1–0.4 mU/L)a
Age >65 years Yes Consider treating
Age <65 years with comorbidities
Heart disease Yes Consider treating
Osteoporosis Yes Consider treating
Menopausal, not on estrogens or bisphosphonates Yes Consider treating
Hyperthyroid symptoms Yes Consider treating
Age <65 years, asymptomatic Consider treating Observe
a
Where 0.4 mU/L is the lower limit of the normal range.
1378 ROSS ET AL.
patients, since remission rates are highest in persons finding will be a suppressed serum TSH, with serum free T4
with mild disease (109). (or total T4) and/or T3 levels above the reference range (overt
Some patients with SH due to GD may remit spontane- hyperthyroidism), or within the reference range (SH). A key
ously without therapy (375–377), so that continued obser- point is that reference ranges for thyroid function tests are
vation without therapy is reasonable for younger patients different during different stages of pregnancy, and these
with SH due to GD. A small subset of elderly patients with changes may be assay dependent.
persistently low TSH and no evidence of true thyroid dys- An understanding of pregnancy-related variations in thy-
function can be followed without intervention, especially roid function tests is important in making the diagnosis
when the serum free T4 and total T3 levels are in the lower of hyperthyroidism in pregnancy. Serum TSH levels may
half of the normal range. Treatment with b-adrenergic be below the nonpregnant reference range in the first half
blockade may be sufficient to control the cardiovascular- of a normal-term pregnancy (435,436), and especially so in
related morbidity from SH, especially that of atrial fibrillation gestational weeks 9–13, during which a subset of pregnant
(430). women may develop a suppressed serum TSH (437–439).
Technical remarks: Some patients with SH due to mild GD The decrease in TSH in early pregnancy is the result of
may remit spontaneously and may be followed without stimulation of the normal thyroid by high levels of serum
therapy with frequent (every 3–6 months) monitoring of human chorionic gonadotropin (hCG) (440), and occasion-
thyroid function. In select patients with SH due to TMNG ally the biochemical findings that develop may correspond to
who have compressive symptoms, or in whom there is con- overt thyrotoxicosis (gestational hyperthyroidism discussed
cern for malignancy, surgery is also an option. below). However, low serum TSH levels with normal free T4
(or total T4) in early pregnancy do not indicate disease in need
[S5] End points to be assessed to determine effective of therapy. During the second half of pregnancy, the lower
therapy of SH limit of normal for TSH in the nonpregnant population can be
The goal of therapy for SH is to render the patient euthy- used (441).
roid with a normal TSH. Since the rationale for therapy of SH Free T4 and T3 measured in an equilibrium dialysate or an
is to a large degree preventive, few end points can be used to ultrafiltrate of serum around week 10 of pregnancy may be
document that therapy has been successful. Based on the slightly higher (5%–10%) than nonpregnancy values, corre-
original indication for treatment, it is reasonable to follow sponding to the period of high serum hCG and low serum
hyperthyroid symptoms or bone density (393,414–416); TSH. From normal or slightly elevated levels, a gradual
otherwise, the major end point is a TSH level within the age- decrease occurs during pregnancy, and late third trimester
adjusted reference range. reference values are 10%–30% below nonpregnancy values
(442).
[T] How should hyperthyroidism in pregnancy Serum total T4 and T3 increase in parallel in early preg-
be managed? nancy, primarily due to increases in TBG. In one longitudinal
study, the increase in T4 and T3 reference ranges were ob-
Normal pregnancy leads to changes in thyroid physiology
served to occur at a rate of 5% of nonpregnant values per
that are reflected by altered thyroid function testing. In early
week over the 10-week period of gestation weeks 7–16 (443).
pregnancy, these changes can mimic biochemical hyperthy-
After this 50% increase, total T4 and T3 values remain stable
roidism that does not require therapy (431). Hyperthyroidism
with reference range limits 1.5 times above nonpregnancy
due to GD occurs in 0.5%–1.0% of women in the reproduc-
ranges over the remaining weeks of pregnancy (442,443).
tive age range (432), and 0.1%–0.2% of them are treated with
Total T4 and T3 values may be combined with a T3 uptake test
ATD during pregnancy (433,434). Both the thyrotoxicosis
or measurements of TBG to adjust for pregnancy-associated
and therapy of the disease may seriously complicate the
variations in TBG. Such ‘‘free T4 index’’ or ‘‘TBG-adjusted
course and outcome of pregnancy. In these guidelines, we
T4’’ values may be useful for diagnosing hyperthyroidism in
will address only the most common issues related to hyper-
pregnancy; however, trimester-specific normal reference
thyroidism in pregnancy, pending full guidelines on thyroid
ranges should be established for each individual test and
disease and pregnancy that are currently being updated by the
assay used. In the absence of these, consideration should be
ATA.
given to utilizing total T4 and T3 levels and multiply the
nonpregnancy reference range by 1.5 after week 16, as pre-
[T1] Diagnosis of hyperthyroidism in pregnancy
viously discussed.
&
Excluding patients with TSH suppression or gestational
RECOMMENDATION 78
thyrotoxicosis during the first trimester, GD is the most com-
The diagnosis of hyperthyroidism in pregnancy should be
mon cause of hyperthyroidism during pregnancy (431,444);
made using serum TSH values, and either total T4 and T3
nodular thyroid disease is less common. Hyperthyroidism
with total T4 and T3 reference ranges increasing to 1.5
caused by a hCG-producing molar pregnancy or a chorio-
times above the nonpregnant range by the second and third
carcinoma presents with a diffuse hyperactive thyroid similar
trimester or free T4 and total T3 estimations with trimester-
to GD, but without eye signs and without TRAb being de-
specific normal reference ranges.
tectable in serum. In these patients, serum hCG will be higher
Strong recommendation, low-quality evidence. than expected, and the cause can be identified by obstetrical
investigation.
The diagnosis of hyperthyroidism in pregnancy can be Technical remarks: The reliability of automated analog-
challenging. In the vast majority of patients, the disease is based assays for free T4 and free T3 has been questioned for
caused by a primary thyroid abnormality, and the principal more than 25 years (445), but these estimates are currently
widely used because of their suitability for large-scale auto- ure to gain weight, heat intolerance, excessive sweating, and
matic analyses within short time periods. In many clinics, they tachycardia beyond that normally associated with pregnancy.
are the standard of measurement in pregnancy. Because The two most common types of biochemical hyperthy-
pregnancy may influence results of these assays from different roidism that occur during pregnancy are gestational hyper-
manufacturers in different ways, and some assays may give thyroidism (e.g., hCG-mediated transient TSH suppression)
spuriously low results (446), method-specific reference ranges and GD. Gestational hyperthyroidism is a generally asymp-
for each trimester of pregnancy should be used and provided tomatic, mild, and self-limiting biochemical hyperthyroidism
by the manufacturer (447,448). If trimester-specific references that may be observed in the first trimester of normal preg-
for free T4 (and free T3) are not provided, and total T4 (and T3) nancy. The disorder lacks the characteristics of GD (431) and
assays are not locally available, samples for thyroid function is caused by the high serum hCG of early pregnancy (440). It
testing in pregnancy should be sent to a reference laboratory. is not associated with adverse pregnancy outcomes (449).
More severe degrees of gestational hyperthyroidism are as-
[T2] Management of hyperthyroidism in pregnancy sociated with hyperemesis; affected women may develop
Table 11 provides a summary of the recommendations biochemically overt hyperthyroidism and clinical symptoms
concerning management of GD during pregnancy. and signs of hyperthyroidism. Complicated cases of gesta-
tional hyperthyroidism should be referred to medical centers
& RECOMMENDATION 79 with expertise in treating these patients.
Transient hCG-mediated TSH suppression in early preg- Technical remarks: There is no evidence that treatment of
nancy should not be treated with ATD therapy. gestational hyperthyroidism with ATDs is beneficial, and use
of ATD in early pregnancy has been associated with an in-
crease in risk of birth defects. In these patients, physical
examination and repeat thyroid function tests at intervals of
Once the diagnosis of hyperthyroidism is made in a 3–4 weeks is recommended. In the case of very symptomatic
pregnant woman, attention should focus on determining the disease, a trial of b-blocker therapy [propranolol or me-
etiology and whether it warrants treatment. Clinical features troprolol, but not atenolol (450,451)] for this transient dis-
that indicate the presence of hyperthyroidism include fail- order may be considered.
Table 11. Summary of Recommendations Concerning Management of Graves’ Disease

