DynaMed Plus - Graves Disease in Adults

4/3/2019 DynaMed Plus: Graves disease in adults
Graves disease in adults

Overview and Recommendations
Background
Graves disease is an autoimmune disorder characterized by thyroidal (hyperthyroidism and goiter) and
extra-thyroidal (Graves ophthalmopathy [GO], pretibial myxedema, and Graves acropachy)
manifestations.
Graves disease is the most common cause of hyperthyroidism. It occurs in all age groups and is more
common in females than males.
It is caused by interplay between genetic (for example, polymorphisms in genes encoding thyrotropin
receptor and proteins involved in T-cell signaling) and environmental factors (such as dietary iodine,
exposure to tobacco smoke, infections, and emotional stress) leading to formation of activating
thyrotropin-receptor antibodies that induce thyroid hormone overproduction.
Exacerbation of Graves disease may lead to thyroid storm, a potentially life-threatening endocrine
emergency with severe signs and symptoms of hyperthyroidism and multiorgan decompensation.
Evaluation
The clinical presentation of patients with Grave disease varies depending on the age of onset, severity and
duration of hyperthyroidism, sex and comorbidities; patients typically present with symptoms and signs of
≥ 1 of:
hyperthyroidism, such as palpitations, tremor, weight loss, or sweating
goiter, such as diffuse thyroid enlargement (with or without thrill or bruit), and rarely symptoms of
upper airway and esophageal obstruction causing globus sensation, dysphagia, or orthopnea
extrathyroidal manifestations of underlying autoimmunity including ophthalmopathy (may present
with proptosis and upper eyelid retraction), thyroid dermopathy (also called pretibial myxedema,
characterized by nodular or diffuse thickening of skin in pretibial area), and rarely acropachy
(characterized by clubbing of fingers and toes)
Diagnosis of Graves disease is based on characteristic clinical features and biochemical abnormalities.
Initial biochemical testing in patients presenting with signs and symptoms suggestive of Graves disease
includes serum thyroid-stimulating hormone (TSH) assay and thyroid hormone assays (free thyroxine
[FT4] and total or free tri-iodothyronine [TT3 or FT3]).
If the patient has a symmetrically enlarged thyroid, recent development of orbitopathy, and
moderate-to-severe hyperthyroidism persisting for 2 months or more, Graves disease is likely and
further evaluation for cause of hyperthyroidism is unnecessary.
If the patient is thyrotoxic with a non-nodular thyroid and no definite orbitopathy, measure either
thyrotropin receptor antibody (TRAb) or radioactive iodine uptake. A thyroid scan should be
obtained if the thyroid is nodular.
Graves disease is indicated if there is thyrotoxicosis (low TSH, and elevated or normal FT4 or TT3
or FT3) if:
TRAb or (or thyroid-stimulating immunoglobulin [TSI]) is present
radionuclide scan shows homogenous increase in uptake
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GO is suggestive by clinical presentation, assessment of activity and severity of ophthalmopathy using

standardized criteria, and orbital imaging.
Management
Give beta-blockers for patients with symptomatic thyrotoxicosis, especially elderly patients and thyrotoxic
patients with resting heart rate > 90 beats/minute or concurrent cardiovascular disease, until thyroid
hormone levels are normalized (Strong recommendation).
Treat Graves hyperthyroidism with antithyroid medications, radioactive iodine, or thyroidectomy (Strong
recommendation).
Antithyroid medication is preferred as first-line treatment to normalize thyroid hormone production
for pregnant women, patients with active GO, and patients with a high likelihood of remission (mild
disease, small goiter, negative or low-titer TRAb).
If antithyroid medication is chosen as initial treatment, administer methimazole (MMI),
except in women during the first trimester of pregnancy (in which case propylthiouracil is
preferred), patients with thyroid storm, and patients with minor reactions to MMI who refuse
radioactive iodine therapy or surgery (Strong recommendation).
Continue MMI for 12-18 months, then taper or discontinue if TSH and TRAb levels are
normal (Strong recommendation).
If the patient is not in remission, consider continuing low-dose MMI treatment for > 12-18
months (and if this option is preferred by patient) (Weak recommendation).
If the patient becomes hyperthyroid after completing MMI treatment, consider treatment with
radioactive iodine or thyroidectomy (Weak recommendation).
Major adverse effects (reported in about 0.2%-0.3%) include agranulocytosis, hepatotoxicity,
and antineutrophil cytoplasmic antibody-associated vasculitis.
Radioactive iodine (given orally) may be preferred as first-line treatment in patients with
contraindications to antithyroid medications and comorbidities increasing surgical risk.
Prior to radioactive iodine administration:
in women with childbearing potential, obtain pregnancy test within 48 hours prior to
radioactive iodine treatment and confirm negative result prior to administering
radioactive iodine (Strong recommendation)
in patients who are at increased risk for complications due to worsening
hyperthyroidism (such as elderly patients and patients with coexisting conditions such
as cardiovascular complications), consider pretreatment with a beta-blocker and MMI
(the latter should be discontinued 2-3 days prior to RAI administration and may be
resumed 3-7 days afterwards) (Weak recommendation)
Administer adequate radiation in a single dose to render patients hypothyroid (Strong
recommendation).
Perform a follow-up evaluation that includes (Strong recommendation):
FT4, TT3, and TSH levels at 1-2 months after radioactive iodine therapy (thyroid
function tests)
continued biochemical monitoring at 4- to 6-week intervals for 6 months or until patient
is hypothyroid and stable on thyroid hormone replacement, or stably euthyroid
When patients develop hypothyroidism (FT4 level below normal range), give levothyroxine.
The dose should initially be determined based on FT4, as TSH may not rise immediately,
taking into consideration residual thyroid function (may require lower dosage than full
replacement), but later adjusted and monitored based on TSH levels.
Thyroidectomy may be preferred as first-line treatment for symptomatic compression, large goiter,
thyroid glands with relatively low uptake of radioactive iodine, documented or suspected thyroid
malignancy, coexisting hyperparathyroidism requiring surgery, especially if TRAb levels are
particularly high, and patients with moderate-to-severe active GO.
If surgery is chosen as the primary therapy for Graves disease, perform a near-total or total
thyroidectomy (Strong recommendation). Definitive therapy may be accomplished with near-
total thyroidectomy.
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Preoperative considerations:
Render patients euthyroid with antithyroid medication with or without beta-blockers
(Strong recommendation).
Stop antithyroid drugs at time of thyroidectomy and wean beta-blockers after surgery
Administer potassium iodide formulation in immediate preoperative period to help
prevent blood loss (Strong recommendation).
Assess calcium and 25-hydroxyvitamin D levels preoperatively and replete or
administer prophylactically if needed (Strong recommendation).
Provide calcitriol supplementation preoperatively in patients at increased risk for
transient or permanent hypoparathyroidism (Strong recommendation).
Postoperative follow-up:
Consider oral calcium and calcitriol supplementation based on results of serum calcium
measurement with or without intact parathyroid hormone (iPTH) levels or empiric
prophylactic administration of oral calcium with or without calcitriol (Weak
recommendation).
Start levothyroxine at a daily dose appropriate for the patient's weight (0.8 mcg/lb or
1.6 mcg/kg) (elderly patients may require somewhat less), and measure serum TSH 6-8
weeks postoperatively (Strong recommendation).
Management of GO
Refer patients with GO to an eye specialist except for mildest cases improving with normalizing
thyroid status and local lubricants (Strong recommendation).
All patients with GO:
Urge smoking cessation with help of smoking cessation programs or clinics if necessary
Promptly restore and maintain euthyroidism (Strong recommendation).
Evaluate for ocular surface disease and treat extensively with nonpreserved artificial tears
with osmoprotective properties unless higher protection (use of gels or ointments) is required
due to corneal exposure (Strong recommendation).
Patients with mild GO:
Treat patients with local treatments (Strong recommendation).
If impact of disease on quality-of-life outweighs risks, consider immunosuppressive therapy
for active GO or rehabilitative surgery for inactive GO (Strong recommendation).
Consider selenium supplementation for 6 months to patients with mild GO of relatively short
duration to improve symptoms and prevent progression of GO (Weak recommendation).
Patients with moderate-to-severe and active GO:
First-line treatment is with high-dose glucocorticoids IV (Strong recommendation).
The second line of treatment for moderate-to-severe GO should be based on shared decision
making approaches (Strong recommendation). Approaches include ≥ 1 of orbital radiotherapy,
cyclosporine with oral glucocorticoid, rituximab, IV immunoglobulins, and teprotumumab.
Patients with moderate-to-severe and inactive GO:
Offer elective rehabilitative surgery when the disease is associated with a significant impact
on visual function or quality-of-life after the disease has been inactive for > 6 months (Strong
recommendation).
Procedures include decompression surgery, strabismus surgery, lid lengthening, and cosmetic
periorbital surgery.
If multiple surgeries are required, orbital decompression should be performed first, followed
by squint surgery, then lid surgery (Strong recommendation).
Patients with sight-threatening GO:
Treat severe corneal exposure medically or by progressively more invasive surgeries as soon
as possible in order to avoid progression to corneal breakdown (Strong recommendation).
Treat dysthyroid optic neuropathy (DON) immediately with (Strong recommendation):
very high doses of IV glucocorticoids (500-1,000 mg of methylprednisolone for 3
consecutive days or on alternate days during the first week)
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orbital decompression if poor or no response within 2 weeks

orbital decompression for recent-onset choroidal folds and eyeball subluxation
pulses of IV methylprednisolone weekly if DON has resolved or improved after 2
weeks
Additional treatment considerations for hyperthyroidism may be required for patients with or at risk of
developing GO, women who are pregnant or lactating, thyroid storm, and subclinical hyperthyroidism.
Related Summaries
Graves disease in children
Hyperthyroidism and other causes of thyrotoxicosis
Thyroid disease in pregnancy
General Information
Description
autoimmune disorder characterized by thyroidal (hyperthyroidism, and goiter) and extra-thyroidal
(Graves’ ophthalmopathy [GO], pretibial myxedema, and Graves acropachy) manifestations (1, 4)
the most common cause of hyperthyroidism in iodine sufficient areas(2)
Also called
Graves' disease
Basedow's disease
autoimmune hyperthyroidism
exophthalmic goiter
toxic diffuse goiter
Definitions
thyrotoxicosis - clinical condition resulting from inappropriately high thyroid hormone activity in
tissues(2)
hyperthyroidism - form of thyrotoxicosis caused by inappropriately elevated synthesis and secretion of
thyroid hormone by the thyroid(2)
overt hyperthyroidism - low, usually undetectable levels of serum thyroid-stimulating hormone
(TSH) with elevated levels of serum tri-iodothyronine (T3) and/or free thyroxine (FT4)
subclinical hyperthyroidism - low or undetectable serum levels of TSH with T3 and FT4 levels
within normal range
thyroid storm (also called thyrotoxic crisis) - life-threatening thyrotoxicosis with multiorgan involvement
that may include cardiovascular, thermoregulatory, gastrointestinal, hepatic, and central nervous system
dysfunction(2)
goiter - an enlargement of thyroid gland and may be nodular or diffuse (Diagn Cytopathol 2008
Jun;36(6):425)
Graves ophthalmopathy (also called Graves orbitopathy, thyroid-associated ophthalmopathy, thyroid-
associated orbitopathy, and thyroid eye disease)(2, 5)
an inflammatory eye disease that develops in the orbit in association with autoimmune thyroid
disorders (about 90% of cases reported to occur in patients with current or past Graves disease)
the main extrathyroidal manifestation of Graves disease
References -
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N Engl J Med 2010 Feb 25;362(8):726 full-text

Eur Thyroid J 2016 Mar;5(1):9 full-text
thyroid dermopathy (also called pretibial myxedema - a nodular or diffuse thickening of pretibial skin (N
Engl J Med 2010 Feb 25;362(8):726 full-text)
thyroid function tests may include(1, 2, 3, 4)
thyroid-stimulating hormone (TSH), also called thyrotropin or thyrotrophin
free thyroxine (FT4)
free tri-iodothyronine (FT3)
tri-iodothyronine (T3), also called total tri-iodothyronine (TT3)
thyroid-binding globulin (TBG)
thyroid antibodies include(1, 2, 3, 4)
thyroid peroxidase antibodies (TPOAb)
thyroglobulin antibodies (TgAb)
thyrotropin receptor antibodies (TRAb), also called TSH receptor antibodies (TSH-RAb) or thyroid-
stimulating immunoglobulin (TSI)
Epidemiology
Who is most affected
occurs at any age, with peak incidence at age 30-60 years(1, 3)

more common in females with female:male ratio of 5:1(4)
may be more common in (1, 3, 4)
white adults compared to Asian adults; recent study suggests higher incidence among Asian adults
white and Asian adults compared to African adults; recent study suggests higher incidence among
African American adults
Incidence/Prevalence
reported annual incidence of Graves disease range from 14 to 50 per 100,000 persons; 3% of women and
0.5% of men reported to develop Graves disease during their lifetime(1, 3, 4)
reported incidence of Graves disease during pregnancy 1-2 cases per 1,000 pregnancies(3)
reported prevalence of hyperthyroidism in the United States is about 1.2% (0.5% with overt disease, 0.7%
with subclinical disease); Graves disease, toxic multinodular goiter, and toxic adenoma are most common
causes(2)
in iodine sufficient areas, 70%-80% of patients with thyrotoxicosis reported to have Graves disease(4)
reported annual incidence of Graves ophthalmopathy(1)
16 cases per 100,000 women
3 cases per 100,000 men
42.2 per million per year in Sweden (20.1% of incidence of Graves hyperthyroidism)
Reference - Eur Thyroid J 2016 Mar;5(1):9 full-text
incidence of Graves disease may be higher in black and Asian adults compared to white adults in
United States
based on retrospective cohort study
all active military personnel aged 20-54 years (86% male) in United States from 1997 to 2011
total follow-up 20,270,688 person-years
compared to white women, increased incidence of Graves disease associated with
black women (incidence rate ratio [RR] 1.92, 95% CI 1.56-2.37)
Asian or Pacific Islander women (incidence RR 1.78, 95% CI 1.2-2.66)
compared to white men, increased incidence of Graves disease associated with
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black men (incidence RR 2.53, 95% CI 2.01-3.18)

Asian or Pacific Islander men (incidence RR 3.36, 95% CI 2.57-4.4)
Reference - JAMA 2014 Apr 16;311(15):1563
Risk factors
interactions between various genetic/epigenetic susceptibility and environmental (nongenetic) factors
thought contribute to risk of developing Graves disease(1, 3, 4)
genetic susceptibility
family history of autoimmune disorder
higher concordance rate of Graves disease reported in monozygotic twins (about
17%-35%) compared to dizygotic twins
higher prevalence in first degree relatives of patients with Graves disease or
autoimmune thyroiditis
polymorphisms and differences in epigenetic regulation of genes such as
CD40 (CD40 molecule, tumor necrosis factor receptor superfamily member 5)
CD25
CTLA4 (cytotoxic T-lymphocyte-associated protein 4
major histocompatibility (HLA) complex genes
PTPN22 (protein tyrosine phosphatase, nonreceptor type 22 [lymphoid])
TG (thyroglobulin)
TSHR (thyroid stimulating hormone receptor)
FCRL3 (Fc receptor-like 3)
Reference - J Endocrinol Invest 2015 Mar;38(3):283
environmental (nongenetic) risk factors
female gender
dietary iodine - may play an important role in the development of Graves disease in
genetically susceptible individuals
periods of immune reconstitution
infections as a possible risk factor supported by
reports of seasonal variation and geographical influence on incidence of Graves disease
more frequent reports among patients with Graves disease of
conditions that render patients more susceptible to infections (for example, blood
group nonsecretors)
recent viral infection
reports of association of Yersinia enterocolitica and Helicobacter pylori infection with
Graves disease
psychological stress
smoking
thyroid damage following from
ethanol injections for autonomous thyroid nodules
radioactive iodine treatment for toxic adenoma and toxic nodular goiter
subacute thyroiditis
vitamin D deficiency
selenium deficiency
immune modulating agents such as
interferon-alpha
alemtuzumab, a CD52 targeting monoclonal antibody
antiretroviral therapy for HIV infections
amiodarone (J Autoimmun 2009 May-Jun;32(3-4):231 full-text)
evidence for risk of Graves disease
immune modulating agents
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alemtuzumab associated with increased thyroid dysfunction compared to interferon-

beta 1a in patients with relapsing-remitting multiple sclerosis, with 65.8% of patients on
alemtuzumab with thyroid dysfunction diagnosed with Graves disease
based on post hoc analysis of randomized trial
334 patients with relapsing-remitting multiple sclerosis received alemtuzumab IV 12-24
mg/day vs. interferon-beta 1a 44 mcg subcutaneously, 3 times weekly and followed for
median 57.3 months
323 patients were included in analysis
25% of patients developed thyroid dysfunction
thyroid dysfunction in 33.8% receiving alemtuzumab vs. 6.5% receiving interferon-beta
1a (p < 0.001, NNH )
65.8% of patients receiving alemtuzumab who developed thyroid dysfunction had
Graves disease
Reference - J Clin Endocrinol Metab 2014 Jan;99(1):80
interferon-alpha reported to result in thyrotoxicosis in 4%, with 60% of patients with
thyrotoxicosis developing Graves disease
based on case-series
246 patients with hepatitis C virus and 75 patients with hepatitis B virus received
interferon-alpha
10 patients (4%) developed thyrotoxicosis; 6 (60%) patients had Graves disease
Reference - Clin Endocrinol (Oxf) 2002 Jun;56(6):793
infections
Helicobacter pylori infection associated with increased risk of Graves disease
based on systematic review of case-control studies
systematic review of 7 case-control studies evaluating association between H. pylori
infection and autoimmune thyroid disease in 862 individuals (patients with autoimmune
thyroid disease or healthy controls)
H. pylori infection confirmed in 432 individuals
H. pylori infection associated with Graves disease (odds ratio 4.35, 95% CI 2.49-7.64)
in analysis of 3 studies with 97 patients with Graves disease and 201 controls
no significant association between H. pylori infection and Hashimoto thyroiditis in
analysis of 4 studies with 159 patients with Hashimoto thyroiditis and 221 patients
without Hashimoto's thyroiditis
Reference - Thyroid 2013 Oct;23(10):1294
psychological stress
negative stressful life events associated with increased risk of Graves disease
based on 2 case-control studies
45 patients with Graves disease and 36 healthy controls (matched by age, sex, and
social status) were assessed for impact of life events in 12 months prior to initiation of
disease
2 methods were used for assessed for impact of life events
life experience survey assessment
evaluates both positive and negative events and their impact
each event evaluated based on 7 point scale ranging from extremely
negative (-3) to extremely positive (3); 0 indicates event with no
impact
Holmes-Rahe stress scale - takes into account stressful life events to
determine influence of each negative event
using life experience survey
comparing Graves disease vs. controls
number of negative stressful life events reported 4 vs. 3 (p = 0.015)
impact of negative events on life experience survey scale median 12
points vs. 5 points (p < 0.001)
no significant difference in number of total negative event
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no significant difference in Holmes-Rahe stress scores

Reference - Int J Psychiatry Clin Pract 2012 Oct;16(4):307
208 patients with newly diagnosed Graves disease and 372 matched controls (matched
by age, sex, and country of residence) without Graves disease answered questionnaire
regarding life-style over 1 year prior to diagnosis
life events scores were obtained from a 4 part life event survey questionnaire
composed of 95 items
compared to negative life event score 0 higher negative life event scores
associated with increased risk for Graves disease
for negative life event score ≥ 5 odds ratio (OR) 7, 95% CI 2.9-16.7
for negative life event score 3-4 OR 3.1, 95% CI 1.7-5.4
for negative life event score 1-2 OR 2.1, 95% CI 1.4-3.3
Reference - Lancet 1991 Dec 14;338(8781):1475, commentary can be found in
Lancet 1992 Feb 15;339(8790):427
smoking
current smoking associated with increased risk of Graves disease and smoking (current
or past) associated with increased risk of Graves ophthalmopathy
based on systematic review of observational studies
systematic review of 25 studies (case-control and cross-sectional studies) evaluating
association between smoking and risk of thyroid disease
smoking associated with increased risk of
Graves disease in current smokers compared with never smokers (odds ratio 3.3,
95% CI 2.09-5.22 ) in analysis of 8 studies with 8,730 adults
Graves ophthalmopathy in ever smokers compared to never smokers (odds ratio
4.4, 95% CI 2.88-6.73) in analysis of 6 studies with 2,543 adults
no significant association between smoking and risk of Graves disease in past smokers
in analysis of 8 studies with 8,730 adults
Reference - Eur J Endocrinol 2002 Feb;146(2):153
smoking associated with increased risk of Graves disease in women
based on cohort study
115,109 women aged 25-42 years in Nurses' Health Study II were followed for 12 years
543 women developed Graves disease
smoking associated with increased risk of Graves disease
in current smokers (hazard ratio 1.93, 95% CI 1.54-2.43)
in past smokers (hazard ratio 1.27 ,95% CI 1.03-1.56)
Reference - Arch Intern Med 2005 Jul 25;165(14):1606
ever smoking associated with Graves disease compared to never smoking
617 patients with hyperthyroidism and 617 matched controls (by age and sex) had
smoking habits assessed
43% of patients with hyperthyroidism and 31% of controls were current smokers
29% of patients with hyperthyroidism and 27% of controls were previous
smokers
28% of patients with hyperthyroidism and 42% of controls were never smokers
median age 55 years and 88% women in both groups
ever smoking associated with increased risk of Graves disease compared to never
smoking (odds ratio 2.05, 95% CI 1.51-2.78)
Reference - Thyroid 2002 Jan;12(1):69
vitamin D
lower serum 25 hydroxyvitamin D3 levels and vitamin D deficiency each associated with
Graves disease
based on case-control study
26 women (mean age 37.3 years) with Graves disease and 46 healthy control women
(mean age 44.3 years) had serum 25-hydroxyvitamin D3 levels measured
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comparing Graves disease vs. controls

serum 25 hydroxyvitamin D3 levels 14.4 ng/mL (35.9 nmol/L) vs. 17.1 ng/mL
(42.7 nmol/L) (p < 0.05)
vitamin deficiency (serum 25 hydroxyvitamin D3 < 15 ng/mL [37.4 nmol/L]) in
65.4% vs. 32.4% (p < 0.05)
Reference - Endocrine 2012 Dec;42(3):739 full-text
selenium
lower serum selenium levels associated with Graves disease
based on case-control study
97 patients with newly diagnosed Graves disease and 830 controls had serum selenium
levels measured
mean serum selenium 89.9 mcg/L in Graves disease vs. 98.8 mcg/L in controls (p <
0.001)
Reference - Clin Endocrinol (Oxf) 2013 Oct;79(4):584
Associated conditions
9.7% prevalence of autoimmune disorders among patients with Graves disease
based on cross-sectional study
2,791 patients with Graves disease screened for personal and parental history of hyperthyroidism,
hypothyroidism, and other autoimmune disorders
9.7% prevalence of other autoimmune disorders in patients with Graves disease
rheumatoid arthritis in 3.2%
vitiligo in 1.4%
pernicious anemia in 1.4%
type 1 diabetes mellitus in 1.1%
inflammatory bowel disease in 1%
celiac disease in 0.9%
multiple sclerosis in 0.3%
myasthenia gravis in 0.2%
systemic lupus erythematosus in 0.5%
Addison's disease in 0.1%
Reference - Am J Med 2010 Feb;123(2):183.e1, commentaries can be found in Am J Med 2010
Oct;123(10), Evid Based Med 2010 Oct;15(5):158
hyperthyroidism in Graves disease associated with higher risk of development of comorbidities such
as cardiovascular disease and diabetes
3,006 patients with hyperthyroidism and 10,899 patients without hyperthyroidism were followed for
mean 6 years
hyperthyroidism in Graves disease associated with increased risk for development of
cardiovascular disease (hazard ratio [HR] 1.93, 95% CI 1.46-2.56)
diabetes mellitus (HR 1.76 , 95% CI 1.14-2.7)
other diseases including dementia, gastric ulcer, liver disease, hemiplegia, kidney disease,
liver failure, and AIDS (HR 1.9, 95% CI 1.17-3.07)
no significant difference in development of rheumatic disease and malignant disease
Reference - PLoS One 2013;8(6):e66711
Graves disease associated with higher risk for development of thyroid and breast cancer
5,025 patients with Graves disease and 20,100 persons without Graves disease were evaluated for
development of cancer
incidence of cancer 4.92 per 1,000 person-years among patients with Graves disease and 3.58 per
1,000 person-years among persons without Graves disease (p < 0.001)
Graves disease associated with increased risk for development of
breast cancer (adjusted hazard ratio 1.58, 95% CI 1.09-2.3)
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thyroid cancer (adjusted hazard ratio 10.4, 95% CI 6.18-17.4)