Causing Overt Hyperthyroidism in Pregnancy
Timing of diagnosis Specific circumstances Recommendations
a
GD diagnosed Diagnosed during Begin PTU
during pregnancy first trimester Measure TRAb at diagnosis and, if elevated, repeat
at 18–22 weeksb and again at 30–34 weeksc
of gestation
If thyroidectomy is required, it is optimally
performed during the second trimester
Diagnosed after Begin MMIa
first trimester Measure TRAb at diagnosis and, if elevated,
repeat at 18–22 weeksb and again at
30–34 weeksc of gestation (all depending
on week of diagnosis).
If thyroidectomy is required, it is optimally
performed during the second trimester
GD diagnosed and Currently taking Switch to PTU or withdraw ATD therapy as soon as
treated prior to methimazole pregnancy is confirmed with early testinga
pregnancy Measure TRAb initially and, if elevated,
again at 18–22 weeksb and 30–34 weeksc
of gestation
In remission after Perform thyroid function testing to confirm
stopping antithyroid euthyroidism. TRAb measurement
medication not necessary
Previous treatment Measure TRAb initially during the first
with RAI or surgery trimester and, if elevated, again at
18–22 weeks of gestationd
a
See remarks under Recommendations 83, 86, and 87 for discussion regarding switching from one ATD to the other during pregnancy or
withdrawing from therapy.
b
If a TRAb-positive woman becomes TRAb-negative during pregnancy, this may indicate a need to reduce or stop ATD therapy to avoid
fetal hypothyroidism. See remarks under Recommendations 89 and 93.
c
If the ATD-treated mother has high TRAb values in late pregnancy, this indicates a risk of delayed neonatal hyperthyroidism (see
remarks to Recommendations 87 and 94).
d
If the mother has undergone some type of thyroid ablation (RAI or surgery) for GD and TRAb is high, evaluate fetus carefully for
hyperthyroidism in second half of pregnancy and adjust or begin ATD therapy accordingly. See remarks to Recommendation 92.
1380 ROSS ET AL.
& RECOMMENDATION 80 normalities than children exposed to other drugs (467), but
ATD therapy should be used for overt hyperthyroidism due these types of defects have not been observed in excess in
to GD during pregnancy. PTU should be used when ATD studies comparing PTU-exposed children with nonselected
therapy is given during the first trimester. MMI should be control children. Similar to other teratogenic drugs (468) the
used when ATD therapy is started after the first trimester. period of highest risk for birth defects from ATDs is gesta-
Strong recommendation, low-quality evidence. tional weeks 6–10 (469).
Concerns about rare but potentially fatal PTU-related hep-
atotoxicity have led the U.S. FDA to recommended that PTU be
Untreated or insufficiently treated hyperthyroidism may reserved for patients who are in their first trimester of preg-
seriously complicate pregnancy (452–454), and patients with nancy or who are allergic to or intolerant of MMI (157,470)
this disorder should be treated at centers with specific ex- MMI and PTU both appear in breast milk in only small
pertise in this area. GD as the cause of hyperthyroidism in concentrations, and studies of breastfed infants of mothers
pregnancy may be diagnosed from typical clinical findings, taking ATDs have demonstrated normal thyroid function and
including the presence of GO and/or serum TRAb in a hy- subsequent normal intellectual development (109). However,
perthyroid patient. Approximately 5% of patients with newly because of the potential for hepatic necrosis in either mother
diagnosed Graves’ hyperthyroidism are TRAb negative in or child from maternal PTU use, MMI is the preferred ATD in
older assays (47,455), and 3% are negative in third-generation nursing mothers.
assays (57), especially those with milder disease. As discussed in other sections of these guidelines, small
A small increase in incidence of GD was found in early doses of b-adrenergic blocking agents are in general useful to
pregnancy in one study (456), and this report fits the clinical reduce pulse rate and the hyperadrenergic symptoms of
observation that existing GD may occasionally worsen in thyrotoxicosis during the time period from the start of ATD
early pregnancy (457). On the other hand, the incidence of therapy until the patient has become euthyroid. These agents
GD drops dramatically in late pregnancy (456), which is have been studied extensively when used for treating hy-
consistent with the notion that thyroid autoimmunity im- pertension in pregnancy, and no major side effects have been
proves in the second half of pregnancy (458). detected, although fetal growth restriction has been associ-
Women who were treated with ATDs for GD and con- ated with the prolonged use of especially atenolol (431,471).
sidered in remission after such previous therapy have a small Therapy with propranolol (e.g., 10–20 mg every 8 hours) or
risk of recurrence when they become pregnant and should metoprolol (e.g., 100 mg once daily) are useful and can be
have their thyroid function tested in early pregnancy. In considered safe for short periods of time to relieve symptoms
contrast, the risk of relapse (as well as the risk of thyrotoxi- in pregnant women suffering from thyrotoxicosis.
cosis from postpartum destructive thyroiditis) during the
postpartum period is relatively high (459), and it remains & RECOMMENDATION 81
elevated for more than 1 year (456). In women who develop hyperthyroidism during their re-
ATDs have much the same effect on thyroid function in productive age range, the possibility and timing of future
pregnant as in nonpregnant women. Both ATDs and TRAb pregnancy should be discussed. Because of the risks of the
pass through the placenta and can affect the fetal thyroid. hyperthyroid state on pregnancy and fetal outcome, we
However, T4 and T3 cross the placenta only in limited amounts suggest that women should postpone pregnancy until they
because of degradation by high deiodinase type 3 activities in have become euthyroid with therapy.
the placenta (460).
PTU generally has been preferred in pregnancy because of
concerns about well-documented teratogenicity associated
Both maternal thyroid dysfunction and therapy of the hy-
with MMI, first described in 1972 (461). Defects that may be
perthyroidism may have negative effects on the pregnancy
observed in 2%–4% of exposed children (462,463) have in-
outcome. These factors should all be considered when de-
cluded aplasia cutis; choanal atresia, esophageal, and other
termining the choice of therapy for the patient who is cur-
types of gut atresias; abdominal wall abnormalities including
rently pregnant or may become pregnant in the future.
omphalocale; and eye, heart, and urinary tract malformations.
A single set of thyroid function tests within the reference
Moreover, typical facial features of MMI-exposed children
range may not guarantee euthyroidism for more than a short
have been described in case reports (464). In a U.S. study,
period during the early phase of hyperthyroidism therapy.
31% of women who had received MMI around the time of
Two sets of tests within the reference range, taken with an
conception had elective termination of pregnancy versus 9%
interval of at least 1 month and without a change of therapy is
of those who received PTU, and it was hypothesized that fear
preferable to indicate euthyroidism.
of MMI-associated birth defects had led to the decision to
terminate pregnancy (465). & RECOMMENDATION 82
Recently, an increase in the rate of birth defects (2.3%
We suggest that women with hyperthyroidism caused by
above the background rate) was also observed after PTU
GD who require high doses of ATDs to achieve eu-
exposure in early pregnancy (463), but these defects tended to
thyroidism should be considered for definitive therapy
be less severe than with MMI and included preauricular si-
before they become pregnant.
nuses and cysts and urinary tract abnormalities (466). In a
large group of children selected because they had major birth Weak recommendation, low-quality evidence.
defects and had been exposed to some type of medication in
early pregnancy, children exposed to PTU had a significantly Both thyroidectomy and RAI therapy are useful for ren-
higher frequency of situs inversus and cardiac outflow ab- dering patients with GD permanently hypothyroid with the
possibility of a stable euthyroid state on thyroid hormone worry from the adverse fetal effects of ATDs. The disad-
replacement therapy, as discussed in these guidelines. Thy- vantage is that the patient will require levothyroxine therapy
roidectomy is often followed by a decrease or disappearance while pregnant and lifelong and will be exposed to either
of TRAb from circulation, whereas RAI is often followed by the potential complications of RAI, including worsening or
a transient increase in TRAb. This increase is a potential induction of GO, or the potential for undesirable surgical
argument in favor of surgical thyroidectomy in women with outcomes.
high TRAb titers who may become pregnant within the years
to come, especially those planning therapy within the next Switching from MMI to PTU before pregnancy. Switching
year (172). However, the importance of this difference in from MMI to PTU before conception would eliminate the
autoimmune activity for pregnancy outcome has not been risk from early pregnancy exposure to MMI in women in
studied, and it should be weighed against the other benefits whom pregnancy is not recognized within the first few weeks
and harms of surgery and RAI therapy. after conception. MMI-associated birth defects occur in 2%–
To predict reduction in TRAb after surgical thyroidectomy, 4% of children exposed in early pregnancy, and abnormali-
a recent retrospective Japanese study of 45 (41 female) patients ties may be severe. PTU-associated birth defects are less
with high TRAb (median 64 IU/L, range 5.6–400, normal for well documented. They may occur in 2%–3% of children but
assay <1.9 IU/L) may be useful. Patients were followed for they mostly seem to be less severe. PTU is associated with
12 months. Smoking and the presence of orbitopathy pre- liver failure with an estimated 1:10,000 risk of severe liver
dicted slow disappearance of TRAb (half-life 162 days, or failure in adult patients (136). Thus, mothers must balance
357 days if both factors were present), whereas TRAb levels the risk of PTU to themselves versus the risk to the child.
in serum decreased with a half-life of 94 days in the re- Switching to PTU before conception may be preferred in
maining patients (472). younger women with regular menses who are expected to be
Medical tradition and experience with different types of able to conceive within 1–3 months. In a German prospective
therapy for GD varies between countries and clinics, and the study of 340 such women, 68% became pregnant within 3
risk of relapse of hyperthyroidism after ATD withdrawal may months (474).
differ considerably, depending on iodine intake, and other A special variant is women who have hyperthyroidism
factors that are only partly understood (473). Thus, advice diagnosed at a time when they hope to become pregnant soon.
given to women with GD on therapy in relation to a possible There are not sufficient data to recommend for or against
future pregnancy may differ. However, irrespective of such starting therapy with PTU and thus bypass a phase of MMI
differences, the physician providing care to a young woman therapy in such patients.
with newly diagnosed GD should include discussion and
guidance on GD and pregnancy. The severely hyperthyroid Switching from MMI to PTU after conception. Alter-
patient may not be in a position to fully comprehend many natively, the patient may continue MMI therapy but be pre-
simultaneous messages, and a more detailed discussion may pared to detect pregnancy very early and modify therapy
be appropriate when the patient has become euthyroid. immediately as recommended below. Switching to PTU as
soon as pregnancy is diagnosed may be preferred in older
& RECOMMENDATION 83 women and women who have conditions that may be asso-
Women with hyperthyroidism caused by GD that is well ciated with delayed conception. This strategy may prevent
controlled on MMI and who desire pregnancy have several prolonged use of PTU prior to conception but has the risk
options: of fetal exposure to MMI if the diagnosis of pregnancy is
delayed.
a. Patients could consider definitive therapy before they
become pregnant.
Withdrawing ATD treatment after conception. Women
b. Patients could switch to PTU before trying to conceive.
with a stable euthyroid state on 5–10 mg MMI per day
c. Patients could switch to PTU as soon as pregnancy is
achieved within a few months and a falling TRAb level are
diagnosed.
likely candidates to withdraw from ATD therapy in early
d. Appropriately selected patients could withdraw from
pregnancy.
ATD therapy as soon as pregnancy is diagnosed. If
No study has directly addressed the risk of relapse of hy-
ATD therapy is withdrawn, thyroid function should be
perthyroidism after ATD withdrawal in early pregnancy, and
assessed weekly throughout the first trimester, then
evidence comes from controlled or cohort studies of non-
monthly.
pregnant patients who had been treated with ATD for varying
Weak recommendation, low-quality evidence. periods before drug withdrawal. Based on the latter studies,
the risk of relapse of hyperthyroidism within a 2-month in-
The evidence is insufficient to give universal guidance on terval after ATD withdrawal in TRAb-negative nonsmoking
how to choose among these options, and therefore the po- patients who have already been treated for 12–24 months is
tential risks and benefits of each option should be discussed <10% (167,475).
with the patient, and patient values and preferences should be However, the risk of early relapse is very high in patients
taken into account. Each option is presented in depth in the who have received ATD for less than 6 months and/or still
following technical remarks. have indicators of high disease activity such as low serum
TSH, high TRAb level, signs of active GO, or need of MMI
Definitive therapy before becoming pregnant. This dose in excess of 5–10 mg/d to remain euthyroid (473).
strategy is discussed in Recommendation 82. It has the ad- If ATD withdrawal is followed by a relapse of hyperthy-
vantage of allowing the patient to become pregnant free of roidism, it will often develop gradually over some weeks, but
1382 ROSS ET AL.
& RECOMMENDATION 85
exact information on such time course in early pregnancy is
not available. Therefore, frequent thyroid function testing dur- We suggest that a woman who tests positive for pregnancy
ing the remaining first trimester of pregnancy is recommended according to recommendation 84 contact the physician
until more data on safety become available. responsible for the ATD therapy within 24 hours to discuss
A subset of women with GD will experience relapse of future treatment options.
hyperthyroidism in pregnancy if ATD therapy is withdrawn Weak recommendation, low-quality evidence.
according to Recommendation 81. Frequent testing of thyroid
function will allow early detection of such relapse and initia-
tion of therapy with PTU (or MMI if relapse occurs in the The time window that will allow medication withdrawal or
second trimester) to keep the mother euthyroid. The risk to the change in early pregnancy to prevent birth defects is narrow
mother from such hyperthyroidism is considered negligible. (468,469), probably confined to gestational week 5. Thus,
Considering the fetus, two recent studies performed in pregnancy should be detected early and action has to be taken
Japan suggest that such transient and mild maternal hyper- immediately.
thyroidism will not increase the risk of malformations. One &
study observed a significantly lower risk of birth defects in RECOMMENDATION 86
mothers who had been shifted from MMI to iodine therapy in We suggest that the physician contacted according to
early pregnancy, even if some of the mothers in the iodine Recommendation 85 evaluate whether ATD withdrawal in
group had developed biochemical hyperthyroidism and the first trimester of pregnancy is likely to cause relapse of
needed retreatment with ATD (476). In another study from hyperthyroidism. Evaluation should be based on patient
the same institution, the presence of a major birth defect was records, especially the severity of GD at time of diagnosis
associated with the use of MMI in early pregnancy but not and current disease activity, duration of ATD therapy,
with maternal thyroid dysfunction (462). current ATD dose requirement, and results of recent thy-
A more pertinent risk may be fetal loss caused by maternal roid function and TRAb testing. If risk of relapse is con-
hyperthyroidism in pregnancy (477,478). However, the risk sidered low, therapy can be withdrawn and followed by
from a brief period of mild maternal thyroid hyperfunction in weekly thyroid function testing during the first trimester.
early pregnancy may be low or absent. In a large cohort of Weak recommendation, low-quality evidence.
pregnant women from the United States, low or suppressed
serum TSH in early pregnancy (presumably mostly caused by In the majority of patients with GD, ATD therapy is fol-
early pregnancy high hCG levels) was not associated with lowed by a gradual remission of disease with a possibility of
adverse pregnancy outcomes (449). In a recent retrospective disappearance of TRAb from circulation (172). When patients
Japanese study of women with GD either treated with MMI in have been treated with ATD for 12–18 months a rapid relapse
early pregnancy or shifted from MMI to iodine therapy in of hyperthyroidism after ATD withdrawal becomes less likely
early pregnancy, no increase in fetal loss occurred in the (119), even if the frequency of relapse may be in the order of
iodine group despite more cases of maternal hyperthyroidism 50% within 1 year. The risk of relapse after ATD withdrawal
in this group (476). varies considerably among individual patients, and it depends
on a variety of factors (473), as already discussed in detail.
& RECOMMENDATION 84
We suggest that women who are treated with ATD and & RECOMMENDATION 87
who may potentially become pregnant should be instructed We suggest that women in early pregnancy who have a
to perform a pregnancy test within the first days after a high risk of recurrent or worsening hyperthyroidism if
missed or unusually light menstrual period. ATD is withdrawn be shifted from MMI to PTU imme-
Weak recommendation, low-quality evidence. diately after diagnosing pregnancy.
The period of major risk of birth defects caused by intake
of medication in pregnancy is gestational weeks 6–10 (468), Even if birth defects may occur after both MMI and PTU
and a study of time of exposure to ATD and risk of defects exposure in early pregnancy (463), defects after MMI expo-
suggests that this time span is also the major period of tera- sure are better documented. The reason seems to be that MMI-
togenic effects of ATD (469). Thus, withdrawal of ATD associated defects are more severe, whereas PTU-associated
therapy before week 5 of pregnancy may theoretically pre- defects tend to be less severe and may not be diagnosed im-
vent birth defects caused by ATD exposure. mediately after birth (466). Birth defects associated with both
The week of pregnancy is calculated starting from the first PTU and MMI were seen in the neonates from women who
day of the last normal menstrual period, with conception shifted drugs during the first trimester (463). Thus, it is critical
taking place about 2 weeks after this. The first real sign of to diagnose pregnancy and shift from MMI to PTU as early as
pregnancy, a missed or unusually light menstrual period, possible in the first trimester.
appears 2 weeks later. By this time, blood and urine con- Both MMI and PTU are effective therapies of hyperthy-
centrations of hCG have started to rise and generally avail- roidism in the majority of patients, and the major effect of
able pregnancy tests based on detection of hCG in urine both drugs is interaction with thyroid peroxidase–catalyzed
normally become positive early in gestational week 5. Very thyroid hormone production (109). Apart from the differ-
early testing for pregnancy to allow medication withdrawal ences in side effects discussed previously, it is important to
before the major period of teratogenicity is recommended for consider differences in potency per milligram of drug and in
other types of drugs that may be teratogenic (479). duration of effect.
A dosage ratio of MMI to PTU of 1:20 is recommended Japan. In one study, cord and maternal sera were tested at
when changing from one drug to another (115,319,480), al- delivery in 35 patients with GD treated with iodine (6–40 mg/
though only two studies have examined this dosage ratio d) initiated at 11–37 weeks of gestation. Similar to ATD
directly (115,319). Moreover, the difference in duration of therapy, thyroid function at term tended to be lower in the
effect should be taken into account. For example, 15 mg of fetus than in the mother, but overall results of therapy were
MMI would be roughly equivalent to 300 mg of PTU, but judged satisfactory, with a low risk of inducing hypothy-
because the half-life of PTU is considerably shorter than that roidism and goiter in the fetus; only 1 of 35 neonates had
of MMI, the dose of PTU should be split over the day subclinical hypothyroidism at birth (483). In a recent study,
(481,482); for example, MMI 15 mg once daily may be outcomes of pregnancy in 1333 women who had continued
substituted with PTU 100 mg three times a day (319). ATD in early pregnancy were retrospectively compared with
283 women who had shifted from ATD to iodine (median
& RECOMMENDATION 88 gestational week of shift was week 6, range 4–12) (476).
Women taking PTU during the first trimester of pregnancy Overall, shifting has been more common in recent years. The
according to Recommendations 80, 83, or 87 may be prevalence of major birth defects was lower in the women
switched to MMI at the beginning of the second trimester, who had shifted to iodine therapy (1.53% vs. 4.14%,
or they may continue PTU therapy for the remaining part p < 0.05). However, according to the authors, some degree of
of pregnancy if ATD is needed. hyperthyroidism was relatively common after shifting, and
free T4 levels were always higher in the group that had shifted
No recommendation; insufficient evidence to assess
to iodine. Despite this, live births were more common in the
benefits and risks.
group that had shifted than in the group that had continued
MMI therapy (91.9% vs. 85.1%, p < 0.05). In the publication,
The reason for the FDA black box warning against PTU data on thyroid function in the MMI group are sparse, but the
therapy after the first trimester of pregnancy is the risk study may indicate that a brief period of mild hyperthyroid-
of PTU-associated liver failure. However, even if this risk ism in the mother will not impair pregnancy.
is real, the absolute risk observed in studies of U.S. health No recent data on iodine therapy for GD in pregnancy
databases was low (433,465). Similarly, a recent Danish are available from outside Japan, but before ATDs be-
national registry study observed one case of reversible liver came available, experience with iodine therapy for GD
failure among 1103 women treated with PTU in pregnancy in general was extensive (484), and it corresponds to the
(129). more recent Japanese studies. The minimal effective dose
The risk of side effects from PTU should be weighed of iodine was around 6 mg/d, but most patients received
against the risk of the shift from PTU to MMI inducing a higher doses (484). Iodine was effective for therapy of
transient thyroid function abnormality in the pregnant woman hyperthyroidism in patients with mild GD, but clearly
who is doing well on PTU therapy. Starting from the second less effective than ATD in patients with more severe
trimester of pregnancy, women with GD may start entering disease (484). Additional data are needed before iodine
gradual remission of the autoimmune abnormality, and full therapy of pregnant women with GD can be generally
focus should be on the feasibility of ATD dose reduction to recommended.
protect the fetus against goiter and hypothyroidism, as dis- Perchlorate is a competitive inhibitor of iodine uptake by
cussed below. Patients who remain on PTU during the second the thyroid, and a few cases have been published in which it
and third trimesters could have hepatic enzymes measured at was used in pregnancy (485). Apparently, teratogenicity of
the same time that thyroid function is assessed. However, no perchlorate has not been demonstrated (486), but more clin-
prospective data show that this type of monitoring is effective ical studies on this are clearly needed. Further, this drug is not
in preventing fulminant PTU-related hepatotoxicity. Another available in the United States.
aspect to consider is that both agranulocytosis and liver Cholestyramine binds thyroid hormones in the gut during
failure developing during MMI and PTU therapy mostly their enterohepatic recirculation and has been used to treat
occur during the initial 3 months of therapy (128), but this hyperthyroidism, mostly in combination with other drugs
risk can recur when the drug is reintroduced after a relatively (487,488). Cholestyramine is not absorbed from the gut,
long period of time (177). For example, in a Japanese study and it is not expected to affect the fetus directly. However,
(177) of 14 patients who developed agranulocytosis after binding in the gut and excretion of vitamins and other
retreatment with the same ATD, no patient who restarted the substances of importance for pregnancy are concerns and
drug less than 5 months after stopping the previous course of have led to a note of caution by the FDA. Cholecystographic
therapy developed this adverse reaction. There are no data to drugs are not generally available any more. Lithium may be
directly evaluate how shifting from PTU to MMI in the teratogenic (489) and it should not be used to treat hyper-
second trimester of pregnancy will affect the risk of these thyroidism in pregnancy.
severe, but rare side effects.
& RECOMMENDATION 89
Other medical treatments for hyperthyroidism during GD during pregnancy should be treated with the lowest
pregnancy. Other types of medical therapy have been used possible dose of ATD needed to keep the mother’s thyroid
to treat hyperthyroidism, such as iodine, perchlorate, chole- hormone levels at or slightly above the reference range for
styramine, cholecystographic agents, and lithium. total T4 and T3 values in pregnancy (1.5 times above
Iodine in supraphysiological doses has multiple mostly nonpregnant reference ranges in the second and third tri-
inhibitory effects on the thyroid, and it has with some suc- mesters), and the TSH below the reference range for
cess been used to treat hyperthyroid women in pregnancy in pregnancy. Similarly, free T4 levels should be kept at or
1384 ROSS ET AL.
& RECOMMENDATION 91
slightly above the upper limit of the pregnancy trimester
reference range for the assay. Thyroid function should be When thyroidectomy is necessary for the treatment of
assessed at least monthly, and the ATD dose adjusted, as hyperthyroidism during pregnancy, the surgery should be
required. performed if possible during the second trimester.
Strong recommendation, low-quality evidence. Strong recommendation, low-quality evidence.
Even if the mother is euthyroid during ATD therapy, Thyroidectomy is best avoided in the first and third tri-
a risk of inducing fetal hypothyroidism and goiter during mesters of pregnancy because of teratogenic effects associ-
the second and third trimesters exists when the fetal thy- ated with anesthetic agents and increased risk of fetal loss in
roid has begun to function (490,491). Thus, the dose of the first trimester and increased risk of preterm labor in the
ATD should be kept as low as possible. Block-replacement third. Optimally, thyroidectomy would be performed in the
therapy consisting of ATD plus levothyroxine should latter portion of the second trimester. Although it is the safest
not be used in pregnancy. If a woman receiving such time, it is not without risk (4.5%–5.5% risk of preterm labor)
therapy becomes pregnant, and she is still in need of ATD (67,68).
therapy, the regimen should be changed to an ATD alone Evaluation by a high-risk obstetrician is advised along
(444). with counseling before surgery regarding the risks involved
Technical remarks: Free T4 is the parameter that has been (68). Thyroidectomy cures the hyperthyroidism and is often
most closely correlated with good fetal outcome. Serum TSH followed by a gradual reduction in circulating TRAb (495).
may still be suppressed in these patients and should not be Until such remission takes place, TRAb produced by the
used as the sole guide in treatment, although normalization of mother may stimulate the thyroid of the fetus or newborn and
maternal TSH during ATD therapy may indicate a need to induce hyperthyroidism. In the setting in which the mother
reduce the dose of ATD (444). In Japanese studies, ATD- still harbors TRAb after thyroidectomy, close fetal monitor-
treated maternal free T4 values were kept above the non- ing for both cardiovascular and skeletal changes with fetal
pregnancy reference range in the last part of pregnancy to ultrasound is essential.
avoid cases of elevated TSH in newborn cord blood There are no data concerning whether SSKI or iodine should
(458,491). However, with some automated free T4 assays be used to prepare pregnant patients for thyroidectomy. The
nonpregnancy free T4 is much higher than late pregnancy free risk of iodide therapy to the fetus relates to inhibition of iodine
T4 (446,492). Thus, maternal free T4 above the nonpregnancy organification via the Wolff–Chaikoff effect. The fetal thyroid
reference with suppressed TSH may leave the mother overtly gland is particularly susceptible to the inhibitory effects of
hyperthyroid, which is not recommended. excess iodine in the second half of gestation, and fetal goiter
Although many patients with GD may enter remission of can occur with chronic therapy (496). However, there is no
the autoimmune abnormality during the second half of evidence that brief iodine preparation of the mother done
pregnancy with a need of ATD dose reduction or with- preoperatively to reduce thyroid blood flow and control hy-
drawal, this is not a universal phenomenon. A small group perthyroidism is harmful to the fetus.
of patients experiences severe disease that may even Technical remarks: In patients with difficult-to-treat hy-
progress during pregnancy, with difficult-to-treat hyper- perthyroidism, preoperative preparation for thyroidectomy
thyroidism, high TRAb levels, and often a considerable during the second trimester of pregnancy includes 10 days of
goiter with high blood flow. Such patients may show a iodine (e.g., SSKI one drop three times a day), along with
‘‘high T3–low T4 pattern’’ during ATD therapy (444) pre- ATD therapy and b-blockers [propranolol or metroprolol, but
sumably caused by a high type 1 deiodinase activity in the not atenolol (450,451)] to control hyperthyroidism (497–
hyperactive thyroid (493) and preferential T3 synthesis in 499). In euthyroid patients with no signs of high thyroid ac-
the hyperstimulated thyroid made iodine deficient from tivity, but who are offered surgical thyroidectomy for other
ATD therapy (494). Maternal thyroid function should be reasons (e.g., intolerance to ATD), the use of iodine for
monitored frequently and noninvasive assessment of fetal surgical preparation is considered unnecessary.
thyroid function (e.g., fetal heart rate, bone maturity, and
fetal goiter on ultrasound), and ATD therapy balanced to [T3] The role of TRAb level measurement in pregnancy
keep acceptable thyroid function in both the mother and the
fetus (444). & RECOMMENDATION 92
TRAb levels should be measured when the etiology of
& RECOMMENDATION 90 hyperthyroidism in pregnancy is uncertain.
Pregnancy is a relative contraindication to thyroidectomy
and should only be used when medical management has
been unsuccessful or ATDs cannot be used.
The two best indicators of the activity of GD during
pregnancy are thyroid function in the untreated patient and
measurement of TRAb levels in the serum. TRAb measure-
In a population-based U.S. study, pregnant women had ment is useful in the diagnosis of GD in pregnant women with
worse clinical and economic outcomes following thyroid newly diagnosed hyperthyroidism who do not have clinical
(and parathyroid) surgery than nonpregnant women, with signs specific for GD, keeping in mind that the diagnostic
disparities in outcomes based on race/ethnicity, insurance, sensitivity of good assays is around 95% and the specificity is
and access to high-volume surgeons (68). 99% (47).
& RECOMMENDATION 93 (weeks 30–34) to guide decisions regarding neonatal mon-

Patients who were treated with RAI or thyroidectomy for itoring. An exception to this recommendation is a woman
GD prior to pregnancy should have TRAb levels measured with an intact thyroid who is no longer in need of ATD
using a sensitive assay initially during the first trimester therapy.
thyroid function testing and, if levels are elevated, again at
18–22 weeks of gestation. Strong recommendation, low-quality evidence.
Strong recommendation, low-quality evidence. TRAb measurement in late pregnancy can be used to as-
sess the risk of delayed neonatal hyperthyroidism, when the
Measurement of TRAb levels can detect persistent TSH mother continues to need ATD to control hyperthyroidism up
receptor autoimmunity in a pregnant woman previously to term. After delivery, ATD delivered to the fetus via pla-
treated with ablative therapy (RAI or thyroidectomy) for GD cental passage is rapidly metabolized by the neonate, whereas
who is now euthyroid with or without thyroid hormone re- the maternal TRAb disappears more slowly, with a half-life
placement (495,500). If the mother still produces TRAb, the of around 3 weeks. Thus, a high level of TRAb in the mother
antibodies will cross the placenta and may affect fetal thyroid in late pregnancy is an indicator that the neonate may need to
function in the last half of the pregnancy. Because of the slow be monitored for the onset of neonatal hyperthyroidism
clearance of maternal immunoglobulin G from the neonatal starting a few days after birth. In a recent study of 47 new-
circulation, thyroid dysfunction in the child may last for borns to mothers who were TRAb positive in pregnancy, nine
several months after birth. To evaluate the risk of such of the children had neonatal biochemical hyperthyroidism,
complications, the TRAb level should be measured in the and five of these (9% of all) needed ATD therapy. All hy-
pregnant woman initially during the first trimester and, if it is perthyroid neonates were born to mothers with TRAb levels
elevated, again at 18–22 weeks of gestation. If the level is ‡5 IU/L (>3 times upper reference for the assay) in the second
high, a program of fetal and neonatal surveillance for thyroid trimester (sensitivity 100%, specificity 43%). All mothers
dysfunction should be initiated (501). who gave birth to hyperthyroid newborns required ATD
The advantage to initial TRAb measurement during the therapy in late pregnancy (504).
first trimester is that it allows time to initiate specialty con-
sultation and, if the levels are especially high at that time, [T4] Postpartum thyroiditis
intervention may be required by the second trimester. Whereas
it has generally been considered that isolated fetal thyrotox- & RECOMMENDATION 96
icosis in a previously ablated mother who is still producing In women developing thyrotoxicosis after delivery,
TRAb might only start developing around weeks 20–22 of selective diagnostic studies should be performed to dis-
pregnancy, a recent case report described severe fetal thy- tinguish postpartum destructive thyroiditis from post-
rotoxicosis that had already developed in gestational week 18 partum GD.
(502). The pregnant woman had previously undergone un-
successful RAI, and a total thyroidectomy had subsequently
been performed, followed by levothyroxine replacement. The
Postpartum thyroid dysfunction occurs in up to 10% of
mother was euthyroid, but her TRAb values remained ex-
pregnancies in the United States. Postpartum thyroiditis is an
tremely elevated.
autoimmune disorder unmasked in predisposed women as
TRAb measurement is not necessary in a euthyroid preg-
immune surveillance rebounds after pregnancy. The classic
nant patient previously found to have GD if she has an intact
triphasic pattern is thyrotoxicosis at 1–6 months postpartum,
thyroid (i.e., not previously treated with surgery or RAI) and
followed by hypothyroidism and return to euthyroidism at 9–
she is not currently taking ATDs (495,503).
12 months postpartum (505,506). However, this sequence is
& not observed in every patient. Among 371 cases in 13 studies,
RECOMMENDATION 94
25% of patients were found to have a triphasic pattern, 43%
Patients receiving ATD for GD when becoming pregnant
had hypothyroidism without preceding thyrotoxicosis, and
or found to have GD during pregnancy should have TRAb
32% had thyrotoxicosis without subsequent hypothyroidism
levels measured at initial pregnancy visit or at diagnosis
(506). In a prospective study of pregnant women, those with
using a sensitive assay and, if they are elevated, again at
positive anti–thyroid peroxidase antibodies in the first tri-
18–22 weeks of gestation.
mester were 27 times more likely to develop postpartum
Strong recommendation, low-quality evidence. thyroiditis than were those with negative serology (507). In
this study, tobacco smoking and bottle-feeding increased the
TRAb (TBII or TSI) measurement may be useful to assist in risk of developing thyroiditis.
the evaluation of disease activity in a woman being treated with Postpartum thyroiditis must be distinguished from GD to
ATDs for GD during pregnancy (444,495). In many patients, recommend proper therapy. The postpartum surge in thyroid
GD gradually remits during pregnancy. Disappearance of TRAb autoimmunity leading to postpartum thyroiditis is also as-
is an indication that ATD therapy may no longer be necessary sociated with a 3- to 4-fold increase in the incidence of
and its continuation may put the fetus at risk for hypothyroidism, GD that peaks 3–12 months after delivery (456). In a Japa-
even if the mother is euthyroid on the medication. nese hospital study, thyrotoxicosis caused by thyroiditis
developed earlier after delivery than GD, although some
& RECOMMENDATION 95 overlap existed. All patients who developed overt thyrotox-
Patients with elevated TRAb levels at 18–22 weeks of icosis within the first 3 months after delivery suffered from
gestation should have TRAb remeasured in late pregnancy destructive thyroiditis, whereas GD developed after this
1386 ROSS ET AL.
3-month period (508). Goiter is generally more pronounced moderate iodine deficiency (13), but it mostly develops in
in GD, and thyroid bruit or GO strongly suggest GD as well. patients after the age of 50 years. In the uncommon case of
TRAb may occasionally be measurable in patients with this type of hyperthyroidism in a pregnant woman, patho-
postpartum thyroiditis, suggesting that some patients may genic differences from GD should be considered.
experience a combination of GD and destructive thyroiditis Thyroid hormone production in autonomy is dependent on
(509), but higher TRAb values are suggestive of GD. When iodine substrate, but no study has addressed the effect of a
in vivo testing is required to make this distinction in women change in iodine intake on thyroid function in pregnant wo-
who are nursing, the gamma-emitters 123I (half-life 13 hours) men with autonomy or on the fetus. It might be benefi-
or 99mTc pertechnetate (half-life 6 hours) should be used cial to keep iodine intake on the low side, but care must be
rather than the b-emitter 131I (half-life 8 days). The shorter taken that the fetus is not iodine deficient, especially in areas
half-lives of these agents (510) will allow breast milk to be where the population is iodine deficient. The degree of ma-
pumped and discarded for 10 half-lives (5 or 3 days, re- ternal hyperthyroidism and assessment of her diet should
spectively) and nursing resumed, whereas breastfeeding be considered before deciding whether to administer iodine
should ideally be discontinued 3 months prior to 131I ad- supplements. Hormone overproduction is often limited in
ministration to avoid radiation exposure to the breast and not patients with autonomy (50). In mild cases, a theoretical
be resumed if 131I is given as treatment for GD (511). possibility exists that the normal pregnancy-associated in-
Most often, the use of radioactive substances can be avoi- crease in thyroid hormone production may catch up with the
ded and the diagnosis can be based on a combination of hormone production in the autonomous areas of the thyroid
clinical presentation, TRAb measurement, and evaluation of and alleviate the need for ATD therapy. However, the high
serum T4 and T3. Thyroidal production of T3 compared with hCG levels in early pregnancy may theoretically stimulate
T4 is relatively high in GD, but not in destructive thyroiditis, the nonfunctioning normal thyroid tissue in these patients and
and T3 tends to be fractionally more elevated above the upper worsen hyperthyroidism. Because there is no TRAb pro-
reference limit compared with T4 in GD, whereas T4 is more duction, the fetal thyroid will not be abnormally stimulated in
elevated than T3 in destructive thyroiditis (50). If needed, thy- the second half of pregnancy as it is in GD. Thus, the fetus
roid color Doppler ultrasonography may assist in distinguishing will not develop hyperthyroidism in parallel with the un-
between destructive thyroiditis and GD (508,512,513). treated hyperthyroid mother as it happens during the second
half of pregnancy in GD, and neonatal hyperthyroidism is not
& RECOMMENDATION 97 a risk. However, the tendency to induce fetal hypothyroidism
In women with symptomatic thyrotoxicosis from post- and goiter in the second half of pregnancy from ATDs given
partum destructive thyroiditis, the judicious use of b- to the mother would be even higher in this type of hyper-
adrenergic blocking agents is recommended. thyroidism than in GD. Based on this theoretical risk, surgical
therapy in the second trimester of pregnancy may be con-
sidered if the hyperthyroidism turns out to require more than
low dose MMI (5–10 mg/d) for control. No firm recom-
Treatment for postpartum thyroiditis is generally sup-
mendations are given because no good evidence is available.
portive in nature, with the use of b-adrenergic blockers such
as propranolol or metroprolol to control pulse rate and hyper-
adrenergic symptoms during the thyrotoxic stage (514). The [U] How should hyperthyroidism be managed
selective b-1 adrenergic receptor-blocking agent atenolol should in patients with GO?
not be used in breastfeeding mothers because it may lead to GO is an inflammatory eye disease that develops in the
symptoms consistent with b-adrenergic blockage in neonates. orbit in association with autoimmune thyroid disorders (516).
This adverse effect presumably develops because atenolol is In the majority of cases (about 90%), it occurs in patients with
<5% bound to maternal plasma proteins (vs. 93% binding of current or past GD. Thyroid-associated orbitopathy, thyroid
propranolol), and thus accumulates in milk, and because of eye disease, and Graves’ ophthalmopathy are other names
low kidney excretion of atenolol in small children with im- used for GO. Approximately a third of patients with Graves’
mature renal function (515). Levothyroxine therapy may be hyperthyroidism have some signs and/or symptoms of GO,
beneficial, at least transiently, for women with symptomatic while only 5% have moderate-to-severe disease (517,518). In
hypothyroidism or those having TSH levels >10 mU/L (506). contrast to GD, for which women are at higher risk, the role of
Technical remarks: Because propranalol and metoprolol sex in GO is more controversial. More recent studies do not
are secreted into breast milk in only very low amounts, no identify a clear sex-related risk for GO (517,518), while some
special monitoring is needed for breastfed infants of mothers older studies point to a possible slightly increased risk for
on these medications (514). men (519,520). This variability in results might be related to
changes in smoking patterns over the years. The disease
& RECOMMENDATION 98 peaks in incidence in the fifth and sixth decade of life
In pregnant women diagnosed with hyperthyroidism due to (517,518,521,522) with a higher prevalence of severe cases
multinodular thyroid autonomy or a solitary TA, special in the elderly population (517).
care should be taken not to induce fetal hypothyroidism by
ATD therapy.
[U1] Assessment of disease activity and severity
Strong recommendation, low-quality evidence. The natural history of the disease is one of rapid deteriora-
tion followed by gradual improvement toward the baseline.
Hyperthyroidism caused by thyroid autonomy is very This active phase is best described by the clinical activity score
common in people having current (or previous) mild to (CAS) (523,524), the elements of which are outlined in
Table 12. Assessment of Graves’ Orbitopathy: Clinical Activity Score Elementsa