Reference - Thyroid 2013 Jul;23(7):879, commentary can be found in Thyroid 2014 Feb;24(2):402
multiple sclerosis (J Autoimmune Dis 2005 Nov 9;2:9 full-text)
Etiology and Pathogenesis

Causes
multifactorial autoimmune disorder caused by a complex interaction between genetic and environmental
factors that lead to loss of immunotolerance to thyroid antigens and the development of autoantibodies
that bind to and activate the thyroid stimulating hormone (TSH) receptor present on thyroid follicular cells
and possibly on subsets of cells within the orbit and skin (1, 4)
Pathogenesis
Physiology and regulation of thyroid hormones
physiologic effects of thyroid hormones

thyroid hormones triiodothyronine (T3) and thyroxine (T4) circulate in the blood and induce a wide
variety of physiologic actions, including effects on growth, metabolism, cardiac effects, and central
nervous system development
circulating thyroid hormones enter certain cell types via variety of membrane transporters including
monocarboxylate transporter 8 (MCT8)
T4
hormone precursor (devoid of intrinsic activity) produced by thyroid follicular cells
about 85 mcg secreted by thyroid gland per day
activated by intracellular deiodinases to form T3
T3
about 20% (6.5 mcg) is synthesized by thyroid gland each day; about 80% (26 mcg) arises
from peripheral conversion from T4
although T4 is the main hormone produced by the thyroid gland, T3 is the more active
hormone in many organs
binds thyroid hormone receptors to modulate target gene expression
thyroid receptors are ligand-inducible transcription factors that bind specific sequences
in regulatory regions of target genes as a heterodimer with retinoid X receptor, as a
homodimer, or as a monomer
in the absence of thyroid hormone, the heterodimer/homodimer recruits a corepressor
complex that represses basal transcription of the gene
when T3 binds the thyroid receptor, the corepressor complex is displaced, and
transcriptional activators are recruited, which ultimately promotes transcription of
target genes
tissue-specific effects of thyroid hormone are mediated by differential expression of 2 types
of thyroid hormone receptors: thyroid receptor alpha (TR-alpha, encoded by THRA gene) and
thyroid receptor beta (TR-beta, encoded by THRB gene); alternative splicing of each gene
produces 2 distinct proteins with differential expression in target tissues
TR-alpha 1 is ubiquitously expressed and present at high levels in the central nervous
system, bone, skeletal muscle, gastrointestinal tract, and myocardium
TR-alpha 2 is unable to bind thyroid hormones and its physiologic effects are poorly
understood; it is expressed in a variety of tissue (for example, brain and testis)
TR-beta 1 is ubiquitously expressed and is the predominant isoform in the liver and
kidney
TR-beta 2 expression is limited to hypothalamus, pituitary, inner ear, and retina
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References -
Thyroid 2014 Dec;24(12):1670 full-text, commentary can be found in Thyroid 2014
Dec;24(12):1667
Best Pract Res Clin Endocrinol Metab 2015 Aug;29(4):647 full-text
regulation of thyroid hormones
systemic regulation of thyroid hormone levels in circulation is achieved via a negative feedback
loop involving the hypothalamus, pituitary, and thyroid glands
when thyroid hormone levels are low, the hypothalamus produces thyrotropin-releasing
hormone (TRH)
TRH stimulates the pituitary gland to produce thyroid stimulating hormone (TSH)
TSH stimulates follicular cells in the thyroid gland to produce more thyroid hormones
as thyroid hormone levels increase, production of TRH by the hypothalamus decreases,
ensuring thyroid hormone homeostasis
intracellular regulation of thyroid hormone levels involves
control of thyroid hormone entry into cell by specific transmembrane transport proteins,
including monocarboxylate transporter 8 (MCT8)
control of thyroid hormone metabolism by iodothyronine deiodinase enzymes required for
activation (converting T4 to T3) or inactivation (converting T4 to reverse T3 or converting T3
to 3,5-di-iodo-L-thyronine [T2])
References - Biochim Biophys Acta 2013 Jul;1830(7):3987 full-text
Hyperthyroidism
in Graves disease, activating autoantibodies are directed against the thyrotropin receptor; these
thyrotropin-receptor antibodies (TRAbs)(1, 4)
belong to the immunoglobulin G1 (IgG1) subclass
are oligoclonal, generated primarily by intrathyroidal B cells
are specific for Graves disease
mimic the actions of thyroid stimulating hormone (TSH) by binding to and activating its receptor
(TSHR) resulting in
increased synthesis and release of thyroid hormones (hyperthyroidism) that is uncontrolled by
the hypothalamic-pituitary axis
hypertrophy of thyroid follicular cells (goiter)
role of B and T cells(1)
important components of the adaptive immunity and required for development of Graves disease
autoreactive T cells against thyrotropin receptor have escaped central and peripheral editing and
interact with major histocompatibility complex (MHC) class II molecules presenting thyrotropin
receptor antigens
antigen binding to B cells stimulate interaction with T cells which leads to production of important
cytokines that stimulate antibody secretion; most of the anti-thyrotropin receptor antibodies are
generated by intrathyroidal B cells, but peripheral blood B cells may also contribute
interleukins and cytokines generated upon infiltration of the thyroid gland by immune cells (B and T
lymphocytes) and antigen producing cells activate and sustain inflammation and alter behavior of
thyroid epithelial cells
role of thyroid epithelial cells(1)
maybe be more passive, secondary to infiltration of immune cells
while thyroid epithelial cells are not antigen-presenting cells, in Graves disease, thyroid epithelial
cells express MHC class II molecules as a result of infiltrating interferon-gamma produced by
lymphocytes, with potential to present thyroid antigens to T cells
CD40 expression by thyroid epithelial cells may also mediate interactions with antigen-specific T
cells
Graves ophthalmopathy
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Graves ophthalmopathy results from inflammation and soft tissue enlargement in the orbit (1)
immune pathogenesis of ophthalmopathy and hyperthyroidism thought to be similar; possible
etiologies include
formation of autoantibodies against a shared antigen in the orbit and thyroid gland (for
example the thyrotropin receptor); supporting evidence for shared immunoreactivity against
the thyrotropin receptor includes
antithyrotropin-receptor antibodies (TRAbs) present in virtually all patients with
Graves ophthalmopathy
5% of patients with Graves ophthalmopathy who are euthyroid or hypothyroid typically
have low titers of TRAbs
TRAb titer correlates positively with clinical features of Graves ophthalmopathy (these
antibody levels are especially elevated in patients with thyroid dermopathy)
formation of antibodies against insulin-like growth factor 1 receptor with secondary effects on
thyrotropin receptor signaling
infiltration of orbital tissues with B and T lymphocytes and CD34+ fibrocytes during active disease
leads to tissue activation and activation of genes with roles in inflammation and tissue remodeling
fibrocytes differentiate into myofibroblasts or adipocytes and these cells can produce various
cytokines, including interleukin- (IL) 1 beta, IL-6, IL-8 and IL-16, tumor necrosis factor-alpha
(TNF-alpha), RANTES (regulated on activation, normal T-cell expressed and secreted), and CD40
ligand, depending on the nature of their microenvironment
these cytokines result in activation of orbital fibroblasts, which in turn synthesize hyaluronan and
other glycosaminoglycans that ultimately results in expansion of orbital tissue, proptosis, and optic
nerve compression
Reference - N Engl J Med 2010 Feb 25;362(8):726 full-text
diplopia occurs due to swelling of extraocular muscles, most commonly the inferior rectus muscle (N Engl
J Med 2010 Feb 25;362(8):726 full-text)
upper eyelid retraction occurs due to
increased activation of Müllers muscle
increased action of levator muscle against restricted inferior rectus muscle
scarring between levator muscle and other layers
symptomatic corneal dryness due to
retraction of eyelids
limitation on blinking
increased evaporation of tears and moisture
incomplete closing of lids over cornea when sleeping
periorbital edema may occur due to decreased venous drainage as a result of vascular compression within
the orbital space (N Engl J Med 2010 Feb 25;362(8):726 full-text)
History and Physical

Clinical Presentation
clinical presentation of patients with Grave disease varies depending on the age of onset, severity and
duration of hyperthyroidism, sex and comorbidities(1, 5)
patients may present with symptoms and signs of ≥1 of the following(1)
hyperthyroidism
goiter
extrathyroidal manifestations of underlying autoimmunity (especially ophthalmopathy)
symptoms and signs of hyperthyroidism
clinical manifestation of thyrotoxicosis
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Organ System Symptoms Signs

Weight loss despite
increased appetite
Heat-related symptoms
such as heat intolerance
Constitutional reported in 40%-90%, Weight loss
sweating reported in
50%-90%, and polydipsia
Weight gain reported in
10%
Tremor reported in 55%
Nervousness and
hyperactivity reported in Tremor of the extremities
80%-95% reported in 40%
Anxiety reported in 40% Hyperactivity
Neuromuscular
Fatigue reported in Hyperreflexia
50%-80% Pelvic and girdle muscle
Muscle weakness weakness
Disturbed sleep
Poor concentration
Tachycardia reported in
80%
Systolic hypertension
Increased pulse pressure
Palpitations reported in reported in 50%
Cardiovascular
65%-99% Irregular heartbeat (atrial
fibrillation)
Heart failure (less
common than atrial
fibrillation)
Shortness of breath reported in
Pulmonary Tachypnea
65%-80%
Hyperdefecation reported
in 20%
Gastrointestinal Abdominal tenderness
Nausea
Vomiting
Increased perspiration
Warm and moist skin reported
Skin Hair loss
in 35%
Onycholysis
Decreased libido, erectile Menstrual disturbances
Reproductive dysfunction, and gynecomastia (Oligomenorrhea reported in
reported in men 45%-80%)
References - (3, 4, 5).
most common presenting symptoms include(1, 5)
weight loss (despite increased appetite, reported in 50%-85%) (more common in elderly
patients)
fatigue (reported in 50%-80%) (may be absent or less pronounced in elderly patients)
heat intolerance (reported in 40%-90%)
tremor (reported in 55%)
palpitations (common in adults > 50 years old; reported in 60%-99%)
anxiety
disturbed sleep
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sweating
most common presenting signs include
tachycardia,
tremor of the extremities
weight loss
in elderly patients, symptoms may be absent or less pronounced with apathy and lethargy being the
main presentation (apathetic hyperthyroidism)(4)
exacerbation of Graves disease may lead to thyroid storm , an endocrine emergency (can be life-
threatening), that involves severe signs and symptoms of hyperthyroidism and multiorgan
decompensation (J Intensive Care Med 2015 Mar;30(3):131)
symptoms and signs of goiter(1, 4, 5)
palpable goiters reported to develop in most patients < 60 years old with hyperthyroidism (reported
in < 50% of older patients)
typically diffuse thyroid enlargement, though patients living in iodine-deficient regions may also
present with coexisting nodular goiter
thrills and bruits can be heard over thyroid, especially in larger goiters owing to the increased blood
flood
large goiters may be associated with
upper airway and esophageal obstruction causing globus sensation, dysphagia, or orthopnoea
change in voice
extrathyroidal symptoms and signs
ophthalmopathy(1, 3, 4)
inflammation and enlargement of orbital tissues
about 77% of patients with Graves ophthalmopathy are reported to be hyperthyroid, 3%
reported to be hypothyroid and 20% reported to be euthyroid
ophthalmic presentation develop prior to or after abnormalities in serum thyroid hormone
levels are detected
extraocular-muscle enlargement detected by magnetic resonance imaging or computed
tomographic scanning in about 70% of patients with Graves hyperthyroidism (subclinical eye
involvement)
25%-50% of patients with Graves’ hyperthyroidism have some signs and/or symptoms of
ophthalmopathy; almost 50% of patients report symptoms of Graves ophthalmopathy
about 3%-5% of patients with Graves ophthalmopathy reported to have severe disease
characterized by severe pain, inflammation, and sight-threatening corneal ulceration or
compressive optic neuropathy
hyperthyroidism and ophthalmopathy typically occur within 1 year of each other but can be
separated by decades
thyroid hormone levels may remain normal or autoimmune hypothyroidism reported to
develop in 10% of patients with ophthalmopathy
most common clinical features of Graves ophthalmopathy include
upper eyelid retraction (reported in 92%)
eyelid lag
edema
erythema of the periorbital tissues and conjunctivae
proptosis (exophthalmos) (reported in 62%)
other features include
double vision (extraocular-muscle dysfunction)
chemosis
dry eye
increased tearing (reported in 23%)
ocular pain (reported in 30%)
scleral injection
exposure keratitis
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optic neuropathy (reported in 6%)

severity of ophthalmopathy can be assessed by various criteria, which may impact
management strategies
References -
Aesthetic Plast Surg 2012 Jun;36(3):638
N Engl J Med 2010 Feb 25;362(8):726 full-text
thyroid dermopathy(1, 4, 5)
also called pretibial myxedema
rare extrathyroidal manifestation of Graves’ disease
virtually all patients have coexisting ophthalmopathy
reported to occur in 1%-4% of patients with thyroid ophthalmopathy; reported to be diagnosed in
about 13% of patients with severe Graves ophthalmopathy during physical exam
characterized by nodular or diffuse thickening of skin (nonpitting edema), primarily involving the
pretibial area (though can develop elsewhere, especially after trauma to skin); may be slightly
pigmented, reddish in color, with occasional papules
in severe cases may resemble elephantiasis
acropachy(1, 5)
the rarest extrathyroidal manifestation of Graves disease
occurs only in patients with dermopathy
about 20% of patients with thyroid dermopathy reported to have thyroid acropachy
characterized by clubbing of fingers and toes
older adults with hyperthyroidism may present with fewer classical symptoms than younger
patients
3,049 patients (mean age 46.6 years) with hyperthyroidism presenting to secondary/tertiary clinic
for care evaluated for presenting symptoms
1,189 patients (39%) had Graves disease
patients > 61 years old were least likely to report ≥ 5 symptoms at presentation
compared to patients aged 16-32 years, older age (age ≥ 61 years) associated with reduced presence
of most classical symptoms (including weight gain, heat intolerance, tremor, palpitation, anxiety,
neck enlargement and increased frequency of bowel movement) but not weight loss and shortness of
breath
among patients with Graves disease, older age, smoking, longer symptom duration, and female
gender associated with increased eye symptoms
older age (per year), higher serum free thyroxine concentrations at diagnosis, male gender, and toxic
nodular hyperthyroidism associated with increased atrial fibrillation
Reference - J Clin Endocrinol Metab 2010 Jun;95(6):2715
History
Medication history
ask about previous intake or current use of(1, 4)

iodine, including medicinal preparations or radiographic contrast media (CMAJ 2003 Mar
4;168(5):575 full-text, commentary can be found in CMAJ 2003 Jul 22;169(2):104)
immune-modulating medications such as
interferon-alfa
alemtuzumab (Campath)
highly active antiretroviral therapy for HIV infection
checkpoint inhibitors (Rev Endocr Metab Disord 2018 Sep 21 early online)
amiodarone
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Past medical history (PMH)
ask about/look for(1, 4)

recent infections
causes for thyroid damage such as
ethanol injections for autonomous thyroid nodule
radio-iodine treatment for toxic adenoma
toxic nodular goiter
subacute thyroiditis
Family history (FH)
ask about family history of thyroid disorders and autoimmune disease(1, 4)
Social history (SH)
ask about(1, 4)
smoking
recent pregnancy
Physical
General physical
check for physical signs of hyperthyroidism(1, 3, 4)

systolic hypertension, increased pulse pressure
weight loss or gain
muscle weakness
fever may suggest thyroid storm (J Intensive Care Med 2015 Mar;30(3):131)
Skin
look for(1, 3, 4)
warm, moist skin
hair loss
localized dermopathy and acropachy
HEENT
check for ocular signs of hyperthyroidism including swelling, pain, redness, and double vision(1)
evaluation of Graves ophthalmopathy(1)
assess activity and severity of Graves ophthalmopathy according to standardized criteria (EUGOGO
Strong recommendation, Moderate-quality evidence); standardized criteria include
activity measured using clinical activity score (CAS scale range 1-7)
1 point each assigned for
spontaneous retrobulbar pain
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pain on attempted upward or downward gaze

redness of eyelids
redness of conjunctiva
swelling of caruncle or plica
swelling of eyelids
swelling of conjunctiva
CAS score < 3 classified as inactive Graves ophthalmopathy
CAS score ≥ 3 classified as active Graves ophthalmopathy
severity of Graves ophthalmopathy categorized according to NOSPECS
no signs or symptoms
only signs no symptoms - increased lid aperture - distance between lid margins in mm
with patient looking in primary position, sitting relaxed with distant fixation
soft tissue involvement including swelling/redness of eyes
proptosis - exophthalmos measured in mm using same Hertel exophthalmometer and
same intercanthal distance for individual patient
extraocular muscle involvement
eye muscle ductions in degrees
measured by subjective diplopia score
intermittent- diplopia when tired or first awakening
inconstant - diplopia at extremes of gaze
constant- continuous diplopia in primary or reading position
corneal involvement - absent/punctuate keratopathy, ulcer
sight loss as a result of optic nerve involvement characterized by
diminished visual acuity
loss of color vision
relative afferent papillary defect
impaired visual fields
impaired optic disk
severity of Graves ophthalmopathy categorized according to EUGOGO
mild Graves orbitopathy - minor impact on daily life insufficient to justify
immunosuppressive or surgical intervention; characterized by ≥ 1 of
minor lid retraction (< 2 mm)
mild soft tissue involvement
exophthalmos < 3 mm above normal for race and gender
no or intermittent diplopia
corneal exposure responsive to lubricants
moderate to severe Graves Orbitopathy - severity not life threatening but disease has
sufficient impact on daily life to justify risks of immunosuppression (if active) or
surgical intervention (if inactive); characterized by ≥ 2 of following signs
lid retraction ≥ 2mm
moderate or severe soft tissue involvement
exophthalmos ≥ 3mm above normal for race and gender
inconstant or constant diplopia
sight threatening (very severe) Graves Orbitopathy characterized by dysthyroid optic
neuropathy and/or corneal breakdown
Reference - European Thyroid Association/European Group on Graves Orbitopathy
(EUGOGO) guidelines for the management of Graves orbitopathy (Eur Thyroid J 2016
Mar;5(1):9 full-text)
serial exophthalmometry can monitor changes over time (N Engl J Med 2008 Jun 12;358(24):2594,
commentary can be found in N Engl J Med 2008 Sep 25;359(13):1408)
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Graves disease in adults.
Neck
check thyroid size, tenderness, symmetry, and nodularity(2)

check for goiter, diffuse thyroid enlargement and thyroid bruit(1, 3, 4)
look for neck fullness(1)
Chest
check for tachypnea(2)

look for gynecomastia(4)
Cardiac
check for signs of(1, 4)

tachycardia
atrial fibrillation
heart failure
palpitations
cardiovascular signs more common in elderly patients who may not present with usual signs of Graves
disease(1, 4)
atrial fibrillation (> 10% prevalence reported in patients > 60 years old)
signs of heart failure (less common)
Abdomen
hepatomegaly may be seen in thyroid storm (J Intensive Care Med 2015 Mar;30(3):131)
Extremities
check for(1, 3, 4)
palmar erythema
onycholysis (Plummer's nails - loosening of the nail bed)
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thyroid acropachy (clubbing of fingers and toes)

assess for localized dermopathy frequently localizes to pretibial region
Neuro
look for fine tremor, hyperkinesis, and hyperreflexia(1, 2, 3)

delirium, confusion to stupor, obtundation, or coma may be indicative of thyroid storm (J Intensive Care
Med 2015 Mar;30(3):131)
Diagnosis
Making the diagnosis
diagnosis of Graves disease is based on characteristic clinical features and biochemical abnormalities(1)
initial testing in patients presenting with signs and symptoms suggestive of Graves disease is thyroid
function testing which includes serum thyroid stimulating hormone assay and thyroid hormone assays
(free thyroxine [FT4] and total or free tri-iodothyronine [TT3 or FT3] should be performed)(2)
if patient has symmetrically enlarged thyroid, recent development of orbitopathy, and moderate to
severe hyperthyroidism, Graves disease is likely and further evaluation for cause of hyperthyroidism
is unnecessary
if patient is thyrotoxic with a nonnodular thyroid and no definite orbitopathy, measure either
thyrotropin receptor antibody (TRAb) or radioactive iodine uptake
Graves disease is indicated if TRAb is present and/or radionuclide scan shows homogenous increase
in uptake
if serum TSH is and FT4 levels are within reference range or elevated, then thyrotoxicosis is
essentially ruled out (exceptions are rare TSH-producing pituitary tumors and thyroid
hormone resistance)
if serum TSH is low and either free thyroxine (FT4) or total or free tri-iodothyronine (TT3 or
FT3) is elevated, then patient has hyperthyroidism
if hyperthyroidism is confirmed, check TRAb (or thyroid-stimulating immunoglobulin
[TSI]), and if present, then diagnose Graves disease
if TSH is low and FT4, TT3, and FT3 are all normal, then patient has subclinical
hyperthyroidism
if subclinical hyperthyroidism confirmed, check TRAb (or TSI), and if present, then
patient may have evolving Graves disease
Graves ophthalmopathy is suggested by clinical presentation, assessment of activity and severity of
ophthalmopathy using standardized criteria, and orbital imaging
Differential diagnosis
other causes of thyrotoxicosis(2, 5, 6)

thyrotoxicosis associated with hyperthyroidism (autonomous release of excess thyroid hormone due
constitutive thyroid hormone synthesis and secretion)
toxic multinodular goiter
toxic thyroid adenoma
thyrotropin-induced thyrotoxicosis
trophoblastic tumors
iodine-induced hyperthyroidism
thyrotoxicosis without hyperthyroidism (release of preformed hormones into the circulation) include
silent (painless) thyroiditis which also includes
post-partum thyroiditis (painless thyroiditis in postpartum period)
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typically present within the first year after childbirth

often have a personal or family history of autoimmune thyroid disease
usually have measurable serum concentrations of anti–thyroid peroxidase
antibodies
drug-induced thyrotoxicosis caused by
lithium
interferon alpha
amiodarone
checkpoint inhibitors ( Rev Endocr Metab Disord 2018 Sep 21 early online)
subacute painful thyroiditis
also called De Quervain thyroiditis
likely viral etiology
characterized by fever and thyroid pain
gland is firm-to-hard on palpation
other rare forms of thyroiditis
acute suppurative thyroiditis (bacterial or fungal infection)
radiation thyroiditis
palpation thyroiditis (following manipulation of the thyroid gland during surgery)
exposure to extrathyroidal sources of thyroid hormone
exogenous thyrotoxicosis, which develops after ingestion of excessive amounts of thyroid
hormone
ectopic hyperthyroidism (extremely rare) including
functional thyroid cancer metastases
struma ovarii (ovarian tumour that contains functioning thyroid tissue)
secondary to elevated human chorionic gonadotropin (hCG) levels
gestational transient thyrotoxicosis
multiple gestation
hydatidiform mole
choriocarcinoma
see also Hyperthyroidism and other causes of thyrotoxicosis
Test Patterns in Patients with Hyperthyroidism and Low TSH:
24-hour
Radioiodine Other Studies or
Disease T4 T3
Uptake/Thyroid Factors
Scan
High TSI or
Elevated uptake and thyrotropin
High (usually T3 > homogeneous receptor
Graves disease High
T4) symmetric antibodies
distribution CFD shows
increased flow
Serum thyroid
peroxidase
Painless thyroiditis antibodies
(silent thyroiditis, usually
High High Low uptake
postpartum positive
thyroiditis) CFD shows
reduced/absent
flow
Painful subacute High High Low uptake Thyroid-
thyroiditis related
antibodies
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usually
negative
CFD shows
reduced/absent
flow
Exogenous Usually high
May be elevated in Serum thyroglobulin
ingestion of thyroid (depends on Low uptake
some preparations very low or absent
hormone preparation)
Increased uptake Thyroid-related
Toxic multinodular Low, normal, or
High and patchy antibodies usually
goiter high
distribution negative
Increased uptake in
Solitary Thyroid-related
Low, normal, or focal nodule,
hyperfunctioning High antibodies usually
high suppression within
nodule negative
surrounding gland
Variable uptake
Occurs in
depending on dose,
Iodine-induced Low, normal, or multinodular goiter
High form of iodine, and
hyperthyroidism high or in iodine deficient
underlying thyroid
areas
disease
Thyrotropin receptor
Drug-induced Maybe high Very low uptake (or
High antibodies
thyroiditis (variable) no uptake)
undetectable
Thyrotropin
receptor
antibodies
Increased uptake
Struma ovarii High High undetectable
over pelvis
CFD shows
reduced or
absent flow
Molar pregnancy High levels of hCG
and High High Increased uptake with thyroid
choriocarcinoma stimulating actions
Abbreviations: CFD, color flow doppler; hCG, human chorionic gonadotrophin;
TSH, thyroid-stimulating hormone; TSI, thyroid-stimulating immunoglobulin;
T3, tri-iodothyronine; T4, thyroxine.
References - (3, 4), N Engl J Med 2008 Jun 12;358(24):2594.