Comparison with
Elementsb Each visit previous visit Score
Painful feeling behind the globe over last 4 weeks X 1
Pain with eye movement during last 4 weeks X 1
Redness of the eyelids X 1
Redness of the conjunctiva X 1
Swelling of the eyelids X 1
Chemosis (edema of the conjunctiva) X 1
Swollen caruncle (flesh body at medial angle of eye) X 1
Increase in proptosis ‡2 mm X 1
Decreased eye movements ‡5 any direction X 1
Decreased visual acuity ‡1 line on Snellen chart X 1
a
Sources: Adapted from Mourits et al. (523,524).
b
A 7-point scale (excluding the last three elements) is used when no previous assessment is available. GO is considered active in patients
with a clinical activity score (CAS) ‡3.
Table 12. The score ranges from 0 to 10 and predicts response therapeutic application. The QoL correlation with disease
to anti-inflammatory therapies (523,524). A 7-point scale, severity has been fair to excellent for two GO specific in-
lacking the last three elements, is used when no previous as- struments published to date in North American populations
sessment is available. GO is considered active in patients with a (527,528), though the effect of GO therapy on these QoL
CAS ‡3. However, some of the eye changes seen in hyper- scores still needs prospective data. Presently, the only in-
thyroidism, like lid retraction or stare, result from the increased strument that has such data is the instrument extensively used
sympathetic state, and when present without associated eye in Europe (529), which has not yet been tested in a North
changes, they are not considered to reflect GO (69). American population. Overall, this area is in need of more
The severity of the disease is best assessed using objective, research emphasis because, despite its agreed-upon impor-
quantifiable parameters and is a useful tool for directing tance, a significant number of intervention trials in GO are
therapy. The main gradations of disease severity are mild, still being reported without associated QoL outcomes (530).
moderate-to-severe, and sight threatening (525). Table 13 The prevention of GO and the management of hyperthy-
lists the elements as agreed upon in a consensus statement by roidism in patients having established GO is discussed in the
the European Group on Graves’ Orbitopathy (525). Both remainder of Section [U]. In particular, we focus on recom-
activity and severity of the disease must be considered in mendations regarding the concurrent use of corticosteroids in
therapeutic decisions regarding treatment of the eye disease patients choosing RAI as treatment for hyperthyroidism
itself, as well as treatment of hyperthyroidism, keeping in (Table 14).
mind that they do not always correlate, particularly in early
and late disease. The overall evaluation and management of [U2] Prevention of GO
GO is best done in a multidisciplinary clinic combining en- Current therapeutic approaches to GO, including local
docrinologists and ophthalmologists with expertise in the measures, corticosteroids, orbital radiation, and surgery
condition and other specialties in consultation (e.g., ENT, (525), often fail to significantly improve the QoL of patients
radiation therapy, plastic surgery, and endocrine surgery). with this debilitating condition. Therefore, efforts should be
Quality of life is clearly impaired by GO (526). The made to prevent the development or progression of GO in
FDA has endorsed QoL information as a component of any patients with Graves’ hyperthyroidism. Identified risk factors
Table 13. Graves’ Orbitopathy Severity Assessmenta

Corneal Optic
Gradeb Lid retraction Soft tissues Proptosisc Diplopia exposure nerve status
Mild <2 mm Mild involvement <3 mm Transient or absent Absent Normal
Moderate ‡2 mm Moderate involvement ‡3 mm Inconstant Mild Normal
Severe ‡2 mm Severe involvement ‡3 mm Constant Mild Normal
Sight threatening — — — — Severe Compression
Upper limits of normal
African American F/M = 23/24 mm
White F/M = 19/21 mm
Asian F/M = 16/17 mm (Thai) or 18.6 mm (Chinese)
a
Sources: Adapted from de Juan et al. (676), Sarinnapakorn et al. (677), Tsai et al. (678), and Bartalena et al. (525).
b
Mild GO: patients whose features of GO have only a minor impact on daily life, generally insufficient to justify immunosuppressive or
surgical treatment. Moderate-to-severe GO: patients without sight-threatening GO whose eye disease has sufficient impact on daily life to
justify the risks of immunosuppression (if active) or surgical intervention (if inactive). Sight-threatening GO: patients with dysthyroid optic
neuropathy and/or corneal breakdown. This category warrants immediate intervention.
c
Proptosis refers to the variation compared to the upper limit of normal for each race/sex or the patient’s baseline, if available.
1388 ROSS ET AL.
Table 14. Use of Oral Glucocorticoids for Prevention of Graves’ Orbitopathy Development
or Progression When Radioactive Iodine Is Used to Treat Graves’ Hyperthyroidisma
RAI without RAI with oral
Recommendation glucocorticoids glucocorticoids
No GO (nonsmoker) 101 Recommend Recommend against
No GO (smoker) 103 Insufficient data
to recommend
for or against
GO present, active and mild (risk factors absent) 105 Acceptableb Acceptableb
GO present, active and mild (risk factors present) 106 Recommend against Recommend
GO present, active and moderate-to-severe 107 Recommend against Recommend against
or sight-threatening
GO present, inactive 108 Recommend Recommend against
a
ATDs or thyroidectomy are also recommended treatment options in each of these scenarios, and they are the preferred choice of therapy
in patients with active and moderate-to-severe or sight-threatening GO.
b
The decision regarding use of concurrent glucocorticoids should be made in light of the risk–benefit ratio relative to the patient’s overall health.
Risk factors for GO deterioration (high TRAb level, smoking) increase the benefit of glucocorticoids in preventing GO deterioration. Poorly
controlled diabetes, osteoporosis, psychiatric illness, and high risk for infections increase the likelihood of complications from glucocorticoids.
for GO are listed in Table 15, and the most pertinent ones to had more severe GO than euthyroid patients (535). Subsequently,
this discussion are RAI therapy for hyperthyroidism (531,532), two cohort studies in which patients received levothyroxine
untreated hyperthyroidism, smoking, high serum pretreatment therapy early after RAI with the specific intent of preventing
TRAb levels (normal <1.75 IU/L, high risk for progression if hypothyroidism noted that deterioration of GO rarely occurred
>8.8 IU/L) (533), and any delay in treating hypothyroidism (0%–2%) (534,536). A randomized study of newly diagnosed
after therapy for hyperthyroidism (106,534). High pretreat- GD found that RAI followed by active prevention of hypo-
ment levels of T3 and T4 were each reported to have a pre- thyroidism by administration of thyroid hormone 2 weeks later
dictive role in GO, but these conclusions were not validated by did not increase the risk of worsening GO compared to therapy
subsequent studies (69,106,532,534), suggesting the possibil- with MMI (relative risk [RR] of 0.95) (69).
ity of higher TRAb values measured on less sensitive assays
early-on being partly responsible for this variation. & RECOMMENDATION 100
We recommend clinicians advise patients with GD to stop
& RECOMMENDATION 99 smoking and refer them to a structured smoking cessation
Euthyroidism should be expeditiously achieved and program. As both firsthand and secondhand smoking in-
maintained in hyperthyroid patients with GO or risk fac- crease GO risk, patients exposed to secondhand smoke
tors for the development of orbitopathy. should be identified and advised of its negative impact.
Strong recommendation, moderate-quality evidence. Strong recommendation, moderate-quality evidence.
A number of studies have suggested that development of per- Smoking is the most important known risk factor for the
sistent, untreated hypothyroidism after therapy for hyperthyroid- development or worsening of GO, unrelated to type of ther-
ism plays a detrimental role in the progression of GO. An early apy for GO (535), and consistent data from several studies
study noted that patients who were either hypo- or hyperthyroid show a detrimental effect of smoking on GO in patients
Table 15. Risk Factors for Graves’ Orbitopathy