other causes of low TSH(2)
nonthyroidal illness syndrome (especially if noted in hospitalized patient)
dopamine and glucocorticoid use ( Arq Bras Endocrinol Metabol 2013 Apr;57(3):193, full-text)
pituitary/hypothalamic disease
early pregnancy (first trimester) ( Nat Rev Endocrinol 2012 Nov;8(11):650) (see Normal thyroid
function in pregnancy section of Thyroid disease in pregnancy for additional information)
causes of euthyroid hyperthyroxinemia (elevated total serum thyroxine [T4] concentrations in the absence
of hyperthyroidism)(2)
elevations in T4 binding globulin or transthyretin, which may occur as hereditary X-linked trait or
with
pregnancy
estrogen administration
21/83
hepatitis
acute intermittent porphyria
during treatment with 5-fluorouracil, perphenazine, or some narcotics
presence of an abnormal albumin which binds T4 with high capacity (familial dysalbuminemic
hyperthyroxinemia)
presence of abnormal transthyretin
immunoglobulins that directly bind T4 or tri-iodothyronine (T3) (rare)
acute psychosis
extreme high altitude
amphetamine abuse
conditions that mimic clinical manifestations of Graves ophthalmopathy(1)
symptoms similar to those found in Graves ophthalmopathy may be found in
acute processes such as
myositis
orbital cellulitis - usually presents with pain, fever, and fatigue.
scleritis
idiopathic orbital inflammatory disease - usually unilateral and presents with pain as the main
differentiating symptom from Graves ophthalmopathy
diplopia and strabismus may be seen in myasthenia gravis and superior oblique palsy
proptosis may occur in patients with
patients with orbital neoplasms (rarely bilateral, with the exception of lymphoma)
carotid cavernous fistulas
arteriovenous malformation
orbital varix ( J Neurosurg 1999 Dec;91(6):1034)
Reference - Aesthetic Plast Surg 2012 Jun;36(3):638
Testing overview
if thyrotoxicosis is suspected, initial biochemical evaluation (thyroid function tests) should be performed,
which includes serum thyroid stimulating hormone (TSH) assay and thyroid hormone assays (free
thyroxine [FT4] and total or free tri-iodothyronine [TT3 or FT3])
if diagnosis is uncertain based on clinical presentation and initial biochemical evaluation, perform other
diagnostic tests, which may include thyrotropin receptor antibody (TRAb) measurement, radioactive
iodine uptake and/or scan, or thyroid ultrasound (ATA Strong recommendation, Moderate-quality
evidence)
interpretation results of thyroid function tests in patients suspected with Graves disease
essentially ruled out (exceptions are rare TSH-producing pituitary tumors and thyroid hormone
resistance)
if serum TSH is low and either free thyroxine (FT4) or total or free tri-iodothyronine (TT3 or FT3)
is elevated, then patient has hyperthyroidism
if hyperthyroidism is confirmed, check TRAb (or thyroid-stimulating immunoglobulin [TSI],
and if present, then diagnose Graves disease
if TSH is low and FT4, TT3, and FT3 are all normal, then patient has subclinical hyperthyroidism
if subclinical hyperthyroidism confirmed, check TRAb (or TSI), and if present, then patient
may have evolving Graves disease
other tests to consider in patients with or suspected of having Graves disease include
thyroid ultrasound to determine thyroid size and to detect thyroid nodules that may not be palpable
during physical exam
color flow Doppler ultrasound to determine thyroidal blood flow (increased in Graves disease) and
may be useful in patients who are contraindicated for radioactive iodine uptake and/or scan, such as
women who are pregnant or breastfeeding
electrocardiography (ECG) to detect atrial fibrillation in patients with irregular heart rhythm
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fine-needle aspiration for evaluation of thyroid nodules for malignancy if nodule is > 1-1.5 cm and
nonfunctioning or hypofunctioning as detected by thyroid scintigraphy
testing for Graves ophthalmopathy
assessment of activity and severity of Graves ophthalmopathy using standardized criteria
(EUGOGO Strong recommendation, Low-quality evidence)
consider orbital imaging when cause of ocular manifestations remain unknown or if there is
significant asymmetry
in pregnant women(6)
if serum TSH level is low (less than reference range) during first trimester (ATA Strong
recommendation, Moderate-quality evidence)
evaluate medical history, perform physical exam, and measure maternal serum FT4 (with
results normalized by weeks gestation), or TT4
measure maternal TRAb and TT3 to help identify etiology of thyrotoxicosis
do not perform radioactive iodine uptake and/or scan (ATA Strong recommendation, High-quality
evidence)
Blood tests
Thyroid function tests
General considerations
reliable interpretation of thyroid function tests requires an intact hypothalamic-pituitary-thyroid axis ( Clin
Med Res 2016 Jun;14(2):83, full-text)
serum thyroid stimulating hormone (TSH) measurement(2, 4)
reported to have highest sensitivity and specificity of any single blood test used in the evaluation of
suspected thyrotoxicosis and should be used as an initial screening test
diagnostic accuracy may be improved (versus TSH measurement alone) by combining TSH
measurement with free thyroxine (FT4) and total or free tri-iodothyronine (TT3 or FT3) level
measurements at initial evaluation
interpretation results of thyroid function tests in patients suspected with Graves disease(1, 2)
essentially ruled out (exceptions are rare TSH-producing pituitary tumors and thyroid hormone
resistance)
if serum TSH is low and either free thyroxine (FT4) or total or free tri-iodothyronine (TT3 or FT3)
is elevated, then patient has hyperthyroidism
if hyperthyroidism is confirmed, check thyrotropin receptor antibodies (TRAb) (or thyroid-
stimulating immunoglobulin [TSI]), and if present, then diagnose Graves disease
if TSH is low and FT4, TT3, and FT3 are all normal, then patient has subclinical hyperthyroidism
if subclinical hyperthyroidism confirmed, check TRAb (or TSI), and if present, then patient
may have evolving Graves disease
thyroid function tests in pregnant women(2, 6)
increase in renal iodine excretion, increase in thyroxine binding proteins and thyroid hormone
production during pregnancy can influence outcomes of thyroid function tests
to diagnose hyperthyroidism, evaluate serum TSH levels and 1 of (ATA Strong recommendation,
Low-quality evidence)
serum TT4 and TT3 with reference ranges for both increased to 1.5 times above
nonpregnancy range by the second and third trimester
FT4 and TT3 estimation using trimester-specific normal reference ranges
see Hyperthyroidism in pregnancy section of Thyroid disease in pregnancy topic for additional
information
23/83
Thyroid stimulating hormone (TSH) assay
serum TSH testing(2)

serum TSH reported to have highest sensitivity and specificity of any single blood test for
hyperthyroidism and should be used as initial diagnostic test for suspected thyrotoxicosis
normal range of serum TSH is 0.3-4.2 milliunits/L (Mayo Clinic TSH accessed 2018 Sep 20)
serum TSH level during pregnancy(2, 6)
serum TSH level is lower than before pregnancy; compared to nonpregnant range, reference serum
TSH level reported to be reduced by about 0.1-0.2 milliunits/L at the lower limit and by about 0.5-1
milliunits/L at the upper limit of normal range
TSH level below lower limit of 0.4 milliunits/L reported in about 15% of healthy women during
first trimester, 10% in second trimester, and 5% in third trimester
use population-based trimester-specific reference ranges for serum TSH as defined by evaluation of
local population data that is representative of the area, if available (ATA Strong recommendation,
Moderate-quality evidence)
information
Thyroid hormone assays
free serum thyroxine (FT4) and tri-iodothyroxine (T3) measurements(2, 4, 6)

FT4 and free T3 (FT3) measurements considered gold standard for detection of thyrotoxicosis
because total T4 (TT4) and T3 (TT3) measurements are influenced by various conditions that affect
the serum thyroxine-binding protein activity/levels
assays for FT3 are less well validated compared to FT4 measurements; therefore, TT3 is often
measured in clinical practice
free thyroid hormone levels can be measured by immunoassay or by direct measurements (such as
equilibrium dialysis, ultrafiltration, or liquid chromatography/tandem mass spectrometry)
in pregnancy, calculate FT4 index or measure TT4 (using pregnancy-adjusted range as
reference)
normal reference range for
FT4 using electrochemiluminescence immunoassay is 0.9-1.7 ng/dL (11.6-21.9 pmol/L)
(Mayo Clinic FT4 immunoassay accessed 2018 Sep 20)
FT4 using equilibrium dialysis 0.8-2 ng/dL (10.3-25.7 pmol/L) (Mayo Clinic FT4 dialysis
accessed 2018 Sep 20)
TT4 is 4.5-11.7 mcg/dL (58-151 nmol/L) (Mayo Clinic TT4 accessed 2018 Sep 20)
FT3 is 2.8-4.4 pg/mL (4.3-6.8 pmol/L) (Mayo Clinic FT3 accessed 2018 Sep 20 )
TT3 is 80-200 ng/dL (1.2-3.1 nmol/L) (Mayo Clinic TT3 accessed 2018 Sep 20)
measuring total T3 to total T4 ratio(2)
may be useful for distinguishing thyrotoxicosis due to hyperthyroidism if scintigraphy is
contraindicated
hyperactive thyroid gland generates more TT3 than TT4
TT3 will be elevated above upper limit of normal more than TT4 in thyrotoxicosis caused by
hyperthyroidism (ratio > 20 reported in Graves disease)
TT4 will be elevated above upper limit of normal more than TT3 in thyrotoxicosis caused by
thyroiditis (ratio < 20 reported in postpartum thyroiditis)
serum T4 and T3 levels in pregnant women(2, 6)
increase in renal iodine excretion, increase in thyroxine binding proteins and thyroid hormone
production during pregnancy can influence outcomes of thyroid function tests
FT4 and FT3 levels
FT4 and FT3 levels around week 10 of pregnancy may be about 5%-10% higher than
nonpregnancy reference values (in equilibrium dialysate or ultrafiltrate of serum)
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FT4 and FT3 levels decrease gradually over the course of pregnancy resulting in about
10%-30% lower values compared to nonpregnancy reference values
rather than measuring FT4 levels, accurate estimation of serum T4 concentration can be
determined by 1 of the following (ATA Strong recommendation, Moderate-quality evidence)
obtaining FT4 index
measuring TT4 levels (using pregnancy-adjusted range as reference)
measurements using automated immunoassays are particularly affected; direct measurement
(such as equilibrium dialysis, ultrafiltration, or liquid chromatography/tandem mass
spectrometry) of FT4 is less affected, but these assays may not be as widely available
since accuracy of FT4 measurements in pregnant women vary by assays used, use assay
method-specific and trimester-specific pregnancy reference values for interpretation of results
(ATA Strong recommendation, Moderate-quality evidence)
TT4 and TT3 levels
serum TT4 and TT3 levels increase during pregnancy at rate of about 5% of nonpregnant
values per week over 10 weeks as a result of increase in thyroxine binding proteins
after first 10 weeks, TT4 and TT3 levels remain stable at about 1.5 times higher levels
compared to nonpregnancy range during the remainder of pregnancy
if TT4 and TT3 levels are measured, the results can be evaluated together with T3 uptake test
or measurements of thyroxine binding proteins to adjust for variations due to pregnancy (FT4
index)
trimester-specific normal range should be determined for each test used
information
other than thyroid dysfunction, serum T4 and T3 levels may be altered by
inherited or acquired conditions that influence plasma proteins such as thyroxine-binding proteins
intake of medications such as salicylates, phenytoin, carbamazepine, furosemide, and exogenous
estrogens
Reference - Arq Bras Endocrinol Metabol 2013 Apr;57(3):193 full-text
Assay for thyroid antibodies
thyrotropin receptor antibodies (TRAb)(1, 2, 3, 4)

also called thyroid stimulating hormone (TSH) binding inhibiting immunoglobulins (TBII), thyroid-
stimulating immunoglobulins (TSI), and TSH receptor antibodies (TSH-RAb)
indications for TRAb measurement
measure TRAb levels in patients with uncertain etiology of thyrotoxicosis based on clinical
presentation and laboratory test results (ATA Strong recommendation, Moderate-quality
evidence)
subclinical hyperthyroidism with diffuse goiter and euthyroid Graves ophthalmopathy
hyperemesis gravidarum with thyrotoxicosis
presence of TRAb
is characteristic of Graves disease and reported to be detectable in ≥ 98% of untreated patients
can help confirm diagnosis of Graves disease, but it is usually unnecessary because other
diagnostic tests (TSH and thyroid hormone assays) and clinical presentation are sufficient for
diagnosis in most patients
can help rule out other thyrotoxicosis conditions
TRAb assays
competitive TSH-binding inhibition assays
original TRAb assay (first generation) used detergent solubilized recombinant 125 I
labeled human or porcine TSH to measure inhibition of TSH binding in a liquid phase
competition assay but reported to have low diagnostic utility
25/83
solid-phase TRAb assay (second generation assay) uses fluorescent readouts instead of
radioactive readouts
third generation assay uses human monoclonal antibody against TRAb in place of
recombinant TSH for competition assays
assays distinguishing between activating or blocking properties of antibodies not yet
available but under development
Reference - Clin Endocrinol (Oxf) 2017 May;86(5):652
second and third generation immunoassays for TRAbs may have high sensitivity
and specificity to diagnose or rule out Graves disease (level 2 [mid-level] evidence)
based on systematic review of diagnostic case-control studies
systematic review of 21 studies with 3,081 patients with untreated Graves disease
and 3,795 controls (healthy or with other diseases) evaluating diagnostic
performance of second and third generation immunoassays from TRAb for
diagnosis of Graves disease
reference standard was clinical diagnosis of Graves disease
performance of second and third generation assays better than first generation
assays
pooled diagnostic performance of second generation TRAb assays for diagnosis
of Graves disease in analysis of 17 studies with 1,451 patients and 1,819 controls
sensitivity 97.1%
specificity 98.3%
pooled diagnostic performance of third generation TRAb assays for diagnosis of
Graves disease in analysis of 12 studies with 1,630 patients and 1,976 controls
sensitivity 97.4%
specificity 99.2%
Reference - Autoimmun Rev 2012 Dec;12(2):107
thyroid-stimulating immunoglobulin (TSI) can measure stimulating TRAb using cAMP
production in cells incubated with patient serum ( Ann Lab Med 2019 Jan;39(1):3)
TRAb measurements in pregnancy(2, 6)
measure TRAb levels in women with uncertain etiology of hyperthyroidism (ATA Strong
recommendation, Low-quality evidence)
in women developing thyrotoxicosis after delivery, measure TRAb levels to distinguish
between diagnosis of postpartum thyroiditis and Graves disease (ATA Strong
indications for performing TRAb measurement in pregnant women with Graves disease
include
previous history of Graves disease with past treatment with ablation therapy
(radioactive iodine or total thyroidectomy); recommended at initial thyroid function test
during early pregnancy (ATA Strong recommendation, Moderate-quality evidence)
treatment with antithyroid medications for Graves hyperthyroidism when pregnancy is
confirmed (ATA Weak recommendation, Moderate-quality evidence)
untreated hyperthyroidism in pregnancy
history of previous delivery of infant with hyperthyroidism
known history of thyroidectomy for treatment of hyperthyroidism in pregnancy
TRAb measurement is also used to monitor Graves disease during pregnancy
see Hyperthyroidism in pregnancy section of Thyroid disease in pregnancy topic for
additional information
serum antithyroid peroxidase and anti-thyroglobulin antibodies detectable in majority of patients with
Graves disease but not useful for diagnosis(4)
Imaging studies
Thyroid scintigraphy
26/83
radioactive iodine/technetium uptake and scanning(2, 3, 4, 6)

if etiology of thyrotoxicosis is not clear from clinical presentation and initial biochemical
evaluation, consider radioactive iodine uptake; perform iodine 123 (123I) or 99mTc-pertechnetate
scan if clinical presentation suggests toxic adenoma or toxic multinodular goiter (ATA Strong
do not perform radioactive iodine scanning or uptake determination during pregnancy (ATA Strong
recommendation, High-quality evidence); color flow Doppler ultrasound may be considered instead
radioactive iodine/technetium uptake
measures percentage of radioactive iodine/technetium uptake by thyroid after fixed amount of
time (usually 24 hours for radioactive iodine, 20 minutes for technetium)
can help distinguish Graves disease from other etiologies in patients with thyrotoxicosis with
non-nodular thyroid and lack of obvious orbitopathy
radioactive iodine uptake
normal values for radioactive iodine uptake 24 hours after administration of radioactive
iodine
20% in iodine sufficient geographic areas
40% in iodine deficient geographic areas
uptake is typically elevated in patients with Graves disease due to activities of the
activating thyrotropin receptor antibodies
normal to high uptake in patients with toxic nodular goiter unless recently exposed to
iodine
little to no uptake in patients with painless, postpartum, or subacute thyroiditis,
factitious ingestion of thyroid hormone, or recent excess in iodine intake
radioactive iodine/technetium scanning
provides planar image of thyroid gland which allows for assessment of variability in
radioisotope uptake within thyroid tissue
scans may be obtained at the same time as radioisotope uptake evaluation with either 123I or
technetium to determine etiology of hyperthyroidism if thyroid nodules are present
technetium scan results in less total body radiation exposure compared to radioactive iodine
scan, but can result in low range of normal uptake and high background activity
pattern of uptake
Graves disease - diffuse unless nodules or fibrosis are also present
single toxic adenoma - focal uptake in adenoma with reduced uptake in surrounding
and contralateral thyroid tissue
toxic multinodular goiter - multiple areas of increased or decreased uptake; if autonomy
is extensive, distinguishing Graves disease may be difficult
in cohort of 325 patients with Graves disease, 39 patients had cold defects ( ≥ 1 discrete, well-
circumscribed photopenic areas) on thyroid scanning; papillary thyroid cancer seen in 6
patients (15.3%) with cold defect, corresponding to 1.9% of all patients with Graves disease (
Thyroid 2002 Apr;12(4):305)
thyroid nodules > 1-1.5 cm and nonfunctioning or hypofunctioning as detected by thyroid
scanning should be evaluated for malignancy by fine-needle aspiration based on ultrasound
characteristics and suspicion for malignancy(2)
in breastfeeding women (ATA Strong recommendation, Moderate-quality evidence)
if 123I (half-life 13 hours) is used, pump and discard breast milk for 3-4 days before resuming
breast feeing
if 99mTc-pertechnetate (half-life 6 hours) is used, pump and discard breast milk during day of
testing
see Thyroid nodule for additional information
Thyroid ultrasound
27/83
thyroid ultrasound(2, 4, 6)
not usually needed in diagnosis of Graves disease
very sensitive and reliable diagnostic tool that may give accurate estimation of thyroid size and
detect thyroid nodules that may not be palpable at physical examination
thyroid pattern is usually hypoechoic in Graves disease due to reduced colloid content, increase in
vascularity, and lymphocytic infiltration
may help in determining etiology of thyrotoxicosis during pregnancy when thyrotropin receptor
antibody measurements are negative or if thyroid nodules are suspected on clinical exam
exclude malignancy using ultrasound-guided fine-needle aspiration if characteristics of thyroid
nodule are suspicious on ultrasound or scintigraphy, for example if nodule is > 1-1.5 cm or if
nonfunctioning or hypofunctioning
thyroid cancer may be more commonly detected in patients with Graves disease with solitary,
homogenous, calcified, or vascular thyroid nodules
423 adults with Graves disease scheduled for surgical treatment had thyroid ultrasound and
were assessed for thyroid cancer based on pathological findings prior to surgery
96 patients (22.7%) had thyroid nodules detected by ultrasound
58 patients (13.7%) had thyroid cancer; thyroid nodule was not detected in 12 patients with
thyroid cancer
thyroid cancer in 56% with solitary nodules vs. 45% with multiple nodules vs. 3.6% without
nodules (p < 0.001)
comparing malignant nodules vs. benign nodules
homogenous nodules in 30.4% vs. 10% (p= 0.012)
no calcification in 69.6% vs. 94% (p = 0.002)
no blood flow in 28.3% vs. 58% (p = 0.049)
Reference - World J Surg 2014 Jan;38(1):80
color flow Doppler ultrasound(2, 3, 4)
if etiology of thyrotoxicosis is not clear from clinical presentation and initial biochemical
evaluation, consider thyroidal blood flow on ultrasound
measures peak systolic velocity from intrathyroidal arteries or inferior thyroidal artery and helps
distinguish thyroid hyperactivity (indicated by increased flow) from destructive thyroiditis
sensitivity and specificity is reported to be lower compared to thyroid scintigraphy evaluation but
helpful for patients who are contraindicated for thyroid scintigraphy, such as women who are
pregnant or breastfeeding
expected results
shows increased blood flow with Graves disease
shows low blood flow in painless and subacute thyroiditis, destructive thyroiditis, factitious
thyrotoxicosis and type II amiodarone-induced thyrotoxicosis
may help differentiate between postpartum thyroiditis (low blood flow) and Graves disease
(increased blood flow) in women with postpartum thyrotoxicosis
inferior thyroid artery peak systolic and end-diastolic velocities on color Doppler ultrasound
appear to discriminate Graves disease from silent thyroiditis (level 2 [mid-level] evidence)
based on diagnostic cohort study without independent validation
229 patients with thyrotoxicosis were evaluated using inferior thyroid artery (ITA) peak
systolic and end-diastolic velocities on color Doppler ultrasound
150 patients (65.5%) diagnosed with Graves disease and 79 with silent thyroiditis by physical
exam, results of thyroid-stimulating hormone (TSH) receptor antibody and Tc-99m
pertechnetate uptake, and follow-up (reference standard)
mean ITA peak systolic and end-diastolic velocities were significantly higher in patients with
Graves disease compared to patients with silent thyroiditis
performance of color Doppler ultrasound for discriminating Graves disease from silent
thyroiditis
ITA peak systolic velocity with cutoff 30 cm/second had
sensitivity 95.3%
28/83
specificity 94.9%
positive predictive value 97.3%
negative predictive value 91.5%
ITA end-diastolic velocity with cutoff 13.2 cm/second had
sensitivity 89.3%
specificity 88.6%
positive predictive value 93.7%
negative predictive value 81.4%
diagnostic accuracy of color Doppler ultrasound was similar to accuracy of TSH receptor
antibody with cutoff 1 unit/L and Tc-99m pertechnetate uptake with cutoff 3%
Reference - Endocr Pract 2014 Apr 1;20(4):310
Orbital imaging
orbital imaging(1)
may be needed in patients with unknown cause of ocular manifestations
helps distinguish extraocular muscle enlargement from fat expansion
may be useful in patients with asymmetrical proptosis to rule out orbital tumor or arteriovenous
malformation
imaging techniques may include computed tomography (CT), magnetic resonance imaging (MRI),
ultrasound, scintigraphy with radiolabeled octreotide, gallium scanning, and thermal imaging
thermal imaging of eyes may help diagnose active thyroid eye disease (level 2 [mid-level] evidence)
based on diagnostic case-control study
17 patients (median age 51 years) with active thyroid eye disease and 13 controls (median age 57
years) with inactive thyroid eye disease as measured by clinical activity score during standard
ophthalmological clinical assessments were evaluated by thermal imaging
5 novel eye parameters developed to quantify thermal characteristics of eyes including
highest level of inflammation
overall level of inflammation
right and left asymmetry in level of inflammation
maximum temperature variability across eyes
right and left asymmetry in temperature variability
for detection of active thyroid eye disease, binary logistic model using combination of all 5
parameters with cutoff of 0.57 for predicted probability of having active eye disease had
94% sensitivity
92% specificity
Reference - J Clin Endocrinol Metab 2014 Dec;99(12):4600
Other imaging studies
neck magnetic resonance imaging (MRI) or computed tomography (CT) (without contrast) imaging may
be indicated in patient with signs and symptoms of upper airway obstruction or difficulty swallowing ( N
Engl J Med 2008 Jun 12;358(24):2594, commentary can be found in N Engl J Med 2008 Sep
25;359(13):1408)
Electrocardiography (ECG)
indicated in patients with irregular heart rhythm to determine if atrial fibrillation is present ( N Engl J Med
2008 Jun 12;358(24):2594, commentary can be found in N Engl J Med 2008 Sep 25;359(13):1408)
electrocardiographic (ECG) findings of thyrotoxicosis

most common findings
sinus tachycardia
29/83
increased QRS voltages

atrial fibrillation
other findings
supraventricular arrhythmias
premature atrial beats
paroxysmal supraventricular tachycardia
multifocal atrial tachycardia
atrial flutter
ventricular extrasystoles
nonspecific ST- and T-wave changes
Reference - BMJ 2002 Jun 1;324(7349):1320 full-text, correction can be found in BMJ 2002 Aug
3;325(7358):259, BMJ 2007 May 26;334(7603):1118
Biopsy and pathology

evaluate and manage thyroid nodules in Graves disease according to recommendations for thyroid nodules
in euthyroid individuals (ATA Strong recommendation, Moderate-quality evidence)(2)
exclude malignancy using ultrasound-guided fine-needle aspiration if characteristics of thyroid nodule are
suspicious on thyroid ultrasound or scintigraphy, for example if nodule is > 1-1.5 cm or if nonfunctioning
or hypofunctioning; if cytology is suspicious or indeterminate or malignancy is confirmed, surgery is
advised after normalization of thyroid function(2)
microscopic evaluation of thyroid tissue in Graves disease may show
cellular with minimal colloid, few lymphocytes, and few oncocytic cells
rarely follicular cells with focal nuclear chromatin clearing and intranuclear grooves
Reference - Best Pract Res Clin Endocrinol Metab 2008 Dec;22(6):929
see also Thyroid nodule
Management
Management overview
treatment for Graves disease should take into consideration(4)

age of patient
severity of hyperthyroidism
goiter size
presence and severity of ophthalmopathy
patient preferences
for patients with symptomatic thyrotoxicosis, especially elderly patients and thyrotoxic patients with
resting heart beat > 90 beats/minute or concurrent cardiovascular disease, offer beta-blockers as part of
initial management until thyroid hormone levels are normalized (ATA Strong recommendation, Moderate-
quality evidence)
treatment of hyperthyroidism
treat patients with Graves hyperthyroidism with 1 of the following (ATA Strong recommendation,
antithyroid medications to normalize thyroid hormone production
if antithyroid medications are chosen as initial treatment, administer methimazole
(MMI) in all patients except (ATA Strong recommendation, Moderate-quality evidence)
women during first trimester of pregnancy (when propylthiouracil (PTU) is
preferred)
patients with thyroid storm
patients with minor reactions to MMI who refuse radioactive iodine therapy or
surgery
30/83
free serum thyroxine (FT4) and total tri-iodothyronine (TT3) should be evaluated about
2-6 weeks after initiation of therapy; dosing should be adjusted accordingly
after achieving euthyroidism with minimal dose medication, clinical and biochemical
evaluation can be performed every 2-3 months; if on long-term methimazole treatment
(> 18 months), evaluation can be performed every 6 months
continue MMI for about 12-18 months, then taper or discontinue if thyroid-stimulating
hormone (TSH) and thyrotropin receptor antibody (TRAb) levels are normal (ATA
Strong recommendation, High-quality evidence)
if patient not in remission consider continued low-dose MMI treatment for > 12-18
months (and if this option is preferred by patient) (ATA Weak recommendation, Low-
quality evidence)
if patient becomes hyperthyroid after completing MMI treatment, consider treatment
with radioactive iodine or thyroidectomy (ATA Weak recommendation, Low-quality
evidence)
some patients may require life-long treatment with antithyroid medication
radioactive iodine therapy for destruction of thyroid
prior to radioactive iodine administration, in patients who are at increased risk for
complications due to worsening hyperthyroidism (such as elderly patients and patients
with coexisting conditions)
for women with childbearing potential obtain pregnancy test within 48 hours
prior to radioactive iodine treatment and confirm negative result prior to
administering radioactive iodine (ATA Strong recommendation, Low-quality
evidence)
in patients who are at increased risk for complications due to worsening
hyperthyroidism (such as elderly patients and patients with coexisting
conditions), consider pretreatment with beta-blocker (ATA Weak
recommendation, Low-quality evidence) and methimazole (ATA Weak
recommendation, Moderate-quality evidence); the latter should be discontinued
2–3 days prior to RAI administration and may be resumed 3-7 days afterwards
(ATA Weak recommendation, Low-quality evidence)
administer enough radiation in single dose (typically mean dose of 10-15 mCi) to
render patient hypothyroid (ATA Strong recommendation, Moderate-quality evidence)
perform follow-up evaluation which includes (ATA Strong recommendation, Low-
quality evidence)
free thyroxine (FT4), total tri-iodothyronine (TT3), and thyroid stimulating
hormone (TSH) levels at 1-2 months after radioactive iodine therapy (thyroid
function tests)
continued biochemical minoring at 4-6 week intervals for 6 months or until
patient is hypothyroid and stable on thyroid hormone replacement
when patients develop hypothyroidism (FT4 level below normal range), levothyroxine
should be administered; dose should be adjusted based on FT4 level, taking into
consideration residual thyroid function (may require lower dosage than full
replacement)
thyroidectomy to remove the thyroid
if surgery is chosen as the primary therapy for Graves disease near-total or total
thyroidectomy is procedure of choice (ATA Strong recommendation, Moderate-quality
evidence); definitive therapy may be accomplished with near-total thyroidectomy
preoperative considerations to help prevent complications of thyroidectomy
because stress of impending surgery or thyroid manipulation may potentially lead
to development of thyroid storm, render patients euthyroid with antithyroid
medication with or without beta-blockers (ATA Strong recommendation, Low-
quality evidence)
administer potassium iodide formulation in immediate preoperative period (ATA
Strong recommendation, Low-quality evidence); may reduce blood loss
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assess calcium and 25-hydroxyvitamin D levels preoperatively and replete or

administer prophylactically if needed (ATA Strong recommendation, Low-quality
evidence)
provide calcitriol supplementation preoperatively in patients at increased risk for
transient or permanent hypoparathyroidism (ATA Strong recommendation, Low-
quality evidence)
postoperative follow-up
consider administration of oral calcium and calcitriol supplementation based on
results of serum calcium measurement with or without intact parathyroid
hormone (iPTH) levels or empiric prophylactic administration of oral calcium
with or without calcitriol (ATA Weak recommendation, Low-quality evidence);
calcium levels can be assessed using slope of 6- and 12-hour postoperative
calcium levels
start levothyroxine at daily dose appropriate for patient's weight (0.8 mcg/lb or
1.6 mcg/kg), with somewhat less for elderly patients, and measure serum thyroid
stimulating hormone (TSH) 6-8 weeks postoperatively (ATA Strong
recommendation, Low-quality evidence); once TSH level is normal, TSH level
should be measured annually or more frequently if required
smoking cessation 2)(1,
advise patients with Graves disease to stop smoking and refer them to structured smoking
cessation program; identify patients exposed to secondhand smoke and advise of negative
impact (increased risk of GO) (ATA Strong recommendation, Moderate-quality evidence)
urge smoking cessation in patients with or without GO (EUGOGO Strong recommendation,
efficacy of treatment is reported to be reduced in patients who smoke or formerly smoked;
smoking cessation should be emphasize
factors to consider when choosing treatment modality
Preferred Treatment Options According to Clinical Setting:
Radioactive Iodine
Clinical Setting ATDs Thyroidectomy
Therapy
Preferred; use with Acceptable; use with
Pregnancy Contraindicated
caution caution
Comorbidities
(increased surgical risk
Acceptable Preferred Contraindicated
and/or limited life
expectancy)
Inactive GO Acceptable Acceptable Acceptable
Depends on disease
Active GO Preferred severity, activity and Preferred
risk of GO progression
Liver disease Use with caution Preferred Acceptable
Major adverse reactions
Contraindicated Preferred Acceptable
to ATDs
Previously operated or
externally irradiated Acceptable Preferred Perform with caution
necks
Lack of access to high-
Acceptable Preferred Perform with caution
volume thyroid surgeon
High likelihood of Preferred Acceptable Acceptable
remission (for example,
women mild disease,
small goiters, and
32/83
negative/low-titer
TRAb)
Periodic paralysis Acceptable Preferred Preferred
Right pulmonary
hypertension or heart Acceptable Preferred Perform with caution
failure
Elderly with
Acceptable Acceptable Perform with caution
comorbidities
Not first-line therapy;
Confirmed/suspected
use depends on clinical Contraindicated Preferred
thyroid malignancy
situation
Not first-line therapy;
≥ 1 large thyroid
Acceptable use depends on clinical Preferred
nodules
situation
Coexisting Not first-line therapy; Not first-line therapy;
hyperparathyroidism use depends on clinical use depends on clinical Preferred
requiring surgery situation situation
Abbreviations: ATD, antithyroid medications; GO, Graves ophthalmopathy; TRAb, thyrotropin
receptor antibody. Reference - (2).
Comparison of Treatment Options for Graves Hyperthyroidism:
Treatment Advantages Disadvantages Precautions
Easily
discontinued or Contraindicated if
High rate of recurrence history of major
modified
(reported in 20%-30%
Treatment easy to adverse reactions
over 3-5 years follow-
administer antithyroid
up)
Low risk of medications
Frequent testing Use of antithyroid
hypothyroidism
required therapy should be
No exposure to
Major side effects reconsidered if
Antithyroid radiation or risk
(reported in about
medications of surgery baseline absolute
0.2%-0.3%) such as
Euthyroid state neutrophil count is
agranulocytosis,
achieved within < 1 × 109 /L or
hepatotoxicity, and
1-2 months baseline liver
antineutrophil
Often induces transaminase level
cytoplasmic antibody-
gradual remission is > 5 times above
associated vasculitis
of autoimmunity upper limit of
Drug interactions
(decreasing normal
antibody titers)
Radioactive Easy oral Potential of radiation Pregnant women
iodine therapy administration hazards or women
Usually curative - Need for adherence to planning to
about 85% of local radiation become pregnant
patients are regulation in next 4-6 months
euthyroid or Radiation thyroiditis and women who
hypothyroid after Decrease in efficacy are breast feeding
single dose with larger goiters should not receive
Few side effects Eventual treatment
Reduces goiter hypothyroidism in Patients with
size effectively most patients requiring coexisting thyroid
lifelong levothyroxine cancer or
treatment suspected thyroid
33/83
Short- term increase of cancer should not

thyroid hormone levels receive treatment
Repeat therapy at times Patients unable to
necessary comply with
Rising antibody titers radiation safety
following treatment guidelines should
may contribute to not receive
worsening orbitopathy treatment
Optimize medical
therapy of any
comorbid
condition prior to
administering
radioactive iodine
Rapid
euthyroidism
Recurrence is Risks associated with
extremely rare anesthesia and surgery
Not suggested if
No exposure to Major complications
significant
radiation reported in 1%-4%
comorbidity (such
Definitive therapy including
as
of hypoparathyroidism,
cardiopulmonary
hyperthyroidism recurrent laryngeal-
disease, end-stage
Rapid resolution nerve damage
cancer, or other
of pressure Perioperative medical
debilitating
Thyroidectomy symptoms management is
disorder)
Stable euthyroid required to minimize
Not suggested if
state easily complications such as
inaccessible to
achieved on hypocalcemia,
high-volume
replacement hyperparathyroidism,
thyroid surgeon
levothyroxine and thyroid storm
Pregnancy is a
therapy Requires lifelong
relative
Post-surgery, treatment with
contraindication
gradual remission levothyroxine starting
of autoimmunity 6-8 weeks after surgery
occurs
Goiter disappears
management of Graves ophthalmopathy (GO)
refer patients with GO to combined thyroid-eye clinics or specialized centers with endocrinological
and ophthalmological expertise, except for mildest cases that may improve upon normalization of
thyroid status and treatment with local lubricants (EUGOGO Strong recommendation, Low-quality
evidence)
urge smoking cessation (EUGOGO Strong recommendation, Moderate-quality evidence)
treatment of hyperthyroidism
restore and maintain euthyroidism (ATA Strong recommendation, Moderate-quality evidence;
EUGOGO Strong recommendation, High-quality evidence)
treatment recommendations depend on severity and activity of GO, risk factors for
progression and smoking status
treatment of ophthalmology
administer oral prednisone prophylaxis, starting dose 0.3-0.5 mg/kg body weight in
radioactive iodine treated patients at high risk of progression or development of GO
(EUGOGO Strong recommendation, High-quality evidence)
treatment for mild GO (EUGOGO Strong recommendation, Moderate-quality evidence)
general measures to control risk factors application of local treatments
34/83
if impact of disease on quality-of-life outweighs risks, consider

immunosuppressive therapy for active GO or rehabilitative surgery for inactive
GO
give selenium supplementation for 6 months to patients with mild GO of
relatively short duration to improve symptoms and prevent progression of GO;
the American Thyroid Association does not take a position on selenium
supplementation
treatment for moderate-to-severe and active GO
high dose glucocorticoids IV is treatment of choice performed in experienced
centers equipped to manage potentially serious adverse events (EUGOGO Strong
recommendation, High-quality evidence)
do not exceed 8 g for total cumulative dose of glucocorticoids (EUGOGO Strong
patients for liver dysfunction, recent viral hepatitis, severe cardiovascular
morbidity, or psychiatric disorders should not receive IV glucocorticoids and
hypertension and diabetes should be well controlled prior to treatment
treatment for sight-threatening GO
manage severe corneal exposure promptly medically or surgically to avoid
corneal breakdown (EUGOGO Strong recommendation, Moderate-quality
evidence)
dysthyroid optic neuropathy (EUGOGO Strong recommendation, Moderate-
quality evidence)
administer high-dose glucocorticoids IV (methylprednisolone 500-1,000
mg for 3 consecutive days or alternate days during first week) and perform
urgent orbital decompression if poor or no response within 2 weeks
if resolved or improved after 2 weeks of methylprednisolone treatment,
continue with treatment as described for patients with moderate-to-severe
and active GO
for recent onset choroidal folds and eyeball subluxation, perform prompt orbital
decompression for (EUGOGO Strong recommendation, Moderate-quality
evidence)
for patients with GO that has significant effects on visual function or quality-of-life and
GO has been inactive ≥ 6 months perform rehabilitative surgery (EUGOGO Strong
additional management considerations may be required for patients with or at risk of developing Graves
ophthalmopathy, thyroid storm, and subclinical hyperthyroidism, and for women who are pregnant or
lactating
Medications
Antithyroid medications (thionamide)
treat patients with Graves hyperthyroidism with antithyroid medications, radioactive iodine therapy, or
thyroidectomy (ATA Strong recommendation, Moderate-quality evidence)(2, 3)
antithyroid drug options include methimazole, propylthiouracil, and carbimazole(1, 2, 3, 4)
antithyroid drugs do not cure Graves disease but(2)
are effective at controlling hyperthyroidism
may have immunosuppressive role by either decreasing thyroid specific autoimmune activity or by
normalization of immune system by improving hyperthyroid state
35/83
failure to achieve euthyroidism is usually due to nonadherence(2)

mechanism of action(1, 3)
antithyroid drugs inhibit thyroid hormone synthesis by interfering with thyroid peroxidase and
iodine incorporation into thyroglobulin
propylthiouracil (PTU) also inhibits conversion of thyroxine (T4) to tri-iodothyronine (T3)
most patients also experience normalization of thyrotropin receptor antibodies (TRAb) levels
antithyroid drugs can be used as(3)
primary treatment (administered for 12-18 months)
pretreatment in some patients before radioactive iodine therapy
pretreatment in most patients before surgery
reported remission (biochemical euthyroidism for ≥ at 12 months after 1 to 2 years of treatment) rate
40%-50%(1)
factors that may favor choosing antithyroid medication as first-choice therapy include(2)
high likelihood of remission (mild disease, small goiters, negative or low-titer TRAb), especially in
women
older age or comorbidities that may increase surgical risk or those with limited life expectancy
residence in nursing home or other care facilities in patients who may have limited life expectancy
and are unable to follow radiation safety protocols
previously operated or irradiated necks
lack of access to high-volume thyroid surgeon
moderate-to-severe active Graves ophthalmopathy
pregnancy
patients in need of rapid biochemical disease control
precautions(2)
antithyroid medication is contraindicated in patients with history of major adverse reactions
antithyroid medications
prior to administering antithyroid therapy, consider testing for baseline complete blood count with
white blood cell count differential and liver profile including bilirubin and transaminases (ATA
Weak recommendation, Low-quality evidence); while there is limited evidence that abnormal white
blood cell count and liver profile increases risk of adverse events, use of antithyroid therapy should
be reconsidered if
baseline absolute neutrophil count is < 1 × 109 /L
baseline liver transaminase level is > 5 times above upper limit of normal
advantages of antithyroid medications include(1, 6)
easily discontinued or modified
treatment easy to administer
low risk of hypothyroidism
no exposure to radiation or risk of surgery
euthyroidism achieved within 1-2 months
often induces gradual remission of autoimmunity (decreasing antibody titers)
disadvantages of antithyroid medications include(1, 3)
high reported rate of recurrence
factors associated with higher rate of recurrence include
previous recurrence of disease
cigarette smoking
ophthalmopathy
large goiter
elevated T4 to T3 ratio
high TRAb titer
continued need for high doses of antithyroid drugs after 12-18 months of treatment
in patients with normalized thyroid stimulating hormone levels after treatment reported
relapse rates 20%-30% over 3-5 years follow up
36/83
frequent testing is required, unless block-replacement therapy is used