Amenable to
Risk factor intervention Comments
Age No Advanced age, risk for more severe GO.
Sex No GO is more frequent in women (as GD is); more severe in men.
Genetics/ancestry No Highest prevalence of GO in Caucasians, lowest in Asians.
Immunomodulatory genes likely involved.
Mechanical factors No Noted wider lateral wall orbital angle in GO.
TSH receptor antibody Noa Predicts GO risk and GO therapy response.
Smoking Yes Increases GO progression and decreases therapy efficacy. Smoking-cessation
clinics favored for intervention.
Thyroid dysfunction Yes Need for expeditious control of hyperthyroidism then
prevention of hypothyroidism post GD therapy.
RAI therapy Yes Risk is additive to smoking; increased with preexistent and active GO;
preventable by glucocorticoids 6–12 weeks post RAI.
a
Decreased TRAb noted with methimazole therapy yet available data are unable to separate that change from the natural history of GO
with improving TRAb.
treated with RAI (69,531). The risk is proportional to the However, in two different studies, active smokers who
number of cigarettes smoked per day, and former smokers received RAI represented the group with the highest inci-
have significantly lower risk than current smokers, even after dence (23%–40%) of new GO or deterioration of pre-existing
adjusting for lifetime cigarette consumption (537). GO during 1 year of follow-up (69,531).
Technical remarks: Clinicians should use smoking cessation
programs based on effective and evidence-based approaches [U4] Treatment of hyperthyroidism in patients with active
to aid in smoking cessation and avoidance of secondhand GO of mild severity (see Tables 12 and 13 for definitions of
smoke (538,539). disease activity and severity)
[U3] Treatment of hyperthyroidism in patients with no ap- & RECOMMENDATION 104

parent GO In patients with Graves’ hyperthyroidism who have mild
active ophthalmopathy and no risk factors for deterioration
& RECOMMENDATION 101 of their eye disease, RAI therapy, ATDs, and thyroidectomy
In nonsmoking patients with GD without apparent GO, should be considered equally acceptable therapeutic options.
RAI therapy (without concurrent steroids), ATDs, or thy-
roidectomy should be considered equally acceptable Strong recommendation, moderate-quality evidence.
therapeutic options in regard to risk of GO.
& RECOMMENDATION 105
Strong recommendation, moderate-quality evidence. In the absence of any strong contraindication to GC use we
suggest considering them for coverage of GD patients with
mild active GO who are treated with RAI, even in the
Several randomized trials have identified the risk of GO
absence of risk factors for GO deterioration.
development or progression after RAI therapy for hyperthy-
roidism to be between 10% and 39% (69,540). With regard to Weak recommendation, low-quality evidence.
the risk of new GO development, that risk appears to be lower.
Two randomized controlled trials found the risk to be 6/78 (8%) Technical remarks: The decision on whether to administer
for RAI compared with 1/74 (1%) for ATDs (531) in one study, concurrent glucocorticoids in a particular patient choosing
and 10/32 (32%) for RAI compared with 6/56 (11%) for ATDs RAI therapy should be made in light of risk–benefit consid-
and 6/58 (10%) for surgery (532) in the older study. Fortunately, erations (i.e., their personal risk of worsening GO, balanced
the cases of new or worse GO were usually mild, with only 6/ against their risk of developing glucocorticoid side effects).
168 patients in this second trial (four in the RAI group, one in Risk factors for side effects of oral corticosteroids include
the ATD group, and one in the surgical group) requiring specific poorly controlled diabetes, hypertension, osteoporosis, psy-
therapy for GO. In contrast, one prospective but nonrandomized chiatric disease, and predisposition to infections. Smokers in
cohort study identified no difference among ATD, surgery, and whom the risk–benefit ratio for the concurrent use of corti-
RAI treatment, with an overall 4.9%–7.1% frequency of GO costeroids is high may be better treated with ATDs or sur-
development (541). The higher risk of GO development after gery. Besides smoking, the main risk factors for deterioration
RAI therapy in the majority of studies may be related to the of GO to be considered in this decision include active and
unique increase in TRAb levels observed following this therapy progressive GO over the preceding 3 months and high serum
(172). Experimental evidence suggests that these antibodies are pretreatment TRAb levels (normal <1.75 IU/L, high risk for
directly involved in GO pathogenesis (516,542,543). GO progression if >8.8 IU/L) (see Table 15).
There is evidence that corticosteroids given concurrently The dose of corticosteroids validated in a randomized clin-
with RAI may prevent worsening of GO in patients with mild ical trial for GO prophylaxis is the equivalent of prednisone
active eye disease (531). However, the evidence is insufficient 0.4–0.5 mg/kg per day, started 1–3 days after RAI adminis-
for recommending prophylactic treatment with corticosteroids tration, continued for 1 month, and then tapered over 2
in nonsmoking patients who do not have clinically apparent months (525). However, a retrospective cohort study sug-
GO. The relatively low absolute risk of nonsmokers developing gested that even lower doses and shorter duration of oral
new-onset severe GO suggests that GO prevention should not prednisone (about 0.2 mg/kg per day for 6 weeks) may be
be a factor in the selection of therapy for hyperthyroidism in equally effective for prevention of GO exacerbation in
this group of patients (531). Table 14 further details the use of patients with initially mild or absent eye disease, (544).
glucocorticoids for various GO clinical scenarios. Currently most task force members use a minimum starting
dose of 30 mg prednisone daily and tapering off within 6–8
& RECOMMENDATION 102 weeks. Table 14 details further the use of glucocorticoids
In smoking patients with GD without apparent GO, RAI for various GO clinical scenarios.
therapy, ATDs, or thyroidectomy should be considered
equally acceptable therapeutic options in regard to risk of GO. & RECOMMENDATION 106
Weak recommendation, low-quality evidence. In GD patients with mild GO who are treated with RAI we
recommend steroid coverage if there are concomitant risk
& RECOMMENDATION 103 factors for GO deterioration.
There is insufficient evidence to recommend for or against Strong recommendation, moderate-quality evidence.
the use of prophylactic corticosteroids in smokers who
receive RAI and have no evidence of GO.
Unfortunately, the initial data regarding the impact of
No recommendation, insufficient evidence. various GD therapies on GO outcome were affected by the
1390 ROSS ET AL.
absence of GO activity assessment and lack of stratification [U6] Treatment of GD in patients with inactive GO (see
on smoking status at randomization as well as by variation in Table 12 for definition of disease inactivity)
the timing of tackling post-RAI hypothyroidism. Two early
nonrandomized studies found no differences between the
three GD therapeutic modalities (541,545). In patients with inactive GO we suggest RAI therapy can
The first randomized study of GD patients (13% with mild be administered without steroid coverage. However, in
preexistent GO) assigned to therapy for hyperthyroidism cases of elevated risk for reactivation (high TRAb, CAS ‡1
with ATDs, surgery, or RAI (532) found the relative risk for and smokers) that approach might have to be reconsidered.
deterioration of eye disease to be elevated at 3.2 for RAI Weak recommendation, low-quality evidence.
compared to ATDs. There appeared to be no difference in
such risk between ATDs and surgery. A large, more recent
randomized controlled trial studying mainly patients with There is a low rate of GO progression or reactivation
previously treated GD showed RAI therapy to be associated following RAI in patients with inactive GO. A series of 72
with an increased risk of GO progression (RR of 5.8 in patients with inactive GO according to the CAS were treated
comparison with ATDs) and found the risk to be eliminated with RAI without concurrent glucocorticoid administration
with concurrent corticosteroid administration (531). Fi- (536). For those in whom hypothyroidism was prevented by
nally, the most recent randomized controlled trial (69) re- early thyroxine therapy, no deterioration in eye disease was
vealed an increased risk for new or worse GO in RAI-treated reported (536). Smoking history did not impact GO outcome
patients (38.7% of the group) compared with ATD-treated in this cohort. A recent trial from Japan (540) random-
patients (21.3% of the group), to be mainly related to de- ized patients without GO or inactive GO (i.e., CAS <3 or
velopment of new GO cases, while worsening of pre- T2-weighted imaging T2SIR £1) to receive either gluco-
existing GO occurred at a similar percentage in both groups corticoid prophylaxis with low-dose prednisolone (on aver-
(45% for RAI and 47% for ATD). Smoking was a strong risk age 0.28 mg/kg per day tapered rapidly over 6 weeks) or no
factor for an undesirable GO outcome. In this last trial there prophylaxis at all. The rate of disease progression in the ab-
was no routine use of prophylactic glucocorticoids. Table 14 sence of risk factors was low (4.2%) and not impacted
further details the use of glucocorticoids for various GO by glucocorticoid therapy. The presence of risk factors for
clinical scenarios. GO (high thyroid stimulating antibody, CAS ‡1) increased
that risk, again without a benefit from low-dose steroid pro-
[U5] Treatment of hyperthyroidism in patients with active phylaxis. Ultimately, most GO cases were mild, and only 7
and moderate-to-severe or sight-threatening GO (see cases (2.4%) required GO-directed therapy. Whether high-
Tables 12 and 13 for definitions of disease activity and severity) dose glucocorticoid therapy would have made a difference in
these patients is not known.
& RECOMMENDATION 107 Another study retrospectively examined the effect of con-
In patients with active and moderate-to-severe or sight- current oral or intravenous glucocorticoid therapy on the de-
threatening GO we recommend against RAI therapy. velopment or deterioration of preexistent GO after RAI
Surgery or ATDs are preferred treatment options for GD in therapy for relapsing GD patients (550). They identified GO
these patients. development, deterioration, or reactivation in approxima-
tely 7% of patients (6/83) considered at low risk who were
Strong recommendation, low-quality evidence. given no steroid prophylaxis. Only two of these cases had
preexistent inactive GO. Despite prophylaxis, 33% of pa-
We are aware of no trials in patients with moderate-to- tients considered at high risk who were treated with oral
severe and active eye disease that compare hyperthyroid- glucocorticoids had worsening of GO. However, because
ism therapies for impact on GO. However, a comparison of of the lack of clarity of this retrospective study regarding
two different surgical approaches (total thyroidectomy vs. prevalence of active and inactive GO in each group and the
subtotal thyroidectomy) for patients with moderate-to- lack of prespecified criteria for dose and route of steroid use
severe GO showed that the eye disease improved during 3 in those considered at risk, we weighed this evidence less in
years of follow-up in all patients (546). In another series of our deliberations regarding the above recommendation.
42 patients with progressive GO treated with total thy- Table 14 further details the use of glucocorticoids for var-
roidectomy, exophthalmos was stable in 60% of cases and ious GO clinical scenarios.
improved in the remainder (547), suggesting that surgery is
not detrimental to GO and may be associated with im- [V] How should iodine-induced and amiodarone-
provement in some patients. Additionally, a more recent induced thyrotoxicosis be managed?
study suggests that surgery might lead to a more rapid [V1] Iodine-induced hyperthyroidism
improvement in GO than ATDs, and it might thus be a
better option for patients that are most concerned about GO & RECOMMENDATION 109
changes (548). Other studies suggest that ATDs may not Routine administration of ATDs before iodinated contrast
adversely impact mild active GO, but they do not address media exposure is not recommended for all patients.
severe GO (531).
Alternatively, if ATDs are selected for GD therapy, there Weak recommendation, low-quality evidence.
are reassuring data that long-term use is relatively safe and
effective at preserving euthyroidism while waiting for GO to Technical remarks: Patients deemed to be at high risk of
enter remission (66,549). developing iodine-induced hyperthyroidism or whose