minor side effects (reported in ≤ 5%) including rash, urticaria, arthralgia, fever, nausea,
abnormalities of taste and smell
major side effects (reported in 0.2%-0.3%, usually in < 3 months of administration) including
agranulocytosis, hepatotoxicity, cholestatic for thionamides and hepatocellular necrosis for PTU,
antineutrophil cytoplasmic antibody-associated vasculitis
drug interactions
anticoagulants - due to potential antivitamin K activity, prothrombin time/INR should be
monitored, especially before surgery
beta-blockers - may increase clearance of beta-blockers with high extraction ratio; dose
reduction may be needed if patient becomes euthyroid
digitalis glycosides - serum my increase when patients become euthyroid (if on stable digitalis
glycoside regimen); digitalis glycoside dose reduction may be needed
theophylline - theophylline clearance my decrease when patient becomes euthyroid (if on
stable theophylline regimen); theophylline dose reduction may be needed
Reference - FDA DailyMed 2016 Feb 4, MHRA United Kingdom Public Assessment Report PDF,
FDA DailyMed 2018 Mar 2
Antithyroid drugs options and dosing
treat with methimazole (MMI) in all patients who choose antithyroid drug therapy for Graves disease,
with the following exceptions (ATA Strong recommendation, Moderate-quality evidence)(2)
during first trimester of pregnancy (when propylthiouracil (PTU) is preferred)
treatment of thyroid storm
patients with minor reactions to methimazole who refuse radioactive iodine therapy or surgery
initial treatment goal is to achieve euthyroidism; once euthyroidism is achieved, subsequent treatment
options include
titration of antithyroid medication - gradual decrease in dose with the goal of reaching normal free
thyroxine (FT4) level; patient is exposed to lower doses of drug (compared to block-replacement
therapy)
block-replacement therapy - addition of levothyroxine to antithyroid medication, essentially
blocking thyroid hormone production while replacing thyroid hormones to avoid hypothyroidism
Reference - Expert Opin Pharmacother 2016 Oct;17(15):2005
suggested dosing regimens(1, 2, 3, 4)
MMI
dosing regimen suggested by American Thyroid Association (ATA) (may be given as single
daily dose, but split dose may be more effective in patients with severe hyperthyroidism);
dosing should be tailored to individual patient depending on degree of thyroid dysfunction
5-10 mg if FT4 is 1-1.5 times the upper limit of normal
10-20 mg if FT4 is 1.5-2 times the upper limit of normal
30-40 mg if FT4 is 2-3 times the upper limit of normal
maintenance dose is usually 5-10 mg/day
PTU - reported to be associated with high risk of recurrence after treatment withdrawal; daily
dosage usually give in 3 equal doses, about 8 hours apart
initial dose 300 mg orally daily
in patients with severe hyperthyroidism and/or very large goiters, initial dose can be increased
to 400 mg orally daily
in some cases 600-900 mg orally daily dose may be required
typical maintenance dose is 100-150 mg orally daily
carbimazole - prodrug converted to MMI (not available in United States)
reported to be associated with high risk of recurrence after treatment withdrawal
10 mg of carbimazole is metabolized in serum to about 6 mg of MMI
dosing
37/83
initial dose 20-60 mg titrated against thyroid function until euthyroid; therapy may be
continued by maintenance regimen or by blocking replacement
maintenance regimen - 5-15 mg per day (can be taken as single dose), continued for ≥
6-18 months
blocking-replacement regimen - dosage maintained at initial level (20-60 mg/day),
supplemented with levothyroxine (L-thyroxine) 50-150 mcg/day to prevent
hypothyroidism, continued for ≥ 6-18 months
higher antithyroid medications doses may be required in combination with levothyroxine to
maintain euthyroid levels (block and replace therapy), but this regimen is not generally
recommended because of reported increase in rate of side effects
potassium iodide together with methimazole may help better control hyperthyroidism with fewer
adverse events compared to MMI alone
Reference - FDA DailyMed 2016 Feb 4, MHRA United Kingdom Public Assessment Report PDF,
FDA DailyMed 2018 Mar 2
see also Management of Graves disease during pregnancy and lactation
Evidence of efficacy
antithyroid drugs may have higher relapse risk than thyroidectomy or radioactive iodine in adults
with Graves disease (level 3 [lacking direct] evidence)
based on systematic review of mostly observational studies
systematic review of 1 randomized trial and 7 cohort studies evaluating interventions for Graves
disease in 1,402 adults
relapse of Graves disease defined as recurrence of hyperthyroidism after ≥ 12 months of treatment
antithyroid drugs associated with higher risk of relapse compared to
thyroidectomy (odds ratio 9.45, 95% CI 4.66-19.17) in analysis of 7 studies
radioactive iodine (odds ratio 6.35, 95% CI 2.4-16.77) in analysis of 6 studies, results limited
by significant heterogeneity
comparative risk of adverse effects not reported
Reference - J Clin Endocrinol Metab 2013 Sep;98(9):3671 full-text
block-replace antithyroid drug regimen associated may decrease relapse of hyperthyroidism but
may increase drug withdrawal due to side effects in patients with Graves disease (level 2 [mid-level]
evidence)
based on Cochrane review of trials with methodologic limitations
systematic review of 26 randomized and quasi-randomized trials evaluating antithyroid medication
for ≥ 6 months in 3,388 patients with Graves disease
overall quality of reporting of trials was poor
only 5 trials reported method of randomization and allocation concealment
only 1 trial reported blinding of patient, carer, and outcome assessor
no trial met all quality criteria
antithyroid drugs evaluated were methimazole, carbimazole, and propylthiouracil
block and replace - sustained high dose of antithyroid drug used to block thyroxine
production (induce hypothyroidism) and L-thyroxine given as hormone replacement
titration block - low initial dose of antithyroid drug given, then titrated up to lowest effective
dose to achieve and maintain euthyroidism
comparing block-replace to titration block regimens
block-replace associated with decreased relapse of hyperthyroidism in analysis of 12 trials
with 1,707 patients
OR 0.79 (95% CI 0.64-0.98)
NNT 10-226 with relapse in 68% of titration block group
block-replace associated with increased withdrawal due to side effects in analysis of 4 trials
with 697 patients
OR 2.03 (95% CI 1.3-3.18)
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NNT 7-42 with withdrawal due to side effects in 9% of titration block group
addition of thyroxine treatment, no significant differences in relapse rates
comparing thyroxine plus low-dose antithyroid drug to antithyroid drug alone, in analysis of 3
trials with 234 patients, results limited by significant heterogeneity
comparing thyroxine to no thyroxine after cessation of antithyroid drug in analysis of 4 trials
with 566 patients
Reference - Cochrane Database Syst Rev 2010 Jan 20;(1):CD003420
methimazole associated with greater resolution of hyperthyroidism and fewer side effects than
propylthiouracil in patients with Graves disease (level 2 [mid-level] evidence)
based on randomized trial without blinding and with high dropout rate
396 patients with untreated hyperthyroidism due to Graves disease in Japan were randomized to 1 of
3 treatments for 12 weeks
methimazole 15 mg twice daily (30 mg/day)
methimazole 15 mg once daily (15 mg/day)
propylthiouracil 100 mg 3 times daily (300 mg/day)
93 patients (22%) excluded due to side effects within 4 weeks (13%), not visiting hospital regularly
(4%), or dropping out (6%)
overall dropout rates were higher with methimazole 30 mg/day (27%) and propylthiouracil (29%)
than methimazole 15 mg/day (16%)
normal serum free thyroxine (FT4) at 12 weeks more likely with methimazole 30 mg/day (96.5%)
than propylthiouracil (78.3%) and methimazole 15 mg/day (86.2%)
side effect rates
highest (52%) with propylthiouracil including 27% hepatotoxicity, 22% skin
eruption/urticaria, and 4.8% leukocytopenia
30% with methimazole 30 mg/day including 6.6% hepatotoxicity, 22% skin eruption/urticaria,
and no leukocytopenia
lowest (14%) with methimazole 15 mg/day including 6.6% hepatotoxicity, 6.6% skin
eruption/urticaria, and 0.7% leukocytopenia
effect of adjuvant treatments
methimazole plus potassium iodide associated with greater reduction of free serum thyroxine
levels compared to methimazole alone in patients with previously untreated Graves disease
(level 3 [lacking direct] evidence)
based on prospective cohort study
310 patients with previously untreated Graves disease (free serum thyroxine [FT4] ≥ 5 ng/dL
[193 pmol/L]) received methimazole 15 mg/day plus potassium iodide 38.2 mg/day (52%) or
methimazole 30 mg/day
potassium iodide discontinued when serum FT4 level reached normal range (0.8-1.6 ng/dL
[10.3-20.6 pmol/L])
comparing methimazole plus iodide vs. methimazole alone
serum FT4 levels within reference range in
45.3% vs. 24.8% (p = 0.0001) in ≤ 30 days
73.9% vs. 63.1% (p = 0.03) in ≤ 60 days
82% vs. 75.2% (not significant) in ≤ 90 days
adverse effects (including pruritus or rash, agranulocytosis, neutropenia) in 7.4%
vs.14.7% (p = 0.03)
Reference - Thyroid 2015 Jan;25(1):43
addition of cholestyramine to antithyroid therapy may accelerate decrease in thyroid hormone
levels (level 3 [lacking direct] evidence)
based on 3 small randomized trials without clinical outcomes
45 patients with hyperthyroid Graves disease given methimazole orally 30 mg/day and
propranolol orally 40 mg/day were randomized to cholestyramine 2 g twice daily vs.
cholestyramine 1 g twice daily vs. placebo orally for 4 weeks
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serum thyroid hormone levels decreased more rapidly and to greater extent in
cholestyramine treated groups
Reference - Endocrine 2008 Aug-Dec;34(1-3):52
30 patients with Graves hyperthyroidism treated with propylthiouracil 100 mg twice daily and
propranolol 40 mg twice daily were randomized to cholestyramine 4 g twice daily vs.
standard care for 4 weeks
significantly lower serum free thyroxine (FT4) and free tri-iodothyronine (FT3) with
cholestyramine vs. standard therapy at 2 and 4 weeks
Reference - Clin Endocrinol (Oxf) 2005 May;62(5):521
30 patients with newly diagnosed Graves disease were randomized to 1 of 3 treatments for 4
weeks
3 treatments included
methimazole, propranolol, and cholestyramine
methimazole, propranolol, and cholestyramine for 2 weeks, followed by
methimazole and propranolol for 2 weeks
methimazole and propranolol
greater reduction in thyroid function tests with treatments including cholestyramine (p
< 0.05)
Reference - J Clin Endocrinol Metab 1996 Sep;81(9):3191
Monitoring while on antithyroid drugs
clinical and biochemical evaluation(2)

early evaluation
evaluate free serum thyroxine (FT4) and total tri-iodothyronine (TT3) after about 2-6 weeks
after initiation of therapy and dosing should be adjusted accordingly
because FT4 levels may normalize despite persistent elevated levels of TT3, TT3 levels
should be monitored
thyroid stimulating hormone levels (TSH) remain low for few months after initiation of
therapy and is not a useful parameter for monitoring
after achieving euthyroidism
methimazole levels are usually decreased by about 30%-50%, after which, thyroid function
tests can be repeated in 4-6 weeks
after reaching minimal dose of medication, clinical and biochemical evaluation can be
performed every 2-3 months; if on long-term methimazole treatment (> 18 months),
evaluation can be performed every 6 months
monitoring for agranulocytosis(2)
obtain differential white blood cell count during febrile illness and at onset of pharyngitis (ATA
Strong recommendation, Low-quality evidence)
insufficient evidence to recommend for or against routine monitoring of white blood cell counts
(ATA No recommendation, Insufficient evidence to assess benefits and risks)
monitoring liver function(2)
insufficient evidence to recommend for or against routine monitoring of liver function (ATA No
recommendation, Insufficient evidence to assess benefits and risks)
assess liver function and hepatocellular integrity in patients taking propylthiouracil presenting with
signs or symptoms suggestive of hepatotoxicity such as (ATA Strong recommendation, Low-quality
evidence)
pruritic rash
jaundice
light-colored stool or dark urine
joint pain
abdominal pain or bloating
anorexia
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nausea
fatigue
Duration of treatment with antithyroid drugs
when considering discontinuation of antithyroid drug measure serum thyrotropin receptor antibody
(TRAb) level prior to stopping antithyroid drug therapy to help predict if patients can be weaned from
medication (normal levels indicate greater chance for remission) (ATA Strong recommendation,
Moderate-quality evidence); patients with persistently high TRAb are less likely to be in remission, while
patients with undetectable or low TRAb levels are more likely to achieve permanent remission
if methimazole (MMI) is chosen as primary therapy for Graves disease
continue medication for about 12-18 months
at 12-18 months measure thyroid-stimulating hormone (TSH) and TRAb levels
if normal, taper or discontinue the drug (ATA Strong recommendation, High-quality
evidence)
if TRAb levels remain high options include
continue with antithyroid drug therapy
TRAb levels should be measured every 1-2 years, and consider discontinuing
medication if TRAb levels become negative
thyroid function should be monitored every 4-6 months
follow-up visits can occur every 6-12 weeks
pursue other treatments including either one of
radioactive iodine
thyroidectomy
remission rates (biochemical euthyroidism for ≥ 12 months, after 1 to 2 years of therapy) are not improved
by(1)
increasing duration of treatment more than 18 months
combining antithyroid drug treatment with levothyroxine
if patient not in remission consider continued low-dose MMI treatment for > 12-18 months (and if this
option is preferred by patient) (ATA Weak recommendation, Low-quality evidence)(2)
if patient becomes hyperthyroid after completing MMI treatment, consider treatment with radioactive
iodine or thyroidectomy (ATA Weak recommendation, Low-quality evidence)(2)
chronic, life-long treatment with antithyroid drug may be needed for some patients(3)
remission reported in 61% after long-term antithyroid drug treatment in adults with Graves disease
(level 3 [lacking direct] evidence)
systematic review of 6 cohort studies evaluating association between long term (> 24 months)
antithyroid drug treatment and remission rates in 508 patients with Graves disease
3 studies included adults (312 patients) and 3 studies only included children (196 children)
mean duration of treatment ranged from 41-98 months
mean follow up duration after treatment ranged from 24-100 months
remission defined as normal serum TSH, free thyroxine and total tri-iodothyronine for 1 year after
discontinuation of antithyroid drug therapy
pooled remission rate 57% (61% among adults) in analysis of 6 studies with all 508 patients
pooled annual remission rate for each year of treatment 16% (19% among adults) in analysis of 6
studies with 508 patients
Reference - Thyroid 2017 Oct;27(10):1223
continuation of low-dose methimazole at reduced frequency may increase remission in patients with
recurrent Graves disease (level 3 [lacking direct] evidence)
based on randomized trial without intention-to-treat analysis
128 patients (mean age 35 years, 84% women) with recurrent Graves disease after antithyroid drug
course with methimazole were randomized to second course with same drug vs. no further treatment
and followed for 48 months after end of treatment
41/83
all patients received methimazole course started at 7.5-30 mg orally once daily, then titrated
down to 2.5 mg orally once daily (based on thyroid hormone levels) and continued for 5
months if normal thyroid function or until incidence of hypothyroidism
patients receiving second antithyroid drug course continued methimazole 2.5 mg orally once
every other day (reduced frequency) for additional 5 months if normal thyroid function or
until incidence of hypothyroidism
89.5% completed trial and were included in analyses
remaining in remission in 85% of second course of low-dose methimazole vs. 67% of no further
treatment (p = 0.024, NNT 6)
Reference - Eur J Endocrinol 2015 Mar;172(3):321 full-text
long-term treatment with low-dose methimazole associated with higher attainment of euthyroidism
compared to radioactive iodine plus L-thyroxine in patients with relapsed Graves disease (level 3
[lacking direct] evidence)
238 patients with relapsed Graves disease after discontinuation of antithyroid drugs for 12-24
months received low-dose methimazole 2.5-7.5 mg/day (in 51%) or radioactive iodine treatment 15
mCi plus L-thyroxine
mean follow up 71 months in low-dose methimazole group and 81 months in radioactive iodine plus
L-thyroxine group; 216 patients included in analysis
compared to radioactive iodine plus L-thyroxine, low-dose methimazole associated with higher
attainment of euthyroidism (serum thyroid-stimulating hormone and free thyroxine levels within
reference range) in significantly higher proportion of patients after 12, 24, 36, 48, and 60 months of
treatment (p < 0.05 for all time points)
Reference - Thyroid 2015 Dec;25(12):1282
Adverse effects of antithyroid drugs
antithyroid drugs are associated with minor allergic side effects (reported in 1%-5% of cases) and serious
allergic or toxic side effects (rare) such as agranulocytosis, vasculitis, or hepatic damage(2)
inform patients (preferably with written documentation) of antithyroid drug side effects (ATA Strong
recommendation, Low-quality evidence)(1, 2, 3)
explain necessity of contacting physician immediately if patient develops
pruritic rash (reported in 1%-5% patients)
jaundice
acholic stools or dark urine
arthralgias
abdominal pain
nausea
fatigue
fever
pharyngitis
before starting antithyroid drugs and at each subsequent visit, remind patient to stop medication
immediately and call physician if symptoms suggestive of agranulocytosis or hepatic injury occur
agranulocytosis (2, 3)
uncommon, but life-threatening adverse event; rare with doses ≤ 10 mg/day
incidence ranges from 0.1% to 0.29%
in cohort of 50,385 patients with Graves disease, cumulative incidence of antithyroid drug-
induced agranulocytosis and pancytopenia 0.29%; median interval between initiation of
antithyroid drug treatment and onset of agranulocytosis 69 days and pancytopenia 41 days (J
Clin Endocrinol Metab 2012 Jan;97(1):E49)
in cohort of estimated 35,000 patients newly diagnosed Graves disease over 30 years
incidence of antithyroid drug-induced agranulocytosis incidence 0.1%-0.15%
among 754 patients with antithyroid drug-induced agranulocytosis
42/83
84.6% developed agranulocytosis within 90 days of treatment initiation

96.2% received methimazole
Reference - J Clin Endocrinol Metab 2013 Dec;98(12):4776
reported to be more common with propylthiouracil (PTU) compared to methimazole (MMI) of any
dose
monitoring
obtain differential white blood cell count during febrile illness and at onset of pharyngitis
(ATA Strong recommendation, Low-quality evidence)
insufficient evidence to recommend for or against routine monitoring of white blood cell
counts (ATA No recommendation, Insufficient evidence to assess benefits and risks)
management
use of another antithyroid drug is not suggested due to potential cross-reactivity
use of PTU may be reconsidered in case of life-threatening thyrotoxicosis (thyroid storm) in
patients treated with MMI if duration of therapy is short
hepatotoxicity(2, 3)
reported in < 0.1%
MMI-associated hepatotoxicity reported to be mostly cholestatic, but hepatocellular disease may
occur; mean reported time of onset 36 days
PTU-associated hepatotoxicity reported be fulminant hepatic necrosis and may be fatal; liver
transplant reported to be required in some cases; median reported time to onset 120 days
monitoring
assess liver function and hepatocellular integrity in patients taking propylthiouracil presenting
with signs or symptoms suggestive of hepatotoxicity such as (ATA Strong recommendation,
pruritic rash
jaundice
light-colored stool or dark urine
joint pain
abdominal pain or bloating
anorexia
nausea
fatigue
insufficient evidence to recommend for or against routine monitoring of liver function (ATA
No recommendation, Insufficient evidence to assess benefits and risks)
management
discontinue PTU if transaminase level is > 3 times upper limit of normal or if elevated
baseline level increases further with PTU use
after discontinuation of drug, liver function tests should be performed weekly; if resolution
does not occur, patient should be referred to gastroenterologist or hepatologist
MMI may be used to manage thyrotoxicosis unless propylthiouracil-induced hepatotoxicity is
severe
vasculitis (2, 3)
antineutrophil cytoplasmic antibody (pANCA)-positive small vessel vasculitis and drug-induced
lupus associated with PTU use and rarely, MMI; more commonly reported in Asian patients
may occur months or years after start of therapy
up to 40% of patients receiving PTU reported to develop ANCA positivity but majority do not
progress to clinical vasculitis; loss of ANCA and resolution of vasculitis observed in most patients
after discontinuation of drug, but some patients may require immunosuppressive therapy
rarely insulin autoimmune syndrome with symptomatic hypoglycemia reported with methimazole
use
allergic reactions - management of reactions (ATA Strong recommendation, Low-quality evidence)(2)
for minor cutaneous reactions, administer concurrent antihistamine therapy without stopping
antithyroid drug
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for persistent minor side effects of antithyroid medication, discontinue antithyroid medication and
change to radioactive iodine therapy or surgery, or switching to another antithyroid drug when
radioactive iodine or surgery are not options
in case of serious allergic reaction, prescribing alternative antithyroid drug is not recommended
comparison of adverse events between MMI/carbimazole and PTU
methimazole 15 mg/day associated with reduced overall adverse events and discontinuation of
treatment compared to methimazole 30 mg/day or propylthiouracil in patients with Graves
disease (level 2 [mid-level] evidence)
449 patients with untreated Graves disease randomized to methimazole 15 mg/day vs.
methimazole 30 mg/day vs. propylthiouracil 300mg/day until free thyroxine levels reached
normal range
hepatotoxicity defined as aspartate aminotransferase (AST) and alanine aminotransferase
(ALT) ≥ 2 times the upper limit of reference range
391 patients (87%) were included in analyses
Incidence of Adverse Events and Discontinuation of Treatment:
Discontinuation Cutaneous
Treatment Overall AEs Hepatoxicity
of Treatment Reaction
8.7% (not 20.5% (p = 0.03
29.1% (p = 0.03 16.5% (p = 0.01
significant vs. vs. MMI 30
vs. MMI 30 vs. MMI 30
MMI 15 mg/day MMI 30 mg/day; mg/day; not
mg/day; p = 0.01 mg/day, p =
p = 0.0003 vs. significant vs.
vs. PTU) 0.0014 vs. PTU)
PTU) PTU)
MMI 30 mg/day 41.7% 29.2% 9% 31.9%
PTU 300mg/day 44.2% 34.2% 25.8% 18.3%
Abbreviations: AE, adverse event; MMI, methimazole; PTU, propylthiouracil.
Reference - Clin Endocrinol (Oxf) 2012 Aug;77(2):310
methimazole/carbimazole associated with increased risk of hepatotoxicity compared to
propylthiouracil in patients with hyperthyroidism (level 2 [mid-level] evidence)
71,379 patients with hyperthyroidism received methimazole/carbimazole or propylthiouracil
median follow up 196 days
hepatotoxicity defined as diagnosis of cholestasis, non-infectious hepatitis, acute liver failure,
and liver transplant
comparing methimazole/carbimazole vs. propylthiouracil
incidence of hepatotoxicity 3.17 per 1,000 person-years vs. 1.19 per 1,000 person-years
(no p value reported); methimazole/carbimazole associated with increased risk of
hepatitis (adjusted hazard ratio 2.89, 95% CI 1.81-4.6)
incidence of acute liver failure 0.32 per 1,000 person-years vs. 0.68 per 1,000 person-
years (no p value reported)
Reference - Br J Clin Pharmacol 2014 Sep;78(3):619 full-text
Radioactive iodine
treat patients with Graves hyperthyroidism with radioactive iodine, antithyroid medication, or
thyroidectomy (ATA Strong recommendation, Moderate-quality evidence)(2, 3)
goal is to achieve hypothyroidism; rate at which hypothyroidism is achieved depends on(3)
size of thyroid
radioactive iodine uptake
severity of thyrotoxicosis
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activity of radioactive iodine administered

hypothyroidism usually achieved within 2-3 months after treatment with single dose of radioactive iodine
(12-15 millicurie [mCi]), but may require longer time; repeat treatment is not usually considered until 6
months after initial treatment(3)
mechanism of action - beta-particles emitted from radioactive iodine incorporated into thyroid hormone
cause ionizing damage to thyroid follicular cells, leading to eventual destruction of the gland(3)
factors that may favor choosing radioactive iodine as therapy(2)
women who plans to become pregnant > 6 months after radioactive iodine treatment (as long as
thyroid hormone levels are normal)
comorbidities that increase surgical risk
previously operated on or with externally irradiated necks
lack of access to high-volume thyroid surgeon
contraindications to antithyroid medication or failure to achieve euthyroid status with antithyroid
medication
periodic thyrotoxic hypokalemic paralysis, right heart failure, pulmonary hypertension, or heart
failure
radioactive iodine treatment contraindicated in(1, 2, 3)
pregnant women or women planning to become pregnant in next 4-6 months
breastfeeding women and for 6 weeks after breastfeeding has stopped
patients with coexisting thyroid cancer or suspected thyroid cancer
patients unable to comply with radiation safety guidelines
advantages include(1, 3)
easy oral administration
usually curative - about 85% of patients are euthyroid or hypothyroid after single dose
few side effects
reduces goiter size effectively
disadvantages include(2, 6)
potential of radiation hazards
need for adherence to local radiation regulation
radiation thyroiditis
decrease in efficacy with larger goiters
short- term increase of thyroid hormone levels
repeat therapy at times necessary
eventual hypothyroidism in most patients requiring lifelong levothyroxine treatment
rising antibody titers following treatment may contribute to worsening orbitopathy
Pretreatment considerations
considerations prior to radioactive iodine therapy(2, 3)

optimize medical therapy of any comorbid condition prior to administering radioactive iodine (ATA
Strong recommendation, Low-quality evidence); comorbid conditions include
cardiovascular complications such as atrial fibrillation, heart failure, or pulmonary
hypertension
renal failure
infection
trauma
poorly controlled diabetes
cerebrovascular or pulmonary disease
destruction of thyroid tissue may result in transient worsening of thyrotoxicosis in weeks following
radioactive iodine therapy; in patients with Graves disease who are at increased risk for
complications due to worsening hyperthyroidism (such as those with severe hyperthyroidism,
elderly patients and patients with coexisting conditions)
45/83
consider treatment with beta blocker (ATA Weak recommendation, Low-quality evidence)
in addition to beta blocker, consider pretreatment with methimazole (MMI) and discontinuing
treatment 2-3 days prior to initiating radioactive iodine therapy (ATA Weak recommendation,
consider resuming MMI treatment 3-7 days after radioactive iodine treatment (ATA Weak
in patients who would normally have been candidates for pretreatment with antithyroid drugs,
but are allergic to antithyroid medications, consider administering iodine (for example,
saturated solution of potassium iodide) starting 1 week after radioactive iodine therapy
for women with childbearing potential obtain pregnancy test within 48 hours prior to radioactive
iodine treatment and confirm negative result prior to administering radioactive iodine (ATA Strong
provide written advice regarding radiation safety precautions following treatment (if precautions
cannot be followed, select alternative therapy) (ATA Strong recommendation, Low-quality
evidence); safety precautions may include
ensuring no adult member of the public is exposed to 0.5 millisievert (mSv) (500
milliroentgen equivalent in man [mrem]) upon patient discharged with retained activity of >
33 millicurie or emits 70 microsievert/hour (7 mrem/hour) at 1 hour
sleeping alone for 3-6 days after 10-15 millicurie (mCi) dose or 15-18 days if partner is
pregnant
keeping a distance of about 3 feet from other adults and 6 feet from pregnant women and
children after 10-15 mCi dose
radioactive iodine may be associated with development or progression of Graves ophthalmopathy,
but effect on eye disease may be prevented with glucocorticoids (see Patients with Graves
ophthalmopathy section for additional information)
use of iodinated radiocontrast should be avoided if possible
nutritional supplements containing high levels of iodine and seaweeds should be avoided prior to
therapy help radioactive iodine uptake especially in cases where relatively low dose is administered
pretreatment with lithium reported to reduce activity of radioactive iodine required for treatment;
however this strategy is not widely used and should not be used during pregnancy
evidence for efficacy of pre-treatment with antithyroid medication
addition of antithyroid drugs to radioactive iodine treatment associated with increased risk of
treatment failure and decreased risk of hypothyroidism (level 2 [mid-level] evidence)
based on systematic review of trials with methodologic limitations
systematic review of 14 randomized trials of adjunctive antithyroid drugs in 1,306 adults
receiving radioiodine treatment for hyperthyroidism and followed for at least 6 months
all trials lacked allocation concealment, only 2 trials had blinding (caregivers only in 1 trial,
assessors only in 1 trial)
antithyroid drugs evaluated were propylthiouracil (5 trials), carbimazole (3 trials), and
methimazole (7 trials)
comparing antithyroid drugs before radioiodine to control in analysis of 7 trials with 565
patients, antithyroid drugs associated with
increased risk of treatment failure (persistent or recurrent hyperthyroidism or need for
further treatment)
relative risk (RR) 1.48 (95% CI 1.09-2)
NNH 5-59 with 18.7% rate of treatment failure in controls
nonsignificantly decreased risk of hypothyroidism (RR 0.76, 95% CI 0.57-1.01)
comparing antithyroid drugs during or after radioiodine to control in 11 trials with 877
patients, antithyroid drugs associated with
increased risk of treatment failure (p = 0.03, NNH 11)
RR 1.32 (95% CI 1.04-1.68)
NNH 5-93 with 26.7% rate of treatment failure in controls
decreased risk of hypothyroidism
RR 0.57 (95% CI 0.41-0.78)
46/83
NNT 7-19 with 24.6% rate of hypothyroidism in controls

Reference - BMJ 2007 Mar 10;334(7592):514 full-text, editorial can be found in BMJ 2007
Mar 10;334(7592):483 full-text, commentary can be found in BMJ 2007 Apr
7;334(7596):710 full-text
pretreatment with methimazole may not affect time to attainment of hypothyroidism after
radioactive iodine therapy in patients with Graves disease (level 3 [lacking direct] evidence)
based on small randomized trial without clinical outcomes
42 patients with Graves disease scheduled to receive radioactive iodine therapy randomized to
pretreatment with methimazole 30 mg for 2 months (stopped 6 days before radioactive iodine
therapy) vs. no methimazole pretreatment
all patients were also pretreated with atenolol (beta-blocker) 50-100 mg/day prior to
administration of radioactive iodine 15mCi (adjusted for goiter size and radioactive iodine
uptake)
all but 1 patient in each group became hypothyroid
power calculation to demonstrate significant difference in time to cure (30-day difference
considered significant)
estimated 12 patients per arm needed to provide statistical power of 80%
estimated 30 patients per arm needed provide statistical power of 90%
no significant differences in time to attain hypothyroidism or normal and subnormal serum
free thyroxine levels
Reference - Thyroid 2002 Feb;12(2):135
pretreatment with carbimazole associated with lower attainment of euthyroidism or
hypothyroidism after radioactive iodine therapy compared to no carbimazole treatment or
withdrawal of carbimazole prior to radioactive iodine therapy in patients with Graves disease
(level 2 [mid-level] evidence)
227 patients with Graves disease (90 patients) or toxic nodular goiter (117 patients) scheduled
for radioactive iodine therapy (target dose 200 Gy) had radioactive iodine uptake evaluated
patients pretreated with carbimazole with radioactive iodine uptake
> 30% had received radioactive iodine therapy while continuing on carbimazole
< 30% had carbimazole treatment withdrawn 3 days prior to radioactive iodine
therapy
patients not pretreated with carbimazole radioactive had iodine therapy without
carbimazole
follow-up 12 months after radioactive iodine therapy
among patients with Graves disease (90 patients), clinical and biochemical evidence of
euthyroidism or hypothyroidism in
38.9% in continuation of carbimazole group (p = 0.005 compared to no carbimazole)
76.9% in withdrawal of carbimazole group (p = 0.019 vs. continuation of carbimazole;
not significant vs. no carbimazole)
70.7% in no carbimazole group
Reference - Eur J Nucl Med Mol Imaging 2006 Jun;33(6):730
radioactive iodine therapy with adjuvant lithium treatment may be associated with higher cure rate
compared to radioactive iodine therapy alone in patients with Graves disease (level 3 [lacking
direct] evidence)
based on 2 retrospective cohort studies
163 patients with Graves disease received radioactive iodine with adjuvant lithium or radioactive
iodine alone and were followed for ≥ 1 year
radioactive iodine therapy (median dose 571 MBq [15.4 milliCi]) with adjuvant lithium (800
mg/day for 10 days) (55% of patients)
radioactive iodine therapy alone median dose 558 MBq (15.1 milliCi) (45% of patients)
cure defined as sustained biochemical euthyroidism or hypothyroidism (biochemical
assessments at ≥ 2 sequential time points) during follow up period
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compared to radioactive iodine therapy alone, radioactive iodine therapy with adjuvant
lithium associated with higher probability of cure at any time during first year (adjusted
hazard ratio 1.69, 95% CI 1.16-2.47)
Reference - Clin Endocrinol (Oxf) 2012 Oct;77(4):621
651 patients with newly diagnosed Graves disease received 289 patients treated with radioactive
iodine therapy plus lithium 900 mg/day orally (44%) or radioactive iodine alone for 12 days
comparing lithium plus radioiodine vs. radioactive iodine alone
cure (defined as permanent hypothyroidism or stable euthyroidism) rates at 1 year 91%
vs. 85% (p = 0.03)
median time to cure 60 days vs. 90 days (p < 0.001)
Reference - J Clin Endocrinol Metab 2010 Jan;95(1):201
Dosing of radioactive iodine therapy
dosing(1, 2, 3, 4)
administer enough radiation in single dose (typically mean dose of 10-15 millicurie [mCi]) to render
patient hypothyroid (ATA Strong recommendation, Moderate-quality evidence)
possible strategies include
administering fixed dose of radioactive iodine
calculating the activity based on the size of the thyroid and its ability to trap RAI
Activity [microCi] = gland weight (in g) × target microCi/g × [1/24 hour uptake in % of
administered activity]Divide by 1,000 to obtain activity in mCiTarget microCi/g range 50-
200
calculating the activity using additional variables including the effective half-life of
radioactive iodide
radioactive iodine (131 I) dose > 150 mcCi/g of thyroid tissue reported to be required to achieve
therapeutic goal (hypothyroid)
dosing by estimated or calculated activity of radioactive iodine associated with similar attainment of
euthyroidism in patients with Graves disease (level 3 [lacking direct] evidence)
based on systematic review of mostly observational studies
systematic review of 8 studies (5 observational studies and 3 randomized trials) comparing
estimated activity of radioactive iodine (fixed activity or standardized activity selected based on
estimated thyroid weight) to calculated of radioactivity iodine (based on radioactive iodine uptake
measurement) to achieve persistent euthyroidism after treatment in 1,261 patients with
hyperthyroidism
studies included patients with Graves disease, toxic multinodular goiter, and toxic adenoma
mean follow up ≥ 6 months
euthyroidism achieved at end of follow-up ranged from 4%-73%
comparing estimated dosing vs. calculated dosing, no significant differences in
attainment of euthyroidism
in patients with Graves disease in subgroup analysis of 6 studies
in patients with hyperthyroidism (from any cause) in analysis of 8 studies with 1,261
patients
cure of hyperthyroidism (defined as euthyroidism or hypothyroidism at end of follow up) in
1,261 patients with hyperthyroidism
Reference - Eur J Endocrinol 2009 Nov;161(5):771
radioactive iodine ablation with 10 mCi or 15 mCi may show similar remission rates in patients with
Graves disease (level 3 [lacking direct] evidence)
based on randomized trial without allocation concealment
128 patients with Graves disease randomized to treatment with radioactive iodine 10 mCi vs.
radioactive iodine 15 mCi and followed for 12 months
remission defined as stable euthyroid or hypothyroid state in absence of antithyroid drugs 12
months after radioactive iodine therapy
48/83
comparing radioactive iodine 10 mCi vs. radioactive iodine 15 mCi

remission in 73.7% vs. 80.8% (not significant)
hypothyroidism in 56.5% vs. 71.1% (not significant)
Reference - Clin Nucl Med 2012 Mar;37(3):241
Monitoring response and follow-up after radioactive iodine therapy
response to radioactive iodine is assessed by evaluation of signs and symptoms, and monitoring size of
thyroid gland and thyroid function(2)
perform follow up evaluation which includes (ATA Strong recommendation, Low-quality evidence)(2)
free thyroxine (FT4), total tri-iodothyronine (TT3), and thyroid stimulating hormone (TSH) levels at
1-2 months after radioactive iodine therapy (thyroid function tests)
continued biochemical monitoring at 4-6 week intervals for 6 months or until patient is hypothyroid
and stable on thyroid hormone replacement, or stably euthyroid
if administered prior to radioactive iodine therapy(2)
beta-blockers should be tapered when FT4 and total TT3 levels have normalized
methimazole should be tapered over 4-6 weeks as FT4 and total T3 levels recover
response(2, 3)
most patients respond to therapy within 4-8 weeks with normalization of thyroid function tests and
improvement of symptoms
hypothyroidism may be achieved by 8 weeks; with appropriate dose, hypothyroidism reported to be
achieved in most patients (about 80%) within 1-6 months
thyroid hormone replacement therapy(2)
timing of thyroid hormone replacement therapy depends on the results of thyroid function tests,
clinical presentation, and physical exam
when patients develop hypothyroidism (FT4 level below normal range), levothyroxine should be
administered; dose should be adjusted based on FT4 level, taking into consideration residual thyroid
function (may require lower dosage than full replacement)
overt hypothyroidism should be avoided, especially in patients with Graves ophthalmopathy
monitor TSH levels and adjust dose as needed
see also Hypothyroidism in adults
life-long annual evaluation of thyroid function should be performed after achieving euthyroidism(2)
consider retreatment with radioactive iodine if (ATA Weak recommendation, Low-quality evidence)(2)
hyperthyroidism persists after 6 months following radioactive iodine therapy
minimal response 3 months after initial therapy
5%-15% patients with Graves disease reported to require retreatment with radioactive iodine(3)
in few patients refractory to several trials of radioactive iodine therapy, surgery should be considered(2)
Adverse effects or radioactive iodine therapy
adverse effects may include(1, 2, 3)

transient worsening of thyrotoxicosis; rarely thyroid storm
development of or worsening of Graves ophthalmopathy but may be preventable with
glucocorticoid therapy for 8-12 weeks after radioactive iodine therapy (see patients with Graves
ophthalmopathy section for additional information on management)
transient anterior neck pain due to radiation thyroiditis (rare) (rarely requires glucocorticoid
therapy)
cancer - evidence is conflicting
weight gain after correction of thyrotoxicosis may occur in some patients likely due to continued excess
food intake despite normalization of metabolism(3)
evidence for development of or worsening of Graves ophthalmopathy
49/83
radioactive iodine therapy increases development or worsening of Graves ophthalmopathy

compared to methimazole in adults with Graves disease (level 1 [likely reliable] evidence)
based on Cochrane review
systematic review of 2 randomized trials comparing radioactive iodine therapy vs. antithyroid
medications in 425 adults with Graves disease
both trials compared radioactive iodine (1.4 to 4.44 megabecquerel/g [0.04-0.12 millicurie/g]
thyroid) to methimazole (10 mg 4 times daily or 15 mg twice daily for 18 months)
radioactive iodine associated with increase in development or progression of Graves
ophthalmopathy at 2-4 years in analysis of 2 trials with 417 patients
risk ratio 1.94 (95% CI 1.4-2.7)
NNH 3-13 with development or progression of Graves ophthalmopathy in 19% of
methimazole group
no significant difference in recurrence of hyperthyroidism at ≥ 4 years (risk ratio 0.2, 95% CI
0.01-2.66) in analysis of 2 trials with 417 patients, results limited by significant heterogeneity
Reference - Cochrane Database Syst Rev 2016 Feb 18;2:CD010094
radioactive iodine may be associated with development or progression of Graves
ophthalmopathy, but effect on eye disease may be prevented with prednisone (level 2 [mid-
level] evidence)
based on 2 randomized trials with allocation concealment not stated
443 patients with Graves disease and mild or no ophthalmopathy and treated with
methimazole for 3-4 months were randomized to radioactive iodine vs. radioactive iodine
followed by prednisone for 3 months vs. continuation of methimazole
patients followed for 12 months
development or progression of ophthalmopathy occurred in
15% with radioactive iodine alone vs. 0% with radioiodine plus prednisone (p <
0.001, NNH 6)
15% with radioactive iodine alone vs. 3% with methimazole (p < 0.001, NNH 8)
improvement of ophthalmopathy (among patients with preexisting ophthalmopathy)
occurred in
0% with radioactive iodine alone vs. 67% with radioiodine plus prednisone (p <
0.00, NNH 1)
0% with radioactive iodine alone vs. 4% with methimazole (p < 0.001, NNH 25)
Reference - N Engl J Med 1998 Jan 8;338(2):73 full-text, editorial can be found in N
Engl J Med 1998 Jan 8;338(2):121, commentary can be found in N Engl J Med 1998
May 21;338(21):1546
333 adults (mean age 51 years) with recent diagnosis of Graves hyperthyroidism were
randomized to 131I vs. 18 months of medical treatment and were followed for 4 years
94% included in analysis
10% dropout by year 3 of observation
comparing 131I vs. medical treatment
worsening or development of thyroid-associated ophthalmopathy (TAO) in
38.7% vs. 21.3% (p < 0.001, NNH 5)
new development of TAO in 38% vs. 18% (p < 0.001, NNH 5)
smoking increased risk of worsening or development of TAO independent of treatment
(p < 0.001)
radioactive iodine treatment increased risk of worsening or development of TAO in
nonsmokers (p < 0.001)
Reference - J Clin Endocrinol Metab 2009 Oct;94(10):3700
evidence for cancer risk
therapeutic and diagnostic radioactive iodine exposure may not be associated with overall
cancer risk, but therapeutic radioactive iodine exposure associated with increased risk of
thyroid and kidney cancer (level 2 [mid-level] evidence)
50/83
systematic review of 7 retrospective cohort studies evaluating association between use of

radioactive iodine for diagnosis or treatment and risk of developing cancer
46,828 patients with benign thyroid diseases were exposed to radioactive iodine
5 studies evaluated therapeutic use of radioactive iodine and 2 studies evaluated diagnostic
use of radioactive iodine
no significant association between
comparing radioactive iodine exposure to no radioactive iodine exposure
radioactive iodine exposure associated with increased risk of
thyroid cancer (RR 1.99, 95% CI 1.22-3.26) in analysis of 4 studies (therapeutic
use) with 24,799 patients
kidney cancer (relative risk [RR] 1.7, 95% CI 1.15-2.51) in analysis of 3 studies
(therapeutic use) with 14,005 patients, result limited by significant heterogeneity
no significant difference in overall cancer risk (therapeutic and diagnostic) in analysis
of 7 studies
Reference - Endocr Relat Cancer 2012 Oct;19(5):645
radioactive iodine treatment for hyperthyroidism associated with increased risk of
cancer (level 2 [mid-level] evidence)
based on retrospective cohort study (included in systematic review)
2,793 adolescents and adults aged 13-98 years (median age 62 years) treated with
radioactive iodine therapy for hyperthyroidism and age- and sex-matched controls
followed for mean 10 years
comparing radioactive iodine therapy vs. control group, cancer incidence rates (per
10,000 person-years)
overall cancer 118.9 vs. 94.9 (rate ratio [RR] 1.25, 95% CI 1.08-1.46)
kidney 6.2 vs. 2.7 (RR 2.32, 95% CI 1.06-5.01)
stomach 9.7 vs. 5.5 (RR 1.75, 95% CI 1-3.14)
breast 27.4 vs. 17.9 (RR 1.53, 95% CI 1.07-2.09)
unspecified site 6.2 vs. 2.8 (RR 1.22, 95% CI 1-1.53)
Reference - Cancer 2007 May 15;109(10):1972, commentary can be found in Cancer
2008 Jan 1;112(1):220
radioactive iodine treatment for hyperthyroidism not associated with increased total
cancer incidence or mortality, but appears to increase small bowel and thyroid cancer
incidence and mortality (level 2 [mid-level] evidence)
based on retrospective cohort study included in systematic review
7,417 patients treated with radioactive iodine for hyperthyroidism between 1950 and
1991 were assessed for cancer diagnoses during 72,073 person-years of follow-up and
compared with population-based cancer incidence data
radioactive iodine associated with
increased incidence and mortality for
small bowel cancer
standardized incidence ratio (SIR) 4.81 (95% CI 2.16-10.72)
standardized mortality ratio (SMR) 7.03 (95% CI 0.3.16-15.66)
thyroid cancer
SIR 3.25 (95% CI 1.69-6.25)
SMR 2.78 (95% CI 1.16-6.67)
decreased total cancer incidence and mortality
SIR 0.83 (95% CI 0.77-0.9)
SMR 0.9 (95% CI 0.82-0.98)
Reference - Lancet 1999 Jun 19;353(9170):2111, commentary can be found in Lancet
1999 Sep 25;354(9184):1122
radioactive iodine treatment associated with increased thyroid cancer mortality in patients
with Graves disease (level 2 [mid-level] evidence)
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35,593 patients (mean age 46 years) with hyperthyroidism in Cooperative Thyrotoxicosis

Therapy Follow-up study had 738,831 person-years of follow-up
19,625 patients with Graves disease received radioactive iodine treatment
followed for 368,934 person-years
mortality from cancer overall 8.2%
among patients with Graves disease, compared to national cancer mortality rates, radioactive
iodine treatment associated with increased mortality from thyroid cancer (standardized
mortality ratio [SMR] 2.84; 95% CI 1.62-4.61)
no significant difference in overall cancer mortality rates among all patients
Reference - JAMA 1998 Jul 22-29;280(4):347
Beta blockers
used for symptomatic relief of adrenergic symptoms of palpitations, tachycardia, tremulousness, anxiety,
and heat intolerance as part of initial management until thyroid hormone levels are normalized(1, 2, 3)
mechanism of action(1)
competitively block beta-adrenergic receptors
propranolol may block conversion of thyroxine (T4) to tri-iodothyronine (T3), but only at high
doses (for example, > 160 mg/day of propranolol)
offer beta blockers to patients with symptomatic thyrotoxicosis, especially elderly patients and thyrotoxic
patients with resting heart beat > 90 beats/minute or concurrent cardiovascular disease (ATA Strong
recommendation, Moderate-quality evidence)(2)
consider beta blockers for patients who are at increased risk for transient worsening of hyperthyroidism
(such as elderly patients or patients with comorbidities) prior to radioactive iodine therapy(ATA Weak
recommendation, Low-quality evidence)(2)
precautions(1, 2, 3)
beta blockers are approved for treatment of cardiovascular diseases but not for treatment of
thyrotoxicosis
generally not suggested for patients with bronchospastic asthma
patients with quiescent bronchospastic asthma who require heart rate control, mild obstructive
airway disease or symptomatic Raynaud's phenomenon, relative beta-1 selective blocker may be
considered with careful monitoring
consider use of cardioselective beta blockers or calcium channel blockers in patients with chronic
obstructive pulmonary disease; oral calcium channel blockers reported to achieve heart rate control
in patients who do not tolerate or are not candidates for beta-blockers
beta blocker options
Additional
Drug Selectivity Dose Frequency
Considerations
Most experience
with drug
May block T4 to
T3 at high doses
Preferred in
women who are
Nonselective nursing or are
Propranolol 10-40 mg orally 3-4 times per day
beta-blocker pregnant
Also available in
once daily
preparations
Long acting
formulations
preferable
52/83
Atenolol Relative 25-100 mg orally 1-2 times daily Increased

beta-1 compliance
selectivity Should be
avoided during
pregnancy
Relative
Also available in once
Metoprolol beta-1 25-50 mg orally 2-3 times daily
daily preparations
selectivity
Less experience
Nonselective with drug
Nadolol 40-160 mg orally Once daily
beta-blocker May block T4 to
T3 at high doses
Used in intensive
50-100 care unit for
relative beta-
Esmolol mcg/kg/minute IV NA severe
1 selectivity
pump thyrotoxicosis or
thyroid storm
Abbreviations: NA, not applicable; T3, tri-iodothyronine; T4, thyroxine. References - 3), FDA
(2,
DailyMed 2017 Dec 31.
Other medications
potassium iodide(2)
lowers hormone secretion and inhibits its own organification (Wolff-Chaikoff effect)
prior to availability of antithyroid medications, iodine was frequently administered to treat
hyperthyroidism associated with Graves disease; however use of potassium iodide has been
discouraged due to
reported escape from beneficial effects
iodine-induced hyperthyroidism in patients with nodular goiter
consider as treatment of hyperthyroidism in some patients with Graves disease who have (ATA No
recommendation, insufficient evidence)
mild hyperthyroidism or prior history of radioactive iodine therapy
adverse reactions to antithyroid drugs
contraindication or aversion to radioactive iodine therapy
aversion for surgery
potassium iodide is also administered to patients having thyroidectomy in the immediate
preoperative period
potassium iodide may be as effective as methimazole in restoring normal thyroid function in
patients with mild Graves disease (level 3 [lacking direct] evidence)
257 patients with Graves disease received potassium iodide (88%; mean dose 53.6mg/day) or
methimazole (mean dose 14 mg/day) and followed for 1 year
20 patients treated with potassium iodide and 20 patients treated with methimazole were
matched using propensity score analysis adjusting for observed clinical features
among propensity matched patients, no significant differences in attainment of normal thyroid
function without side effects (85% in potassium iodide group vs. 95% in methimazole group)
Reference - Endocrine 2014 Nov;47(2):506
treatment with lower doses (< 200 mg) of potassium iodide may result in higher remission
rates compared to higher doses of potassium iodide in patients with Graves disease showing
thionamide associated side effects (level 2 [mid-level] evidence)
1,388 patients with Graves disease treated with thionamides were assessed
53/83
204 (14.7%) had thionamides related side effects