cardiac status is tenuous at baseline may be considered for
prophylactic therapy with ATDs. Beta-adrenergic blocking agents alone or in combination
Iodine-induced hyperthyroidism (the Jod–Basedow phe- with MMI should be used to treat overt iodine-induced
nomenon) is uncommon in modern series and generally self- hyperthyroidism.
limited, but it may occasionally persist for months (551,552) Strong recommendation, low-quality evidence.
and may be life-threatening (553–556). Individuals who are
the most susceptible are elderly patients with autonomously
functioning nodular goiters (557) and, less commonly, pa- Treatment of iodine-induced hyperthyroidism includes
tients with occult GD (558) or patients with a prior history of avoidance of additional iodine and administration of b-blockers
GD who are in remission after a course of ATDs (559). Very alone or with ATDs, depending on the severity of hyperthy-
rarely, iodine excess may trigger thyrotoxicosis in patients roidism and the clinical status of the patient. RAI is not an
with a previously normal thyroid gland (560). Chronic iodine option until the iodine load has been cleared and might not be
deficiency increases the prevalence of autonomous thyroid desirable given the reversibility of this condition. Recent data
nodules, and therefore iodine repletion in this setting has his- suggest that urinary iodine normalizes more rapidly than pre-
torically been linked to iodine-induced hyperthyroidism (561). viously believed, with a return to baseline urinary iodine ex-
Multiple observational studies have examined changes in cretion within 1–2 months in most patients (565,572).
thyroid hormone levels following a single exposure to in- Technical remarks: Dosing of MMI for iodine-induced
travenous iodinated contrast in both iodine-sufficient (562– thyrotoxicosis is 20–40 mg/d, given either as a daily or twice-
565) and iodine-deficient (566–569) regions. A study of pa- daily dosing. There may be relative resistance to ATD in
tients living in Boston showed that 5 of 49 (10.2%) developed patients with iodine-induced hyperthyroidism. Urinary io-
a suppressed TSH value 1–4 weeks following exposure to a dine (a spot urine iodine adjusted for urine creatinine con-
single computed tomography (CT) study with contrast, with centration or a 24-hour urine iodine) may be monitored to
only one patient developing overt hyperthyroidism (565). assess the rate of clearance of the iodine load.
Additional observational studies in the United States and
Japan involving 56 and 22 patients, respectively, found no [V2] Amiodarone-induced thyrotoxicosis
new cases of hyperthyroidism following coronary angiogra- &
phy (564) or hysterosalpingography (563), whereas an Aus- RECOMMENDATION 111
tralian study from a region of iodine sufficiency found that 2 We suggest monitoring thyroid function tests before and
of 72 (2.8%) of patients developed overt hyperthyroidism and within the first 3 months following the initiation of amio-
an additional two patients developed subclinical hyperthy- darone therapy, and at 3- to 6-month intervals thereafter.
roidism within 8 weeks of iodinated contrast exposure (562). Weak recommendation, low-quality evidence.
Overall, similar rates of iodine-induced hyperthyroidism have
been described in iodine-deficient regions, including a study Amiodarone is a drug that is frequently used in the treat-
from Germany in which 2 of 788 (0.25%) patients developed ment of refractory atrial or ventricular tachyarrhymias.
overt hyperthyroidism following coronary angiography (566), Amiodarone-induced thyrotoxicosis (AIT) occurs in up to
a New Zealand study in which subclinical hyperthyroidism 6% of patients taking this medication in iodine-sufficient
developed in 2 of 102 (2%) patients after a CT scan with areas of the world (573–575) and in up to 10% in iodine-
iodinated contrast (567), a study from Italy that found that deficient areas, such as parts of Europe (576). Studies eval-
1.9% of 1752 patients undergoing coronary angiography uating the adequacy of monitoring for adverse effects from
developed a suppressed TSH with normal free T4 and T3 amiodarone have shown suboptimal results (577,578).
levels (568), and finally, a Turkish study identifying new Two distinct mechanisms have been proposed in the
subclinical hyperthyroidism in 5.9% of 101 patients by 8 development of AIT, including an iodine-induced form of
weeks following coronary angiography (569). hyperthyroidism (type 1 AIT) due to the high iodine content
A recent case–control study in the United States found that of amiodarone (37% by molecular weight) and a destruc-
iodinated contrast exposure in patients without baseline tive thyroiditis (type 2 AIT) due to direct toxicity of amio-
thyroid abnormality resulted in hyperthyroidism (defined darone on follicular cells. Type 1 AIT tends to occur in
only as a suppressed TSH value) with an odds ratio of 1.98 patients with underlying thyroid autonomy in a nodular
([95% CI, 1.08–3.60], p = 0.03), and that 23 patients would goiter, or GD, whereas type 2 AIT occurs as a result of direct
need to be exposed before encountering one case of iodine- damage or induction of apoptosis in thyrocytes by amio-
induced thyrotoxicosis (570). Interestingly, a recent meta- darone (579–582).
analysis including nine randomized-controlled trials and
eight observational studies involving iodine supplementation & RECOMMENDATION 112
of young children and pregnant women in regions of mild to The decision to stop amiodarone in the setting of thyro-
moderate iodine deficiency did not find an increased risk of toxicosis should be determined on an individual basis in
thyroid dysfunction following iodine supplementation of consultation with the treating cardiologist, depending on
200–300 mg/d (571). the clinical manifestations and presence or absence of ef-
In summary, iodine-induced hyperthyroidism is uncom- fective alternative antiarrhythmic therapy.
mon and generally subclinical, but it can occasionally be
severe. For most clinical circumstances, the likelihood of Strong recommendation, low-quality evidence.
developing overt thyrotoxicosis after iodinated contrast ex-
posure is too low to justify the risk of adverse effects asso- The need for amiodarone discontinuation is controversial
ciated with prophylactic ATD therapy. because (i) this drug is frequently the only medication able to
1392 ROSS ET AL.
control cardiac arrhythmia, (ii) the effects of this fat-soluble may actually occur with both subtypes, given the prevalence
drug may persist for many months, (iii) amiodarone may have of these abnormalities in the general population. Interleukin-
T3-antagonistic properties at the cardiac level and inhibit T4 6 levels and RAIU values, once promoted as useful for dis-
to T3 conversion in the heart (583) such that withdrawal may tinguishing between subtypes (590), actually overlap exten-
actually aggravate cardiac manifestations of thyrotoxicosis sively between the two subtypes and are therefore also not
(573). Deaths from ventricular fibrillation have occurred after useful (594). Several modern series of patients with AIT
stopping amiodarone in patients with AIT (584). In addition, make no attempt to classify patients into type 1 or type 2
type 2 AIT typically responds to treatment even if amiodar- disease (585,595–598).
one therapy is continued (585–587), but continuation may Several studies have shown that increased vascularity on
lead to a more prolonged time to recovery and a higher rate of CFDS may be seen in patients with type 1, but not type 2 AIT
future recurrences of AIT (588). (599–601). Two studies showed a clear separation into type 1
and type 2 AIT, allowing successful application of targeted
& RECOMMENDATION 113 therapy (599,600). However, CFDS is not universally useful
In clinically stable patients with AIT, we suggest mea- (584,589). In a series of 24 cases of AIT, 12 patients were
suring thyroid function tests to identify disorders associ- classified as type 2 due to an absence of vascularity (CFDS 0)
ated with iodine-induced hyperthyroidism (type 1 AIT), and treated with corticosteroids, but only 7 (58%) proved
specifically including toxic nodular disease and previously responsive (584). Likewise, the authors found that among 11
occult GD. patients classified as type 1 AIT based on CFDS scores of I–
III, only four (36%) responded to ATD therapy. In another
series of 30 patients with AIT requiring therapy, 10 (33%)
&
patients could not be subtyped on the basis of CFDS, in-
RECOMMENDATION 114
cluding several patients with goiters but normal vascular flow
MMI should be used to treat overt thyrotoxicosis in pa-
(589). In a series of 55 patients in whom a CFDS qualitative
tients with proven underlying autonomous thyroid nodules
assessment of vascular flow was used to distinguish type 1
or GD as the cause of AIT (type 1 disease), and cortico-
from type 2 AIT, 81.3% of patients determined to have type 1
steroids should be used to treat patients with overt
AIT had pattern I vascularity (the lowest level above zero),
amiodarone-induced thyroiditis (type 2 disease).
illustrating the skill and nuance needed to successfully make
Strong recommendation, low-quality evidence. this distinction (599). Among European thyroidologists sur-
veyed on the use of diagnostic imaging in the differential
& RECOMMENDATION 115 diagnosis of AIT, approximately 20% preferred RAIU alone,
Combined ATD and corticosteroid therapy should be used 20% preferred CFDS alone, nearly 40% utilized both meth-
to treat patients with overt AIT who are too unstable ods simultaneously, and 20% thought both techniques were
clinically to allow a trial of monotherapy or who fail to useless (602). Recently, sestamibi uptake by the thyroid,
respond to single modality therapy, or patients in whom which is diminished with thyroiditis, has been applied for
the etiology of thyrotoxicosis cannot be unequivocally distinguishing AIT subtypes with preliminarily promising
determined. results (603,604).
A recent retrospective report including 200 AIT patients
found that the onset of thyrotoxicosis was significantly earlier
in type 1 (median 3.5 months, range 1–61 months) than type 2
As the pathogenesis of AIT is not fully understood, the (median 30 months, range 1–95 months; p < 0.001) (605).
classic division of AIT into two subtypes likely represents an Since 80% of type 1 patients in this study had autonomous
oversimplification. First, as discussed further below, many thyroid nodules or TMNG, it is not unexpected that iodine-
patients cannot be readily classified into one of the two AIT induced thyrotoxicosis occurred early in the course of
subtypes. Secondly, once classified as having type 1 or type 2 amiodarone therapy. However, based on these data, a patient
AIT, patients often fail to respond to therapy specifically with late onset of AIT in whom GD has been excluded is
directed to that subtype (583,589,590). Finally, findings of more likely to have type 2 AIT. Another observation reported
responsiveness in patients with type 2 AIT to measures not in this study is the development of AIT following amiodarone
typically useful in destructive thyroiditis, such as perchlorate discontinuation. Nineteen percent of patients (38/200) de-
(586,591) and oral cholecystographic agents (592,593), cannot veloped AIT a mean of 5.5 months after the drug was stop-
be adequately explained on the basis of the current classifi- ped, 36 of whom had type 2 AIT.
cation system, although spontaneous resolution independent of Patients who are clinically stable and have definite evi-
therapy is one possible explanation. dence supporting a distinct subtype of overt AIT may be tried
Several methods have been examined to distinguish type 1 on appropriate monotherapy. When identified with certainty,
from type 2 AIT, but with the possible exception of color flow type 1 AIT is best treated with MMI to prevent new hormone
Doppler study (CFDS), most are considered unreliable (574). synthesis and rarely with added potassium perchlorate
For example, the T3-to-T4 ratio, which tends to be higher in (250 mg four times daily; not available in the United States)
patients with autonomous thyroid glands than in those with (590). Type 2 AIT is better treated with anti-inflammatory
destructive thyroiditis, is not helpful in this instance because therapy such as prednisone, with improvement occasionally
of amiodarone-associated inhibition of T4 monodeiodination seen as early as 1 week, and usually within a few weeks (590).
(594). Further, features historically used to distinguish the As noted above, some patients with mild type 2 AIT (ap-
subtypes, such as antibodies against thyroid peroxidase and proximately 20%) resolve spontaneously without stopping
the presence of thyroid nodules in patients with type 1 AIT, amiodarone or administering corticosteroids (606,607).
Most series of patients with AIT contain cases in which Importantly, individuals with moderate thyrotoxicosis and
sequential therapy for both subtypes was required before compromised cardiac status should be considered for initial
resolution of AIT occurred. These patients are frequently combined therapy rather than sequential empiric therapy. Some
referred to as having ‘‘mixed’’ types of AIT. In a study of 20 centers recommend starting combined therapy with ATDs and
patients with AIT that included both type 1 and type 2 pa- corticosteroids at the time of initial AIT diagnosis (594,609),
tients, perchlorate was administered alone for 1 month, re- and between 16% and 25% of surveyed thyroidologists prefer
sulting in euthyroidism in 12 patients (seven with type 1 AIT combination ATD and corticosteroid therapy for patients with
and five with type 2 AIT) (591). Corticosteroids were then apparent type 2 AIT (610). A rapid response to combined cor-
given to the eight nonresponders (including seven patients with ticosteroid and ATD therapy is believed to favor type 2 AIT
presumed type 1 disease), and euthyroidism was achieved in all (594) and allows a reduction in ATDs, although some patients
after an average of approximately 6 weeks (591). Patients are with type 2 AIT have a prolonged course, particularly those with
often reclassified retrospectively from type 1 to type 2 AIT larger thyroids or worse thyrotoxicosis at the time of diagnosis
based on a positive response to corticosteroid therapy or after (611). A suggested approach to the management of AIT is
an outcome of permanent hypothyroidism, both of which shown in Figure 1.
would be unlikely in iodine-induced thyrotoxicosis (598,606). Technical remarks: The suggested starting dose of MMI in
Patients recovering from apparent type 2 AIT should be mon- this setting is 40 mg once daily until the patient is euthyroid
itored for permanent hypothyroidism, which appears to occur (generally 3–6 months). If high doses of MMI continue to be
more often with AIT than with subacute thyroiditis (608). required, splitting the dose may be more effective. The
FIG. 1. A suggested approach to the management of amiodarone-induced thyrotoxicosis.