44 patients received potassium iodide
follow up median 17.6 years
in 44 patients receiving potassium iodide, remission in
70.8% of patients treated with < 200 mg potassium iodide vs. 35% of patients treated
with ≥ 200 mg potassium iodide at long term followup (p < 0.05)
38.6% of patients treated with potassium iodide alone after 7.4 years
15.9% of patients treated with potassium iodide plus low dose thionamides after 7.2
years
Reference - J Clin Endocrinol Metab 2014 Nov;99(11):3995
Surgery and procedures
Thyroidectomy
treat patients with Graves hyperthyroidism with thyroidectomy , radioactive iodine, or antithyroid
medication(ATA Strong recommendation, Moderate-quality evidence)(2, 3)
goal of treatment is hypothyroidism, followed by replacement with L-thyroxine(1, 2)
surgery recommended in < 1% of patients as initial management due to development of radioactive iodine
therapy and antithyroid medications, but may be the main definitive therapy in areas of low
socioeconomic status(3)
if surgery is chosen as the primary therapy for Graves disease(2, 3)
near-total or total thyroidectomy is procedure of choice (ATA Strong recommendation, Moderate-
quality evidence); definitive therapy may be accomplished with near-total thyroidectomy
refer patient to high-volume thyroid surgeon (ATA Strong recommendation, Moderate-quality
evidence); complications reported to be less frequent
factors that may favor choosing thyroidectomy as therapy(2)
symptomatic compression or large goiter (≥ 80 g)
low uptake of radioactive iodine
thyroid malignancy documented or suspected (for example, suspicious or unclear cytology)
large (> 4 cm) nonfunctioning, photopenic, or hypofunctioning nodule as determined by thyroid
scintigraphy
coexisting hyperparathyroidism requiring surgery
women who plans to become pregnant in < 6 months as long as thyroid hormone levels are normal
thyrotropin receptor antibody (TRAb) levels that are particularly high
moderate-to-severe Graves ophthalmopathy
factors weighing against surgery as treatment include(2)
significant comorbidity (such as cardiopulmonary disease, end-stage cancer, or other debilitating
disorder)
lack of access to high-volume thyroid surgeon (example of high-volume suggested as surgeon
performing > 25 thyroid surgeries per year)
pregnancy is relative contraindication
should only be considered if rapid control of hyperthyroidism is required and antithyroid
medications are not an option
should be avoided during first and third trimester due to teratogenic effects of anesthetics,
increase in risk of fetal loss during first trimester and risk of preterm labor during third
trimester
reported to be associated with increased risk of complications such as hypoparathyroidism
and recurrent laryngeal nerve injury
advantages 6)
(1,
54/83
rapid euthyroidism
recurrence is extremely rare (related to residual thyroid tissue volume)
no exposure to radiation
definitive therapy of hyperthyroidism
rapid resolution of pressure symptoms
stable euthyroid state easily achieved on replacement levothyroxine therapy
post-surgery, gradual remission of autoimmunity occurs
goiter disappears
disadvantages(1)
risks associated with anesthesia and surgery
minor complications reported in 1%-2% including bleeding, infection, and scarring
major complications reported in 1%-4% including hypoparathyroidism, recurrent laryngeal-nerve
damage
does not influence Graves ophthalmopathy(1)
Preoperative considerations
preoperative considerations to help prevent complications of thyroidectomy(1, 2, 3)

because stress of impending surgery or thyroid manipulation may potentially lead to development of
thyroid storm, patients scheduled for thyroidectomy should be rendered euthyroid prior to surgery
render patients euthyroid with antithyroid medication with or without beta-blockers (ATA
if patient does not become euthyroid prior to thyroidectomy, if need for thyroidectomy is
urgent or patient is allergic to antithyroid medication, treat with beta blocker, potassium
iodide, glucocorticoids, and possibly cholestyramine in immediate preoperative period (ATA
example glucocorticoid dosing - dexamethasone 2 mg orally or IV 4 times daily
example cholestyramine dosing - 4 g, 4 times daily
stop antithyroid drugs at time of thyroidectomy and wean beta-blockers after surgery (ATA
potassium iodide treatment 1 week prior to surgery may decrease thyroid blood flow, vascularity,
and blood loss(1, 2)
administer potassium iodide formulation in immediate preoperative period (ATA Strong
potassium iodide may be given as 5-7 drops (0.25-0.35 mL) of Lugol's solution (8 mg
iodide/drop) or 1-2 drops of super saturated potassium iodide (SSKI) (50 mg iodide/drop) 3
times daily mixed with water or juice 10 days prior to surgery
oral calcium and/or vitamin D supplementation may help reduce risk of hypocalcemia due to
parathyroid injury or increased bone turnover(2)
assess calcium and 25-hydroxyvitamin D levels preoperatively and replete or administer
prophylactically if needed (ATA Strong recommendation, Low-quality evidence)
provide calcitriol supplementation preoperatively in patients at increased risk for transient or
permanent hypoparathyroidism (ATA Strong recommendation, Low-quality evidence)
preoperative iodine may decrease intraoperative blood loss and thyroid vascularity (level 3 [lacking
direct] evidence) but may not reduce postoperative complications (level 2 [mid-level] evidence) in
patients with Graves disease having thyroidectomy
based on nonclinical and clinical outcomes in systematic review limited by heterogeneity
systematic review of 5 randomized trials and 4 observational studies comparing preoperative iodine
vs. no premedication or placebo in 510 patients with Graves disease having thyroidectomy
iodine treatments included Lugol's solution (5 studies), potassium iodide (3 studies), and saturated
solution of potassium iodide (1 study)
preoperative iodine associated with decreased
55/83
intraoperative blood loss (standardized mean difference 0.8, 95% CI 0.23-1.37) in analysis of
5 studies with 244 patients, results limited by significant heterogeneity
perioperative thyroid vascularity (standardized mean difference 0.87, 95% CI 0.23-1.51) in
analysis of 5 studies with 263 patients, results limited by significant heterogeneity
no significant differences in
perioperative thyroid volume in analysis of 6 studies with 282 patients
postoperative vocal cord palsy in analysis of 7 studies with 527 patients, results limited by
significant heterogeneity
postoperative hypoparathyroidism in analysis of 7 studies with 491 patients, results limited by
postoperative hemorrhage or hematoma in analysis of 5 studies with 309 patients, results
limited by significant heterogeneity
Reference - Otolaryngol Head Neck Surg 2019 Feb 5 early online
pretreatment with calcium carbonate associated with reduced hypocalcemia symptoms in patients
with Graves disease having total thyroidectomy (level 2 [mid-level] evidence)
83 patients with Graves disease received calcium carbonate 1 g 3 times per day for 2 weeks prior to
total thyroidectomy (54%) (mean age 44 years, 84% women) or no calcium carbonate treatment
prior to surgery (mean age 40 years, 87% women)
40 patients (mean age 43 years, 88% women) having total thyroidectomy alone for indications other
than Graves disease were also included in analyses
patients received calcium supplementation post-operatively as needed for symptoms; calcitriol was
administered based on post-operative parathyroid hormone level
mean preoperative calcium level 9.2 mg/dL in all groups
serum calcium levels 4 hours post-surgery (p = 0.05 among all groups; pairwise comparisons not
reported)
8.6 mg/dL in patients with Graves disease treated with calcium carbonate preoperatively
8.3 mg/dL in patients with Graves disease without calcium carbonate pretreatment
8.6 mg/dL in patients without Graves disease
symptoms of hypocalcemia (numbness and tingling) in (p = 0.049 among all groups; pairwise
comparisons not reported)
9% in patients with Graves disease treated with calcium carbonate preoperatively
26% in patients with Graves disease without calcium carbonate pretreatment
10% in patients without Graves disease
no significant differences in calcium level 1 day after surgery or parathyroid hormone levels on day
of surgery or 1 day after surgery
Reference - Ann Surg Oncol 2015 Mar;22(3):952 full-text
Postoperative follow-up after thyroidectomy
postoperative follow-up after thyroidectomy(2)

assessment and management of calcium status
postoperative supplementation with calcium and calcitriol may decrease risk of hypocalcemic
symptoms and need for IV calcium treatment
consider administration of oral calcium and calcitriol supplementation based on results of
serum calcium measurement with or without intact parathyroid hormone (iPTH) levels or
empiric prophylactic administration of oral calcium with or without calcitriol (ATA Weak
calcium levels can be assessed using slope of 6- and 12-hour postoperative calcium levels
low iPTH levels (< 10-15 pg/mL) immediately after surgery may predict development of
symptomatic hypocalcemia and need for treatment
example oral calcium dosing - 1,250-2,500 mg (500-1,000 mg of elemental calcium) 4 times
daily, tapered by 500 mg of elemental calcium every 2 days or 1,000 mg every 4 days as
56/83
tolerated
example calcitriol dosing - starting dose of 0.5 mcg daily continued for 1-2 weeks and dosing
adjusted (increased or tapered) according to calcium and/or iPTH levels
patient may be safely discharged if asymptomatic and serum calcium level corrected for
albumin is ≥ 8 mg/dL (2mmol/L) and not falling over 24-hours
stop antithyroid drugs at time of thyroidectomy and wean beta-blockers after surgery (ATA Strong
levothyroxine treatment
start levothyroxine at daily dose appropriate for patient's weight (0.8 mcg/lb or 1.6 mcg/kg),
with somewhat less for elderly patients, and measure serum thyroid stimulating hormone
(TSH) 6-8 weeks postoperatively (ATA Strong recommendation, Low-quality evidence)
levothyroxine dosing depends on patient body mass index and percent absorbed from gut
once TSH level is normal, TSH level should be measured annually or more frequently if
required
establish effective communication among different members of multidisciplinary team during
transition of care in pre and postoperative setting (ATA Strong recommendation, Low-quality
evidence)
calcium plus vitamin D associated with decreased risk of symptomatic hypocalcemia after
thyroidectomy (level 2 [mid-level] evidence)
based on systematic review of trials with methodologic limitations
systematic review of 9 randomized trials evaluating supplementation with calcium and/or vitamin D
in 2,285 patients (mean age 50 years) after thyroidectomy
all trials had ≥ 1 methodologic limitation including
unclear allocation concealment or method of randomization
unclear blinding
small trial size
26.1% had post-thyroidectomy hypocalcemia (definition of hypocalcemia varied between trials)
compared to no intervention
calcium plus vitamin D associated with reduced risk of symptomatic hypocalcemia in analysis
of 5 trials with 1,084 patients
odds ratio 0.37 (95% CI 0.2-0.67)
NNT 6-15 with symptomatic hypocalcemia in 26% of controls
no significant difference in symptomatic hypocalcemia after treatment with calcium alone in
analysis of 3 trials with 748 patients, results limited by heterogeneity
no significant differences comparing calcium plus vitamin D to calcium alone in analysis of 4 trials
with 687 patients, results limited by heterogeneity
Reference - Oncologist 2013;18(5):533 full-text
teriparatide may reduce rate of hypocalcemia and length of hospital stay in patients at high risk of
hypocalcemia after thyroidectomy (level 2 [mid-level] evidence)
based on small randomized trial without placebo control group
26 patients (mean age 53 years) with iPTH < 10 pg/mL at 4 hours after thyroidectomy were
randomized to teriparatide 20 mcg subcutaneously every 12 hours until discharge vs. standard
clinical care (control)
all patients were prescribed calcium and calcitriol supplements at discharge
comparing teriparatide vs. control
hypocalcemia in 23.1% vs. 84.6% (p = 0.006, NNT 2)
median length of hospital stay 2 days vs. 3 days (p = 0.012)
mean calcium supplementation after 1 month 308 mg/day vs. 1083 mg/day (p = 0.04)
calcium carbonate supplementation discontinued after 1 month in 76.98% vs. 38.4% (no p
value reported)
no serious adverse events reported
Reference - THYPOS trial (J Clin Endocrinol Metab 2016 Nov;101(11):4039)
Complications of thyroidectomy
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complications of total or near-total thyroidectomy may include(2, 3)

hypocalcemia
hypoparathyroidism
recurrent or superior laryngeal nerve injury
postoperative bleeding
complications related to general anaesthesia
consider preoperative medical management to help prevent development of complications after surgery(2)
Consultation and referral

consult with experienced obstetrician or maternal-fetal medicine specialist regarding fetal surveillance in
pregnant women with uncontrolled hyperthyroidism and/or high thyrotropin receptor antibody (TRAb)
levels (> 3 times upper limit of normal) (ATA Strong recommendation, Moderate-quality evidence)(6)
counsel women with Graves disease seeking pregnancy regarding complexity of disease management
including risks and benefits of treatment options, timing of future pregnancies, and association of birth
defects with antithyroid drug use (ATA Strong recommendation, High-quality evidence)(6)
refer patients with Graves ophthalmopathy to combined thyroid-eye clinics or specialized centers with
endocrinological and ophthalmological expertise, except for mildest cases that improve with achieving
normal thyroid status and local lubricants (EUGOGO Strong recommendation, Low-quality evidence)
(Eur Thyroid J 2016 Mar;5(1):9 full-text)
Management of special patient populations
Patients with Graves ophthalmopathy (GO)
Recommendations
American Thyroid Association (ATA) recommendations for management of hyperthyroidism in patients

with or at risk for GO(2)
euthyroidism should be quickly achieved and maintained in patients with or at risk for developing
GO (ATA Strong recommendation, Moderate-quality evidence); risk factors include
advanced age - associated with more severe GO
sex - GO more common in women, but may be more severe in men
genetics/ethnicity - more common among Caucasian patients, lowest in Asian patients
mechanical factors - wider lateral wall orbital angle noted in GO
thyroid stimulating hormone receptor antibody - predictor of risk and response to therapy for
GO
smoking - may increase GO progression and decrease treatment efficacy
thyroid dysfunction
radioactive iodine therapy
advise patients with Graves disease to stop smoking and refer them to structured smoking cessation
program; identify patients exposed to secondhand smoke and advise of negative impact (increased
risk of GO) (ATA Strong recommendation, Moderate-quality evidence)
management hyperthyroidism for patients with GO depends on the activity and severity of GO
patients without apparent GO
in nonsmoking patients, treat with radioactive iodine (without concomitant steroid
therapy), antithyroid drugs, or thyroidectomy (all equally acceptable) (ATA Strong
in smoking patients
treat with radioactive iodine, antithyroid drugs, or thyroidectomy (ATA Weak
58/83
insufficient evidence to recommend for or against use of prophylactic

corticosteroids in smokers receiving radioactive iodine therapy (ATA No
recommendation, insufficient evidence)
patients with mild GO
without risk factors for worsening of their eye condition, treat with radioactive iodine,
antithyroid drugs, or thyroidectomy (ATA Weak recommendation, Moderate-quality
evidence)
consider glucocorticoids if not contraindicated, in patients treated with radioactive
iodine, even in the absence of risk factors for worsening GO (ATA Weak
administer glucocorticoids in patients treated with radioactive iodine, in the presence of
risk factors for worsening of GO (ATA Strong recommendation, Moderate-quality
evidence)
in patients with active and moderate-to-severe or sight-threatening GO, perform
thyroidectomy or administer antithyroid drugs, but do not administer radioactive iodine (ATA
in patients with inactive GO, consider radioactive iodine without steroid prophylaxis, but
steroid may be reconsidered in case of elevated risk for reactivation (high thyroid receptor
antibody level, clinical activity score ≥ 1, and smokers) (ATA Weak recommendation, Low-
quality evidence)
European Group on Graves Orbitopathy (EUGOGO) recommendations for management of GO
refer patients with GO to combined thyroid-eye clinics or specialized centers with endocrinological
and ophthalmological expertise, except for mildest cases that improve with achieving normal
thyroid status and local lubricants (EUGOGO Strong recommendation, Low-quality evidence)
general measures to alleviate symptoms of GO
assess effects of disease and its treatment on quality-of-life and psychosocial well-being of
patients using validated GO specific quality-of-life tool (EUGOGO questionnaire accessed
2018 Sept 6) (EUGOGO Strong recommendation, Low-quality evidence)
prophylactic measures
urge smoking cessation with help of smoking cessation programs or clinics if necessary
(EUGOGO Strong recommendation, Moderate-quality evidence)
administer oral prednisone prophylaxis, starting dose 0.3-0.5 mg/kg body weight in
radioactive iodine treated patients at high risk of progression or development of GO
(EUGOGO Strong recommendation, High-quality evidence)
lower dose prednisone can be used in low risk patients
patients with inactive GO can be treated with radioactive iodine without steroid
prophylaxis if hypothyroidism is avoided and other risk factors for development
of GO, especially smoking are absent
in all patients
promptly restore and maintain euthyroidism (EUGOGO Strong recommendation, High-
quality evidence)
evaluate for ocular surface disease and treat extensively with nonpreserved artificial
tears with osmoprotective properties unless higher protection (use of gels or ointments)
is required due to corneal exposure (EUGOGO Strong recommendation, Low-quality
evidence)
treatment for mild GO (EUGOGO Strong recommendation, Moderate-quality evidence)
general measures to control risk factors
treat with local treatments
if impact of disease on quality-of-life outweighs risks, consider immunosuppressive therapy
for active GO or rehabilitative surgery for inactive GO
give selenium supplementation for 6 months to patients with mild GO of relatively short
duration to improve symptoms and prevent progression of GO
treatment for moderate-to-severe and active GO
first-line treatment - glucocorticoids
59/83
high dose glucocorticoids IV is treatment of choice performed in experienced centers

equipped to manage potentially serious adverse events (EUGOGO Strong
patients for liver dysfunction, recent viral hepatitis, severe cardiovascular morbidity, or
psychiatric disorders should not receive IV glucocorticoids and hypertension and
diabetes should be well controlled prior to treatment (EUGOGO Strong
do not exceed 8 g for total cumulative dose of glucocorticoids (EUGOGO Strong
glucocorticoid dosing
for most patients, administer methylprednisolone at starting dose of 0.5 g once
weekly for 6 weeks, followed by 0.25 g once weekly for 6 weeks (cumulative
dose 4.5 g) (EUGOGO Strong recommendation, High-quality evidence)
for worst cases within moderate-to-severe spectrum use high dose regimens with
starting dose 0.75 g once weekly for 6 weeks followed by 0.5 g once weekly for
6 weeks (cumulative dose 7.5 g) (EUGOGO Strong recommendation, High-
quality evidence)
consider monitoring patients receiving glucocorticoids for response to treatment and
adverse effects and consider withdrawal and replacement of glucocorticoid therapy with
other treatment or watchful monitoring if side effects outweigh benefits (EUGOGO
Weak recommendation, Low-quality evidence)
second line of treatment should be based on shared decision making approaches (EUGOGO
limited evidence regarding alternative treatment options for patients who fail IV
glucocorticoid treatment
treatment options if GO include
second course of glucocorticoid treatment as long as cumulative dose of 8 g is
not exceeded
orbital radiotherapy may improve diplopia and range of ductions
common regimen - 20 Gy cumulative dose, divided in 10 daily doses given
over 2 week period
alternative regimen - 1 Gy per week over 20 weeks
can be used in conjunction with oral glucocorticoids
mild and transient exacerbation of ocular symptoms may occur but can be
managed with concomitant administration of low dose glucocorticoids
combination of cyclosporine with oral glucocorticoid more effective than either
treatment alone
rituximab (depletes B cells); GO not listed among FDA approved indications(1)
watchful monitoring
ocular findings of orbital vascular congestion such as eyelid edema, eyelid
and conjunctival redness, and chemosis are similar to those with active GO
patients with long-lasting GO with high clinical activity score should be
assessed for orbital vascular congestions, followed by orbital
decompression to increase venous outflow of the orbit if appropriate, to
relieve clinical symptoms
other medications
somatostatin analogues, azathioprine, and ciamexone are not suggested
IV immunoglobulins; GO not listed among FDA approved indications
teprotumumab
treatment for sight-threatening GO
manage severe corneal exposure promptly medically or surgically to avoid corneal breakdown
(EUGOGO Strong recommendation, Moderate-quality evidence)
dysthyroid optic neuropathy (EUGOGO Strong recommendation, Moderate-quality evidence)
60/83
administer high-dose glucocorticoids IV (methylprednisolone 500-1,000 mg for 3

consecutive days or alternate days during first week) and perform urgent orbital
decompression if poor or no response within 2 weeks
if resolved or improved after 2 weeks of methylprednisolone treatment, continue with
treatment as described for patients with moderate-to-severe and active GO
for recent onset choroidal folds and eyeball subluxation, perform prompt orbital
decompression for (EUGOGO Strong recommendation, Moderate-quality evidence)
treatment for moderate-to-severe and inactive GO
offer elective rehabilitative when the disease is associated with a significant impact on visual
function or quality-of-life after the disease has been inactive for ≥ 6 months (EUGOGO
Strong recommendation, Low-quality evidence); options for surgeries include
decompression surgery
goal is to reduce the raised intraorbital pressure, resulting in reduction of
exophthalmos periorbital puffiness (swelling and fat prolapse) and lid retraction
different techniques of decompression, lid lengthening and cosmetic surgery may
be performed depending on severity of GO, anatomy, coexisting illnesses, and
patient preference
squint surgery
goal is to restore fusion in primary position avoiding diplopia in down gaze and
correction of residual incomitances
involves extension of extraocular rectus muscle recessions and retro equatorial
myopexias
eyelid surgery
goal is correction of upper- and lower-lid retraction (recession of lid retractors)
spacers are used provide height and stiffness to support lower lid against gravity
when severely retracted, but not required for upper lid procedures
if multiple surgeries are required orbital decompression should be performed first, followed
by squint surgery, then lid surgery (EUGOGO Strong recommendation, Low-quality
evidence)
refer to specialized centers and surgeons to determine optimal surgical option for each patient
Reference - European Thyroid Association/European Group on Graves Orbitopathy (EUGOGO)
guidelines for the management of graves orbitopathy (European Thyroid Association/European
Group on Graves' Orbitopathy Guidelines for the Management of Graves' Orbitopathy)
Evidence of efficacy of medications for management of GO
glucocorticoids
IV glucocorticoids associated with greater treatment response and retrobulbar injections of
glucocorticoids associated with greater reduction in proptosis compared to oral
glucocorticoids in patients with Graves ophthalmopathy (level 2 [mid-level] evidence)
based on systematic review with trial-specific quality measures not reported
systematic review of 7 randomized trials comparing IV glucocorticoids, retrobulbar injections
of glucocorticoids, or orbital radiotherapy vs. oral glucocorticoids in 328 patients (mean age
range 34-50 years) with Graves ophthalmopathy
patients had moderate-to-severe disease in 5 trials, moderate disease in 1 trial, or was
unspecified in 1 trial
follow-up range 3-12 months
response to therapy defined as improvement in clinical parameters; examples included
decrease in proptosis and eyelid retraction ≥ 2 mm, improvement in orbital soft tissue
swelling, resolution of diplopia in primary gaze, and/or improvement in eye activity and
vision
response rate
61/83
compared to oral glucocorticoids, IV glucocorticoids associated with increased

response rate in analysis of 3 trials with 173 patients
risk ratio [RR] 1.48 (95% CI 1.18-1.87)
NNT 7-25 with response in 52% of oral glucocorticoid group
no significant difference between oral glucocorticoids and
retrobulbar injections of glucocorticoids in analysis of 3 trials 99 patients
orbital radiotherapy in 1 trial with 56 patients
proptosis
compared to oral glucocorticoids, retrobulbar injections of glucocorticoids associated
with greater reduction of proptosis (mean difference 0.92 mm, 95% CI 0.57mm-
1.27mm) in analysis of 3 trials with 99 patients
no significant difference between oral glucocorticoids and
IV glucocorticoids in analysis of 3 trials with 173 patients, results limited by
orbital radiotherapy in 1 trial with 56 patients
weight gain
compared to oral glucocorticoids, IV glucocorticoids associated with decreased risk of
weight gain in analysis of 3 trials with 173 patients
RR 0.24 (95% CI 0.07-0.79)
NNT 7-28 with weight gain in 17% of oral glucocorticoids group
orbital radiotherapy (RR 0.25, 95% CI 0.08-0.79) in 1 trial with 56 patients
hypertension
compared to oral glucocorticoids, IV glucocorticoids associated with decreased risk of
hypertension in analysis of 3 trials with 160 patients
RR 0.12 (95% CI 0.02-0.66)
NNT 8-23 with hypertension in 13% oral glucocorticoids group
Reference - PLoS One 2015;10(10):e0139544 full-text
glucocorticoid treatment may reduce risk of progression but not development of Graves
ophthalmopathy in patients with Graves disease having radioactive iodine therapy (level 2
[mid-level] evidence)
based on systematic review of subgroup analyses of randomized trials
systematic review of 8 studies (5 randomized trials and 3 retrospective cohort studies)
evaluating glucocorticoid treatment for prevention or progression of Graves ophthalmopathy
in 850 patients with Graves disease having radioactive iodine therapy
glucocorticoids administered included oral prednisone, betamethasone, prednisolone, and IV
methylprednisolone
pre-existing Graves ophthalmopathy present in
> 50% of patients in 5 studies
< 50% of patients in 1 study
0% of patients in 2 studies
glucocorticoid treatment initiation
before radioactive iodine therapy in 3 studies
day of radioactive iodine therapy in 1 study
1-3 days post radioactive iodine therapy in 4 studies
1 week post radioactive iodine therapy in 1 study
comparing glucocorticoid to control, glucocorticoid treatment associated with
reduced risk of progression of Graves ophthalmopathy in analysis of 3 trials with 233
patients with pre-existing Graves ophthalmopathy, result limited by heterogeneity
(consistent result when 1 retrospective cohort is included in analysis)
odds ratio 0.08, 95% CI 0.03-0.24
NNT 4-5 with progression of Graves ophthalmopathy in 29% of patients not
treated with glucocorticoids
among patients without pre-existing Graves ophthalmopathy
62/83
no significant difference in development of Graves ophthalmopathy in analysis of