1394 ROSS ET AL.
suggested dose of corticosteroids in this setting is equivalent cells (24). Therefore, early in the course of the disease, pa-
to 40 mg prednisone given once daily for 2–4 weeks, fol- tients may have clinical findings of thyrotoxicosis, although
lowed by a gradual taper over 2–3 months, based on the this is often mild. The serum TSH level is suppressed, and the
patient’s clinical response. free T4 level may be elevated preferentially compared to the
total T3 level, in contrast to other endogenous forms of thy-
& RECOMMENDATION 116 rotoxicosis, although substantial overlap occurs among the
Patients with AIT who are unresponsive to aggressive etiologies (618). In addition to laboratory evidence of thy-
medical therapy with MMI and corticosteroids should rotoxicosis, the erythrocyte sedimentation rate (ESR) or C-
undergo thyroidectomy. reactive protein is elevated, and mild anemia and elevation of
the WBC count are common. Up to 25% of patients have low
concentrations of antithyroid antibodies (24,619,620). RAIU
is low, as is uptake on a thyroid scintigram. Thyroid ultra-
Patients with AIT who fail to respond to medical therapy
sonography shows diffuse heterogeneity, focal hypoechoic
should be offered thyroidectomy before they become exces-
areas, and decreased or normal color flow Doppler, rather
sively debilitated from inadequately controlled thyrotoxico-
than the enhanced flow characteristic of GD (621,622). A
sis. The patient should be counseled that while thyroidectomy
biopsy of the thyroid gland is usually not necessary in sub-
in this setting carries with it significant morbidity and a high
acute thyroiditis. However, if a biopsy is performed due to
mortality rate (9%), delay or deferral of surgery imparts an
uncertainty of the diagnosis, its result shows granulomatous
even higher risk of death (612). Thyroidectomy done under
infiltrate and giant cells, consistent with a viral infection (24).
regional anesthesia when available may be preferred for very
The thyrotoxic phase usually lasts 3–6 weeks, ending when
ill patients (613). Several surgical series involving patients
the thyroid stores of preformed hormone are depleted. About
with AIT have now been published, with generally favorable
30% of patients subsequently enter a hypothyroid phase that
results (612,614–616). Patients in whom amiodarone was
can last up to 6 months. Thyroid pain and the elevated ESR
stopped during an episode of AIT should be considered for
have usually resolved by this time, and the predominant
definitive therapy with RAI or surgery in order to facilitate
clinical features are those of hypothyroidism with a small
reintroduction of amiodarone without concerns about recur-
nontender goiter. Most patients become euthyroid again
rent AIT (617).
within 12 months of disease onset, although 5%–15% have
persistent hypothyroidism (24,620,621). In addition, recur-
[W] How should thyrotoxicosis due to destructive
rence rates of 1%–4% have been reported (24,620,623).
thyroiditis be managed?
Several varieties of thyroiditis can present with tempo- & RECOMMENDATION 117
rary thyrotoxicosis as part of a classic triphasic course Patients with mild symptomatic subacute thyroiditis should
(thyrotoxicosis, hypothyroidism, recovery), including sub- be treated initially with b-adrenergic-blocking drugs and
acute thyroiditis, painless (silent) thyroiditis, acute (suppura- nonsteroidal anti-inflammatory agents (NSAIDs). Corti-
tive) thyroiditis, palpation (traumatic) thyroiditis, postpartum costeroids should be used instead of NSAIDs when patients
thyroiditis, and drug-induced thyroiditis. In general, thyroid fail to respond or present initially with moderate to severe
dysfunction caused by thyroiditis is less severe than that seen pain and/or thyrotoxic symptoms.
with other forms of endogenous thyrotoxicosis (50); RAIU is
universally low during the thyrotoxic stage, owing to leaking of
preformed thyroid hormone with suppression of serum TSH
concentrations. In this section, subacute, painless, acute, and Subacute thyroiditis is treated with b-blockers and anti-
palpation thyroiditis will be discussed; see Section [T4] for a inflammatory therapy. Beta-blockers are used as needed to
discussion of postpartum and Section [X] for a discussion of control thyrotoxic symptoms. NSAIDs provide pain relief in
drug-induced thyroiditis. patients with mild symptoms and should be considered first-
line therapy. With NSAIDs, the median time for resolution of
[W1] Subacute thyroiditis pain is 5 weeks (range 1–20 weeks) (24). Patients who fail to
Subacute thyroiditis, also called subacute granulomatous respond to full doses of NSAIDs over several days should be
or de Quervain thyroiditis, is a common cause of thyroid pain treated instead with corticosteroid therapy. Standard recom-
(24). The diagnosis of subacute thyroiditis is based on clinical mendations are to use prednisone 40 mg daily for 1–2 weeks
history, physical examination, laboratory data, and RAIU. followed by a gradual taper over 2–4 weeks or longer, de-
Subacute thyroiditis presents with moderate-to-severe pain in pending upon clinical response. A retrospective review found
the thyroid, often radiating to the ears, jaw, or throat. The pain that patients treated with corticosteroids at similar doses had
may begin focally and spread from one side to the other of the more rapid resolution of pain (mean duration, 8 days) com-
gland over several weeks. Patients may have a prodrome of pared with those treated with NSAIDs (mean duration,
malaise, low-grade fever, pharyngitis symptoms, and fatigue. 35 days). However, symptoms can recur as the dose of cor-
The thyroid may be slightly enlarged and is firm and painful ticosteroid is reduced (24). A more recent study reported that
to palpation. Subacute thyroiditis is thought to be due to a a lower initial daily dose of 15 mg of prednisolone, with ta-
sequela of an upper respiratory viral infection that involves pering by 5 mg every 2 weeks, was effective. However, 20%
the thyroid gland. of patients required longer than 8 weeks to discontinue the
About 50% of patients with subacute thyroiditis have an glucocorticoid (624). Levothyroxine may be employed dur-
initial thyrotoxic phase due to unregulated release of pre- ing the hypothyroid stage but should be withdrawn after 3–6
formed thyroid hormone from damaged thyroid follicular months, with recovery of normal function verified by thyroid
function testing. ATDs have no role in the treatment of Patients with acute thyroiditis (also referred to as suppu-
subacute thyroiditis. rative thyroiditis or thyroid abscess) are generally euthyroid.
However, on occasion, the condition presents as destructive
[W2] Painless thyroiditis thyroiditis with thyrotoxicosis (630). Ultrasound or CT ex-
Painless or silent thyroiditis classically presents with the aminations are usually diagnostic, showing hypoechoic le-
same triphasic course described for subacute thyroiditis, but sions in and around the affected thyroid lobe, destruction of
with no prodrome, neck pain, or elevated ESR, WBC count, the lobe, and abscess formation. However, early in the pro-
or C-reactive protein (625). The postpartum period is the cess, radiologic examination may be nonspecific, often lead-
most common time when painless thyroiditis is seen, but ing to the erroneous diagnoses of subacute thyroiditis (631).
painless thyroiditis can also occur in nonpregnant women and The etiology of acute thyroiditis is most frequently a bacterial
in men. Painless thyroiditis has been described in some types infection affecting the thyroid, either through hematogenous
of drug-induced thyroid dysfunction, including that associ- spread or direct extension through a fistula from an infected
ated with lithium or cytokine therapy. Postpartum and drug- pyriform sinus. Therapy involves systemic antibiotics as well
induced thyroiditis are discussed in detail in Sections [T4] as abscess drainage or removal, and excision or occlusion of
and [X], respectively. A small nontender goiter is common in the offending pyriform sinus. Thyrotoxicosis should be trea-
all types of painless thyroiditis. ted symptomatically with b-blocking agents. As in other
The thyrotoxic phase occurs in 5%–20% of patients and forms of destructive thyroiditis, there is no role for ATDs.
typically lasts 3–4 months. The hypothyroid phase is more
common or at least is recognized more often, lasting up to 6 [W4] Palpation thyroiditis
months. Normal thyroid function is reestablished by 12 months In 1975, Carney et al. (632) described a nonspecific multi-
in most patients, but 10%–20% have persistent hypothyroid- focal granulomatous folliculitis in thyroid glands removed at
ism. Recurrence rates are about 5%–10%, but may be higher in surgery for thyroid-related or unrelated conditions. They
Japan, with one Japanese study reporting a long-term recur- named this pathologic entity ‘‘palpation thyroiditis,’’ con-
rence rate of 65% (626). Recurrences are managed in the same cluding that it was due to palpation of the thyroid gland at
manner as the initial occurrence, but rare patients with multiple surgery. It was generally thought to be of little clinical im-
recurrences have opted for surgery or RAI ablation of the gland portance, except for rare case reports of patients who developed
following recovery from the thyrotoxic phase (626). thyrotoxicosis following manipulation of the thyroid gland
Painless thyroiditis is probably an autoimmune disease during surgery (633–636). However, a recent study suggested
manifested by positive anti–thyroid peroxidase antibodies in that the rate of transient overt or subclinical thyrotoxicosis
about 50% of patients and findings of lymphocytic infiltra- following parathyroid surgery may be as high as 30%, although
tion on pathology (626,627). During the thyrotoxic phase, the there was likely ascertainment bias because not all patients had
serum TSH level is suppressed and free T4 levels are elevated, postoperative TSH levels measured (637). There are no data on
often out of proportion to T3 levels. Patients with painless treatment of palpation thyroiditis, although the use of b-
thyroiditis have a low RAIU and low uptake on a thyroid blockers for symptomatic thyrotoxicosis seems reasonable.
scintigram during the thyrotoxic phase, and ultrasound often
shows inhomogeneous hypoechogenic texture with decreased [X] How should other causes of thyrotoxicosis
blood flow. These tests and the absence of TRAb antibodies be managed?
help distinguish painless thyroiditis from GD (628).
Tables 16 and 17 summarize drug-associated and unusual
&
causes of thyrotoxicosis.
RECOMMENDATION 118
Patients with symptomatic thyrotoxicosis due to painless & RECOMMENDATION 120
thyroiditis should be treated with b-adrenergic-blocking
Patients taking medications known to cause thyrotoxico-
drugs to control symptoms.
sis, including interferon (IFN)-a, interleukin-2, tyrosine
Strong recommendation, low-quality evidence. kinase inhibitors, and lithium, should be monitored clini-
cally and biochemically at 6-month intervals for the de-
Beta-adrenergic blockers can be used to treat thyrotoxic velopment of thyroid dysfunction. Patients who develop
symptoms in patients with painless thyroiditis, but ATDs thyrotoxicosis should be evaluated to determine etiology
have no utility, since new hormone synthesis is already low in and treated accordingly.
these patients. Rarely, corticosteroids have been used to
ameliorate the severity and the time course of thyrotoxicosis
due to painless thyroiditis (629), but they should be reserved
[X1] Interferon-a and interleukin-2
for severe cases only.
Patients treated with IFN-a and interleukin-2 patients are
at increased risk for developing thyrotoxicosis, especially
[W3] Acute thyroiditis
those with pre-existing thyroid autoimmunity. A recent study
&
including 1233 patients who were euthyroid at baseline found
RECOMMENDATION 119
that 79 (6.4%) patients developed a biphasic thyroiditis and
Acute thyroiditis should be treated with antibiotics and
an additional 57 (4.6%) patients developed a suppressed TSH
surgical drainage as determined by clinical judgement.
value (638). The latter group included 33 patients with mild
Beta-blockers may be used to treat symptoms of thyro-
TSH suppression and 24 with a TSH value <0.1 mU/L,
toxicosis.
among whom 11 had free T4 elevation and five required ATD
Strong recommendation, low-quality evidence. therapy (638). Thyrotoxicosis in patients treated with IFN-a
1396 ROSS ET AL.
Table 16. Causes of Drug-Associated Thyrotoxicosisa

Timing of onset
following initiation
Drug Mechanism(s) of the drug Therapy
Amiodarone Iodine induced (type 1) Months to years Supportive careb
ATDs; perchloratec
Surgery
Thyroiditis (type 2) Often >1 year Supportive careb
Corticosteroids
Surgery
Lithium Painless thyroiditis Often >1 year Supportive careb
GD ATDs and/or RAI (GD only)
Interferon a Painless thyroiditis; Months Supportive careb
Interleukin-2 Painless thyroiditis Months Supportive careb
Iodinated contrast Underlying thyroid Weeks to months Antithyroid drugs
autonomy
Tyrosine kinase inhibitors Destruction 3–12 months Supportive care
Radioactive iodine, early Destruction 1–4 weeks Observation; if severe, administer
corticosteroids
Radioactive iodine for GD 3–6 months Antithyroid drugs
TMNG, late Repeat RAI
Surgery
a
Thyroid hormone ingestion, including levothyroxine, liothyronine, thyroid extract, and nonprescription supplements that contain thyroid
hormone, may cause thyrotoxicosis—see Section [X7], thyrotoxicosis factitia.
b
Supportive care may include beta-adrenergic blockers during the thyrotoxic stage and levothyroxine if hypothyroidism develops.
c
Not available in the United States.
can be due to either painless thyroiditis or GD (639). In a [X3] Lithium

review of published cases from eight series, 69% of 49 pa- Patients taking lithium for bipolar disorder are at a high
tients with IFN-a–associated thyrotoxicosis for whom an risk of developing thyroid dysfunction, including both hy-
etiology was identified were found to have GD, based on pothyroidism and to a lesser extent thyrotoxicosis (652).
either positive TRAb titers or requirement for a prolonged Two published series have identified the development of
course of ATDs (640). An earlier literature review found that thyrotoxicosis in 0.6% and 3.0% of patients, respectively
2.4% of 1664 patients treated with IFN-a therapy for hepatitis (653,654). An epidemiological study of hyperthyroidism
C infection developed thyrotoxicosis, although the specific occurring over a 3-year period in Denmark identified lithium-
etiology was not consistently identified (641). associated thyrotoxicosis as the etiology in 0.7% of all cases
(432). A case series of 24 patients with lithium-associated
[X2] Tyrosine kinase inhibitors thyrotoxicosis identified GD in 12 (50%), painless thyroiditis
The tyrosine kinase inhibitors sunitinib (642–647), sor- in two patients, TMNG in three patients, and no identified
afenib (648–650), and nilotinib (651) have each been asso- etiology in seven patients (655). Another more recent series
ciated with a transient thyrotoxicosis due to destructive found that 1.4% of referrals to a thyroid clinic over a 12-year
thyroiditis. One study of 69 patients treated with sorafenib for period were for lithium related thyrotoxicosis (656). Patients
metastatic renal cell carcinoma found that 11 (16%) devel- in this series had been taking lithium for a median duration of
oped transient thyroiditis followed by hypothyroidism (649). 6 years (range 0.6–25 years), and 87% were women. Diag-
Another study found that 6 of 31 (19.3%) receiving sunitinib nostic evaluation found that 11 (47.8%) had GD, nine (39%)
therapy for metastatic renal cell carcinoma developed thy- had painless thyroiditis, two had TMNG, and one patient had
rotoxicosis, including one case of thyroid storm (644). subacute thyroiditis (656). A smaller series described three
Table 17. Unusual Causes of Thyrotoxicosis

Disorder Diagnosis Primary management
TSH-producing adenoma Pituitary MRI, a-subunit to TSH ratio Surgical removal
Struma ovarii RAI uptake over pelvis Surgical removal
Choriocarcinoma hCG elevation in the absence of pregnancy Surgical removal
Thyrotoxicosis factitia Absence of goiter; suppressed thyroglobulin Psychosocial evaluation
(surreptitious LT4 or LT3)
Functional thyroid cancer metastases Whole-body RAI scanning RAI ablation, embolization
and/or surgical removal
hCG, human chorionic gonadotrophin; MRI, magnetic resonance imaging.
cases of GD occurring in patients receiving lithium (657). In a tive therapy with octreotide and dopamine agonist therapy
retrospective review of 100 cases of thyroiditis and 400 cases has been examined. Treatment with octreotide results in a
of GD occurring at a single medical center, six cases of >50% reduction in serum TSH values in the majority of pa-
painless thyroiditis had a history of recent lithium exposure, tients treated and a concurrent return to euthyroidism in most
representing a nearly 5-fold increase compared to cases of (43). A reduction in tumor size has been observed in 20%–
lithium exposure in patients with GD (19). 50% of patients treated with octreotide (43,660), but less
impressive results have been obtained with bromocriptine
[X4] TSH-secreting pituitary tumors therapy (660). However, presurgical medical treatment did
not significantly improve surgical outcome (63% vs. 57% had
& RECOMMENDATION 121 negative tumor imaging after surgery) (659). In a recent case
The diagnosis of a TSH-secreting pituitary adenoma should series of seven patients treated with octreotide without prior
be based on an inappropriately normal or elevated serum surgery, mean free T4 and T3 levels were reduced by nearly
TSH level associated with elevated free T4 and total T3 50% in the first 3 months of therapy and six of seven patients
concentrations, generally associated with a pituitary tumor experienced tumor volume reduction (661).
on MRI or CT and the absence of a family history or genetic Sterotactic or conventional radiotherapy has also been used
testing consistent with resistance to thyroid hormone. in cases that prove refractory to medical therapy. Radio-
therapy controlled thyroid hypersecretion in 37% of patients
treated with this modality, but hypopituitarism occurred in
32% of those treated (659). For patients with TSH-producing
TSH-secreting pituitary adenomas are rare tumors and adenomas who are considered poor surgical candidates, pri-
represent an even rarer cause of hyperthyroidism. Recent data mary medical therapy with octreotide can be considered
from the Swedish registry reported an incidence of 0.15 per 1 (661). Patients who fail to respond to pituitary surgery and
million inhabitants, with a prevalence of 2.8 cases per million somatostatin analog therapy or those who have tumor en-
(658). After excluding laboratory interference with either the largement despite these measures are sometimes treated with
free T4 or TSH assay, as may occur with T4 antibodies and radiation therapy.
heterophilic antibodies, respectively, distinction between a
TSH-secreting adenoma and resistance to thyroid hormone is & RECOMMENDATION 122
important since thyroid function test results are similar, yet Patients with TSH-secreting pituitary adenomas should
management is quite different for these two disorders. TSH- undergo surgery performed by an experienced pituitary
secreting adenomas are more likely to have a concurrent surgeon.
a-subunit elevation (not useful in postmenopausal women be-
cause of concurrent gonadotropin elevation), a blunted TSH
response to thyrotropin-releasing hormone (when avail-
Technical remarks: Postoperative adjunctive therapy with
able), elevated sex hormone–binding globulin and resting
octreotide and/or external beam radiation therapy may be
energy expenditure, and clinical evidence of thyrotoxicosis,
useful in managing patients with persistent central hyper-
as well as an anatomic abnormality on MRI of the pituitary.
thyroidism after a debulking procedure for nonresectable
Finally, a response to somatostatin analog therapy with
TSH-secreting adenomas (43).
clinical improvement lends support to the diagnosis of a
TSH-secreting adenoma in cases in which diagnostic un-
[X5] Struma ovarii
certainty persists. Although most TSH-secreting pituitary
adenomas only secrete TSH, co-secretion of prolactin or & RECOMMENDATION 123
growth hormone is possible and should be assessed con-
Patients with struma ovarii should be treated initially with
currently along with assessment of the pituitary–adrenal
surgical resection following preoperative normalization of
axis and pituitary–gonadal axes.
thyroid hormones.
Technical remarks: Genetic testing for resistance to thy-
roid hormone is commercially available and may be useful in Strong recommendation, low-quality evidence.
equivocal cases, especially in patients without family mem-
bers available for thyroid function testing. Calculation of the Struma ovarii, defined as ectopic thyroid tissue existing as
molar a-subunit/TSH ratio can be accomplished by dividing a substantial component of an ovarian tumor, is quite rare,
the a-subunit concentration (ng/mL) by TSH (mU/L) and mul- representing <1% of all ovarian tumors. Approximately 5%–
tiplying by 10. A ratio greater than 1 favors a TSH-secreting 10% of patients with struma ovarii present with thyrotoxi-
pituitary adenoma. cosis (662) due to either autonomous ectopic thyroid function
Pituitary surgery is generally the mainstay of therapy for or the coexistence of GD, and up to 25% of struma ovarii
TSH-producing pituitary tumors. In a recent series of 68 pa- tumors contain elements of papillary thyroid cancer. Patients
tients undergoing transsphenoidal surgery, 75% normalized previously treated for GD may have persistent or recurrent
thyroid function after surgery, 58% normalized both pituitary hyperthyroidism due to the action of TRAb on the ectopic
imaging and TSH hypersecretion, 9% developed new defi- thyroid tissue (663). The diagnosis should be considered in
ciencies, and 3% experienced tumor recurrence (659). The any thyrotoxic patient with a very low or absent RAIU over
patient should be made euthyroid preoperatively. Long-term the eutopic thyroid gland. Other conditions that present
ATD therapy and other measures directed at the thyroid, such with this constellation of findings include various forms of
as RAI or thyroidectomy, are generally avoided because of thyroiditis, factitious thyrotoxicosis, and iodine-induced hy-
theoretical concerns of tumor growth. Preoperative adjunc- perthyroidism. In struma ovarii, the RAI is concentrated in
1398 ROSS ET AL.
the pelvic region over the teratoma. Cosynchronous primary roxine has been measured as a means of distinguishing sur-
thyroid cancer occurred in 9% of patients in one series of 68 reptitious use of thyroid hormone from painless thyroiditis
patients identified in the Surveillance, Epidemiology, and End (54). A disproportionately elevated T3 level suggests that the
Results database (664). Treatment of struma ovarii generally patient may be ingesting liothyronine or a combination T4/T3
involves surgical removal, performed both to cure the hyper- preparation.
thyroidism and to eliminate the risk of untreated ectopic thyroid Severe thyrotoxicosis and rarely, thyroid storm, have been
cancer. Preoperative treatment with b-adrenergic-blocking reported following thyroid hormone overdose or poisoning.
agents and ATDs is warranted to restore euthyroidism before Treatment with cholestyramine (671) and charcoal hemo-
surgery. perfusion (672) have been used in this circumstance.
Technical remarks: In cases of suspected metastatic ma-
lignant struma ovarii, RAI is generally given following sur- [X8] Functional thyroid cancer metastases
gical removal of both the ovarian tumor and the patient’s Thyrotoxicosis due to functional metastases in patients
thyroid to facilitate delivery of isotope to any potential re- with thyroid cancer has been described in a handful of cases.
sidual malignant cells. Typically, patients have either a very large primary follicular
cancer or widely metastatic follicular thyroid cancer, and
[X6] Choriocarcinoma they may have coexisting TRAb as the proximate cause of the
thyrotoxicosis (673) or activating mutations in the TSH re-
& RECOMMENDATION 124 ceptor (674). In general, functioning metastases are treated
Treatment of hyperthyroidism due to choriocarcinoma with RAI with the addition of ATDs as needed for persistent
should include both MMI and treatment directed against hyperthyroidism. Recombinant human TSH should be avoi-
the primary tumor. ded in these patients. Patients with massive metastatic fol-
licular thyroid cancer may also exhibit T3 thyrotoxicosis,
most likely due to increased conversion of T4 to T3 by tumor
expressing high type 1 and type 2 deiodinase activities (675).
Patients with choriocarcinoma, including molar pregnancy Thus, occasional measurement of serum T3 in addition to FT4
and testicular cancer, may present with thyrotoxicosis be- and TSH is recommended in patients with a large metastatic
cause of the effect of tumor-derived hCG upon the TSH re- tumor burden, particularly if FT4 decreases on fixed doses of
ceptor (665–668). This cross-stimulation only occurs at very levothyroxine.
high levels of hCG, since hCG is only a weak agonist for the
TSH receptor. Therefore, patients with testicular choriocar- ENDORSEMENTS
cinoma presenting with overt thyrotoxicosis may have widely
The final document was officially endorsed by the Amer-
metastatic disease at presentation (667,668). Treatment of
ican Association of Clinical Endocrinologists; American
hyperthyroidism due to choriocarcinoma involves both
Association of Endocrine Surgeons; Canadian Association of
treatment directed against the primary tumor and ATDs.
Otolaryngology Head and Neck Surgery; International As-
sociation of Endocrine Surgeons; International Federation of
[X7] Thyrotoxicosis factitia
Head and Neck Oncologic Societie; Latin American Thyroid
Thyrotoxicosis factitia includes all causes of thyrotoxi-
Society; The Endocrine Society of Australia.
cosis due to the ingestion of thyroid hormone. This may
include intentional ingestion of thyroid hormone either
AUTHOR DISCLOSURE STATEMENT
surreptitiously or iatrogenically, as well as unintentional
ingestion either accidentally, such as in pediatric poisoning Julie Ann Sosa discloses significant financial interests or
or pharmacy error, or through ingestion of supplements that other relationships as a Member, Data Monitoring Commit-
contain thyroid hormone (669). Historically, accidental tee for Medullary Thyroid Cancer Registry supported by
thyroid hormone ingestion has occurred as a result of eating Novo Nordisk, AstraZeneca, GlaxoSmithKline, and Eli Lilly.
meat contaminated with animal thyroid tissue (‘‘hamburger The remaining authors disclose no significant financial in-
thyrotoxicosis’’) (670). terests or other relationships with commercial interests.
Whereas iatrogenic causes of thyrotoxicosis factitia are
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ABBREVIATIONS NSAID ¼ nonsteroidal anti-inflammatory agent

AACE ¼ American Association of Clinical pANCA ¼ antineutrophil cytoplasmic antibody
Endocrinologists PTU ¼ propylthiouracil
AIT ¼ amiodarone-induced thyrotoxicosis QoL ¼ quality of life
ANCA ¼ antineutrophil cytoplasmic antibody RAI ¼ radioactive iodine
ATA ¼ American Thyroid Association RAIU ¼ radioactive iodine uptake
ATD ¼ antithyroid drugs rhTSH ¼ recombinant human thyrotropin
BWPS ¼ Burch–Wartofsky point scale RLN ¼ recurrent laryngeal nerve
CAS ¼ clinical activity score RFA ¼ radiofrequency ablation
CFDS ¼ color flow Doppler study SH ¼ subclinical hyperthyroidism
CT ¼ computed tomography SSKI ¼ saturated solution of potassium iodide
ESR ¼ erythrocyte sedimentation rate T3 ¼ triiodothyronine
GD ¼ Graves’ disease T4 ¼ thyroxine
GO ¼ Graves’ orbitopathy TA ¼ toxic adenoma
hCG ¼ human chorionic gonadotropin TBII ¼ thyrotropin binding inhibition
IFN ¼ interferon immunoglobulin
iPTH ¼ intact parathyroid hormone TBG ¼ T4 binding globulin
JTA ¼ Japanese Thyroid Association TcO4 ¼ technetium
KI ¼ potassium iodide TMNG ¼ toxic multinodular goiter
MMI ¼ methimazole TRAb ¼ thyrotropin receptor antibodies
MNG ¼ multinodular goiter TSH ¼ thyrotropin
MRI ¼ magnetic resonance imaging TSI ¼ thyroid-stimulating immunoglobulin
WBC ¼ white blood cell
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THYROID SPECIAL ARTICLE

Volume 26, Number 10, 2016

2016 American Thyroid Association Guidelines

DEDICATION of interest at the initial meeting of the group and periodi-

T hyrotoxicosis is a condition having multiple eti-

Table 1. Grading of Recommendations, Assessment, Development, and Evaluation System

Table 2. Organization of the Task Force’s Recommendations

RESULTS thyroidism associated with a diffuse enlargement of the thyroid

Table 4. Beta-Adrenergic Receptor Blockade in the Treatment of Thyrotoxicosis

Table 5. Clinical Situations That Favor a Particular Modality as Treatment

& RECOMMENDATION 6 cardiovascular disease, resuming MMI or carbimazole 3–

[D4] Treatment of persistent Graves’ hyperthyroidism & RECOMMENDATION 15

[F3] Postoperative care & RECOMMENDATION 30

& RECOMMENDATION 32 or thyroid storm 2 (TS2) with evidence of systemic de-

Table 6. Point Scale for the Diagnosis of Thyroid Storma

Table 7. Thyroid Storm: Drugs and Doses

Table 8. Clinical Situations That Favor a Particular Modality as Treatment

& RECOMMENDATION 50 & RECOMMENDATION 54

Technical remarks: The management of hypocalcemia & RECOMMENDATION 55

Table 9. Theoretical Projections of Cancer Incidence or Cancer Mortality Related

& RECOMMENDATION 72 gression from SH to overt hyperthyroidism appears more

Table 10. Subclinical Hyperthyroidism: When to Treat

Table 11. Summary of Recommendations Concerning Management of Graves’ Disease

& RECOMMENDATION 93 (weeks 30–34) to guide decisions regarding neonatal mon-

Table 12. Assessment of Graves’ Orbitopathy: Clinical Activity Score Elementsa

Table 13. Graves’ Orbitopathy Severity Assessmenta

Table 15. Risk Factors for Graves’ Orbitopathy

[U3] Treatment of hyperthyroidism in patients with no ap- & RECOMMENDATION 104

& RECOMMENDATION 110

FIG. 1. A suggested approach to the management of amiodarone-induced thyrotoxicosis.

Table 16. Causes of Drug-Associated Thyrotoxicosisa

can be due to either painless thyroiditis or GD (639). In a [X3] Lithium

Table 17. Unusual Causes of Thyrotoxicosis

ABBREVIATIONS NSAID ¼ nonsteroidal anti-inflammatory agent

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