3 trials (retrospective cohort studies not included in analysis) with 246 patients
increased risk of development of Graves ophthalmopathy (odds ratio 2.1, 95% CI
1.07-4.15) in analysis of 7 studies (including randomized trials and retrospective
cohort studies) with 512 patients, result limited by heterogeneity
Reference - Thyroid 2014 Oct;24(10):1515, editorial can be found in Thyroid 2014
Oct;24(10):1441
weekly IV methylprednisolone associated with increased response compare to daily IV
methylprednisolone at 12 weeks in patients with active moderate-to-severe Graves
ophthalmopathy (level 2 [mid-level] evidence)
based on randomized trial with baseline differences
80 adults with active moderate-to-severe Graves ophthalmopathy were randomized to
methylprednisolone IV weekly for 12 weeks vs. daily for 4 weeks (total dose 4.5 g for each)
weekly protocol consisted of 0.5 g weekly for 6 weeks, then 0.25 g weekly for 6 weeks
daily protocol consisted of 0.5 g daily for 3 consecutive days per week for 2 weeks,
then 0.25 g daily for 3 consecutive days per week for 2 weeks and tapering to oral
prednisone
at baseline, weekly protocol group had longer duration of eye symptoms (mean difference 7
months, p = 0.01) and lower mean thyroid-stimulating hormone (TSH) receptor antibody
levels (p = 0.05)
response was composite of lid width, soft tissue involvement, proptosis, intraocular pressure,
Clinical Activity Score, diplopia, and visual acuity
comparing weekly methylprednisolone vs. daily methylprednisolone
response at 12 weeks in 76.9% vs. 41% (p = 0.0025, NNT 3)
response at 4 weeks in 56.4% vs. 56.1% (not significant)
serious adverse events in 0% vs. 4.9% (no p value reported)
daily protocol associated with increased risk for retreatment at 6 months (hazard ratio 3.73,
95% CI 1.33-10.42)
IV methylprednisolone reported to result in recovery of vision without need for surgical
decompression at 6 months in patients with dysthyroid optic neuropathy (majority with
Graves disease) (level 3 [lacking direct] evidence)
based on case series
24 patients (mean age 66.7 years, 40 eyes treated) with dysthyroid optic neuropathy (23
patients had Graves disease) treated with methylprednisolone 500 mg or 100 mg IV daily for
3 days and tapered off orally or IV were followed for 12 months
at 6 months, 42.5% of eyes had complete recovery of vision and did not require surgical
decompression
Reference - Thyroid 2014 May;24(5):897
rituximab and methylprednisolone associated with similar reduction in proptosis compared to
methylprednisolone in patients with Graves disease (level 2 [mid-level] evidence)
based on systematic review of randomized trials limited by clinical heterogeneity
systematic review of 4 randomized trials comparing rituximab vs. methylprednisolone or saline in
293 patients with moderate-to-severe Graves ophthalmopathy
results limited by heterogeneity in
previous treatment for Graves ophthalmopathy
dosing and method of delivery (IV or intraorbital injection) of rituximab
comparing rituximab to methylprednisolone
rituximab associated with reduction in clinical activity score (scale 0-7 points assessing pain,
redness, and swelling) (weighted mean difference 0.61, 95% CI 0.31-0.91) at 24 weeks in
analysis of 3 trials with 196 patients
no significant difference in proptosis reduction in analysis of 2 trials with 164 patients
Reference - Pharmacotherapy 2018 May;38(5):503
63/83
teprotumumab improves clinical activity score and proptosis at 24 weeks in patients with active,
moderate-to-severe, thyroid-associated ophthalmopathy (level 1 [likely reliable] evidence)
based on randomized trial
88 adults (mean age 53 years, 73% female) with moderate-to-severe thyroid-associated
ophthalmopathy diagnosed within 9 months of symptom onset were randomized to teprotumumab
(human monoclonal antibody inhibitor of insulin-like growth factor I receptor) vs. placebo (0.9%
saline) IV once every 3 weeks for 24 weeks
all patients had clinical activity score ≥ 4 points (scale 0-7 points assessing pain, redness, and
swelling, with ≥ 3 points indicating active thyroid-associated ophthalmopathy)
teprotumumab given at 10 mg/kg for first infusion then 20 mg/kg for remaining infusions
primary outcome was ≥ 2-point reduction in clinical activity score plus ≥ 2-mm reduction in
proptosis in most-affected eye without worsening in nonstudy eye at 24 weeks
86% completed trial but 99% included in analysis
comparing teprotumumab vs. placebo
primary outcome in 69% vs. 20% (p < 0.001, NNT 2)
any adverse event in 74% vs. 73% (no p value reported)
any serious adverse event in 12% vs. 2% (no p value reported)
teprotumumab group had significant increase in primary outcome as early as 6 weeks
teprotumumab also associated with improved Graves ophthalmopathy-specific quality of life (visual
functioning and appearance) at 24 weeks (p = 0.012; results also significant for visual functioning
subscale alone)
adverse effects that may be increased with teprotumumab include nausea, muscle spasms, diarrhea,
and hyperglycemia
Reference - N Engl J Med 2017 May 4;376(18):1748
selenium improves quality-of-life and ophthalmologic outcomes in adults with mild Graves
orbitopathy (level 1 [likely reliable] evidence)
based on randomized trial
159 adults aged 18-70 years with mild Graves orbitopathy randomized to selenium 100 mcg orally
twice daily vs. pentoxifylline 600 mg orally twice daily vs. placebo for 6 months then followed for 6
months
overall ophthalmic outcome was composite of eyelid aperture, soft tissue signs, proptosis, and eye-
muscle motility
quality-of-life scores included measures of visual function and appearance; change of ≥ 6 points on
100-point scale was considered clinically important
comparing selenium vs. placebo at 6 months
clinically important improvement in quality of life score in 74% vs. 24% (p < 0.001, NNT 2)
clinically important worsening in quality of life score in 17% vs. 44% (p < 0.001, NNT 3)
ophthalmologic outcome improvement in 61% vs. 36% (p < 0.01, NNT 4)
similar findings at 12 months
no significant differences between pentoxifylline and placebo for quality-of-life score changes or
ophthalmologic outcomes
no adverse events reported in selenium and placebo groups; 7 adverse events (skin and
gastrointestinal disorders) reported in pentoxifylline group
Reference - N Engl J Med 2011 May 19;364(20):1920 full-text, commentary can be found in N
Engl J Med 2011 Aug 25;365(8):770
IV immunoglobulin (IVIG) associated with similar improvements in Graves ophthalmopathy (level
2 [mid-level] evidence)
65 patients with moderately severe Graves ophthalmopathy were treated with high-dose IVIG
(54%) or methylprednisolone
IVIG dosing - 400 mg/kg/day administered over 3-4 hours on 5 consecutive days, repeated 3
times every 21 days; after the third 5-day cycle, maintenance treatment (same dosage for 1
day) for 9 additional cycles every 21 days
64/83
methylprednisolone dosing - initial dose 80 mg/day for 2 weeks, gradually tapered until
discontinuation 5 months after initiation of treatment
comparing IVIG vs. corticosteroids
improvement in soft tissue involvement in 90% vs. 92.5% (no p value reported)
improvement in proptosis in 65% vs. 62% (no p value reported)
treatment response in 76% vs. 66% (no p value reported)
Reference - Thyroid 1997 Aug;7(4):579
see Immune Globulin for additional information on risks of use
Evidence of efficacy of radiation therapy for GO
orbital radiation therapy improves eye function and symptoms but does not reduce number of
rehabilitative surgeries in adults with mild-to-moderate thyroid eye disease (level 1 [likely reliable]
evidence)
systematic review of 5 randomized trials evaluating orbital radiation therapy in 244 adults with
thyroid eye disease
additional randomized trials were excluded due to
randomization of orbits - lymphocytes affected by radiation therapy would circulate and treat
both orbits
combining other treatment modalities - confounding effect of radiation therapy
comparing orbital radiation therapy to sham radiation therapy
orbital radiation therapy associated with increased treatment success in analysis of 2 trials
with 147 adults
risk ratio 1.92 (95% CI 1.27-2.91)
NNT 2-13 with treatment success in 29% of sham radiation therapy group
treatment success used composite outcomes scores but defined differently in different
trials
no significant differences in
number of rehabilitative surgeries in 2 trials with 147 patients
clinical activity score at 12 months in 1 trial with 88 patients
comparing orbital radiation therapy vs. oral prednisolone in 1 trial with 56 adults
improvement in NOSPECS score at 24 weeks in 46% vs. 50% (not significant)
rehabilitative surgery in 71% vs. 79% (not significant)
in single trials comparing orbital radiation therapy plus steroids vs. steroids alone
orbital radiation therapy plus steroids associated with increased response rate (p < 0.01) in 1
trial with 24 adults
mean change in total NOSPECS eye score -11.75 vs. -5 (p = 0.029 favoring combination
therapy) in 1 trial with 15 adults
Reference - Cochrane Database Syst Rev 2012 Jul 11;(7):CD007114
orbital radiation therapy 1 Gy weekly over 20 weeks may result in greater treatment response
compared to radiation therapy 1 Gy daily over 2 weeks or 2 Gy daily over 2 weeks in euthyroid
patients with untreated and clinically congestive and inflamed Graves ophthalmopathy (level 2
[mid-level] evidence)
based on small randomized trial
65 euthyroid patients with untreated and clinically congestive and inflamed Graves ophthalmopathy
randomized to 1 of
telecobalt 60 1 Gy weekly over 20 weeks
telecobalt 60 1 Gy daily, 5 days per week over 2 weeks
telecobalt 60 2 Gy daily over 2 weeks
response to therapy defined as significant improvement in ≥ 3 objective signs including
change in lid fissure width > 2 mm
change in proptosis > 2 mm
change in intraocular pressure (upgaze) > 3 mm Hg
65/83
change in eye muscle area > 5 mm2

absence of diplopia in primary position (normgaze)
comparing telecobalt 1 Gy weekly over 20 weeks vs. telecobalt 2 Gy daily over 2 weeks at 24
weeks
treatment response in 67% vs. 55% (p = 0.007)
decrease in NOSPECS classification of eye changes in 67% vs. 59% (p = 0.01)
satisfaction in 67% vs. 59% (p = 0.01)
radiotherapy induced conjunctivitis in 0% vs. 36% (p = 0.003)
comparing telecobalt 1 Gy weekly over 20 weeks vs. telecobalt 1 Gy daily over 2 weeks at 24
weeks
treatment response in 67% vs. 59% (no p value reported)
decrease in NOSPECS classification of eye changes in 67% vs. 59% (p = 0.01)
satisfaction in 67% vs. 55% (p = 0.008)
radiotherapy induced conjunctivitis in 0% vs. 18% (p value not reported)
Reference - J Clin Endocrinol Metab 2000 Jan;85(1):102, commentary can be found in J Clin
Endocrinol Metab 2001 May;86(5):2327
Evidence of efficacy of surgery and procedures for GO
insufficient evidence to guide orbital decompression surgery in patients with thyroid eye disease
systematic review identified 2 small randomized trials evaluating surgical orbital decompression
techniques in patients with thyroid eye disease
transantral approach compared to endoscopic transnasal technique for decompression in 1 trial with
35 patients (44 eyes) with Graves disease exophthalmos
both techniques associated with reduction in exophthalmos
transantral technique associated with higher incidence of diplopia and infraorbital nerve
damage
treatment success rates not reported
surgical orbital decompression compared to methylprednisolone IV in 1 trial with 15 patients with
dysthyroid optic neuropathy
no significant difference in treatment success
improvement in visual acuity, total eye, and clinical activity scores at 52 weeks in 17% of
surgical group vs. 56% of methylprednisolone group (no p value reported)
Reference - Cochrane Database Syst Rev 2011 Dec 7;(12):CD007630
subconjunctival botulinum toxin injections reported to improve upper eyelid retraction associated
with thyroid disease (level 3 [lacking direct] evidence)
based on case series
lid position acceptable to patient achieved in 10 of 11 patients
improvements lasted 1-40 months
4 patients had ptosis for 1-3 weeks
3 patients had diplopia up to 3 weeks
Reference - Ophthalmology 2002 Jun;109(6):1183, commentary can be found in Ophthalmology
2003 Nov;110(11):2262
thyroidectomy
total thyroid ablation (near total thyroidectomy plus radioiodine ablation) associated with
greater improvement in Graves orbitopathy at 9 months compared to near total
thyroidectomy in patients receiving glucocorticoid treatment (level 2 [mid-level] evidence)
based on small single-blind randomized trial
60 patients with mild-to-moderate Graves orbitopathy randomized to total thyroid ablation vs.
near total thyroidectomy and followed for > 9 months
total thyroid ablation group had near total thyroidectomy followed by ablation with
iodine-131 45 days later
66/83
all patients received methylprednisolone acetate IV twice on alternate days biweekly

(total of 12 infusions over 10 weeks) following thyroidectomy
10% dropped out and 7% lost to follow-up
total thyroid ablation associated with higher rate of improved or stable Graves orbitopathy at
9 months (p = 0.0014)
no significant difference between groups in distribution of Graves orbitopathy diplopia or
clinical activity scores at 9 months
Reference - J Clin Endocrinol Metab 2007 May;92(5):1653
total thyroid ablation (near total thyroidectomy plus radioiodine ablation) and near
total thyroidectomy associated with similar improvement in Graves orbitopathy after 7
years but total ablation associated with shorter time to improvement (level 2 [mid-level]
evidence)
based on follow-up of randomized trial above
87% of randomized patients were followed for mean 7.3 years
no significant difference in overall Graves orbitopathy outcomes at end of follow-up
comparing total thyroid ablation vs. near total thyroidectomy
mean time required for Graves orbitopathy improvement 3 months vs. 60 months
(p = 0.034)
mean time to best possible outcome achieved 3 months vs. 24 months (p = 0.044)
additional treatment in 25.9% vs. 28% (not significant)
Reference - J Clin Endocrinol Metab 2012 Jan;97(1):E44
recombinant human thyroid-stimulating hormone-aided radioactive iodine ablation of thyroid
remnants following total thyroidectomy may improve Graves orbitopathy (level 2 [mid-level]
evidence)
based on small randomized trial without blinding
40 adults with moderate-to-severe Graves orbitopathy who had total thyroidectomy were
randomized to radioiodine ablation of thyroid remnants vs. no ablation and followed for 24
months
ablation group had stimulation with recombinant human thyroid-stimulating hormone
(rhTSH) prior to ablation
45 days after thyroidectomy or radioiodine ablation, patients received 6-week course of IV
methylprednisolone acetate
Graves orbitopathy improvement defined as at least 2 of the following in at least 1 eye
(without deterioration in other eye)
improvement in clinical activity score ≥ 2 points (7-point scale)
reduced eyelid width ≥ 2 mm
reduced proptosis ≥ 2 mm
improvement in diplopia
improvement in Snellen acuity of ≥ 2 lines
comparing rhTSH-aided radioiodine ablation vs. no ablation
Graves orbitopathy improvement at 12 months in 70% vs. 20% (p = 0.007, NNT 2)
second course of IV corticosteroids needed in 30% vs. 80% (no p value reported)
all patients with improvement at 12 months maintained improvement at 18 and 24 months
Reference - J Clin Endocrinol Metab 2014 May;99(5):1783
Management of thyroid storm
treatment strategies for thyroid storm may involve(2)

suppression of thyroid hormone secretion and synthesis
suppression of peripheral thyroid hormone activity in tissues
reversal of systemic decompensation
treatment of coexisting illness or event that resulted in development of thyroid storm
definitive therapy
67/83
adopt multimodality treatment approach in patients with thyroid storm, including (ATA Strong
recommendation, Low-quality evidence)(2)
beta blockers
antithyroid drug therapy (propylthiouracil preferred over methimazole)
inorganic iodide
corticosteroids - to block peripheral conversion of thyroxine (T4) to tri-iodothyronine (T3) and treat
possible relative adrenal insufficiency
aggressive cooling with acetaminophen and cooling blankets
volume resuscitation
respiratory support and monitoring in intensive care unit
nutritional support
avoid medications that interfere with thyroid hormone metabolism and binding including salicylates (see
Levothyroxine interactions for additional information)
see also Thyroid storm
Management of subclinical hyperthyroidism
patients with thyroid stimulating hormone (TSH) is persistently < 0.1 milliunits/L(2)
treatment recommended in patients with the following risk factors (ATA Strong recommendation,
≥ 65 years old
postmenopausal women not on estrogens or bisphosphonates
cardiac risk factors, heart disease, or osteoporosis
hyperthyroid symptoms
consider treatment in asymptomatic individuals < 65 years old without risk factors (ATA Weak
recommendation, Moderate-quality evidence )
patients with TSH below lower limit of normal but ≥ 0.1 milliunits/L(2)
consider treatment in the following patients (ATA Weak recommendation, Moderate-quality
evidence)
individuals ≥ 65 years old
patients with cardiac risk factors
patients with hyperthyroid symptoms
consider observation without further investigation of etiology of subnormal TSH or treatment in
asymptomatic patients < 65 years old and
without cardiac disease or osteoporosis
if treatment is required treatment strategy depends on etiology of thyroid dysfunction and follow same
principles as for overt hyperthyroidism (ATA Strong recommendation, Low-quality evidence)(2)
see Hyperthyroidism and other causes of thyrotoxicosis for additional information
Management of Graves disease in pregnancy and lactating women
management during pregnancy(6)

antithyroid drugs are the mainstay of treatment
treatment goal should balance effects on maternal and fetal thyroid function
antithyroid drugs can cross the placenta and potential impact on fetal thyroid function is
often greater than risks in mother
in general, lowest possible dose should be used
treatment goal is to maintain maternal total or free thyroxine (T4) at or just above
pregnancy-specific upper limit of normal
propylthiouracil (PTU) is the preferred antithyroid drug during first trimester due to potential
teratogenicity of other antithyroid medications such as methimazole (MMI)
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PTU is associated with liver toxicity and use limited to first trimester is suggested
decision to continue, to switch, or to stop antithyroid drug depends on risk of developing
thyrotoxicosis after removing antithyroid drugs
high-risk patients (hyperthyroid status or requiring MMI > 5-10 mg/day or PTU > 100-
200 mg/day to maintain euthyroid status)
give or continue PTU through week 16 of pregnancy (ATA Strong
consider switching women who are taking MMI to PTU as early as possible
use a dose ratio of approximately 1:20 when switching from MMI to PTU (for
example, MMI 5 mg/day is equivalent to 100 mg/day in 2 divided doses) (ATA
Strong recommendation, Moderate-quality evidence)
after 16 weeks, no recommendation can be made regarding whether PTU should
be continued or therapy changed to MMI since both medications are associated
with potential adverse effects and shifting potentially may lead to a period of
less-tight control (ATA No recommendation, Insufficient evidence)
give MMI and PTU at lowest effective dose with target serum FT4/TT4 at the
upper limit or moderately above the reference range (ATA Strong
low-risk patients (euthyroid status taking MMI ≤ 5-10 mg/day or PTU ≤ 100-200
mg/day)
consider stopping all antithyroid medication after assessment of disease history
and other risk factors in patients who are newly pregnant (ATA Weak
risk of rapid relapse after stopping antithyroid medication is higher if
size of goiter is large
duration of therapy < 6 months
prepregnancy thyroid-stimulating hormone (TSH) was low while on
medication
thyroid receptor antibody titer is high
after stopping medications, follow up every 1-2 weeks with clinical examination
and maternal thyroid function testing (TSH and FT4 or TT4), this can be
extended to every 2-4 weeks during second and third trimester if euthyroid status
maintained (ATA Weak recommendation, Low-quality evidence)
consider clinical and biochemical data at each assessment of maternal thyroid
status when deciding whether or not to continue withholding antithyroid
medication (ATA Weak recommendation, Low-quality evidence)
block-replacement therapy that combines levothyroxine and antithyroid drugs should not be
used in pregnancy except in rare cases of isolated fetal hyperthyroidism (ATA Strong
adverse effects associated with antithyroid drugs
PTU and MMI reported to be associated with similar incidence of birth defects, but
birth defects appear to be less severe with PTU than MMI
PTU-associated birth defects include face and neck cysts (considered minor) and
urinary tract abnormalities in males
MMI-associated birth defects include aplasia cutis, methimazole embryopathy,
choanal or esophageal atresia, ventricular septal defects, and other defects of
abdominal wall, eye, and urinary system
thyroidectomy
thyroidectomy may be indicated for unique scenarios; consider in cases of (ATA Strong
allergies or contraindications to both propylthiouracil and methimazole
noncompliance with drug therapy
euthyroid status not achieved despite high doses of antithyroid drugs
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if required, optimal time for thyroidectomy is second trimester (ATA Strong recommendation,
High-quality evidence)
beta blockers
can be used to treat adrenergic symptoms until euthyroid state achieved with antithyroid
drugs
may be used in preparation for thyroidectomy
Reference - Curr Opin Obstet Gynecol 2015 Dec;27(6):406
monitoring disease during pregnancy(6)
monitor free T4 (FT4) or total T4 (TT4) and TSH (and in cases of severe hyperthyroidism, also
serum tri-iodothyronine [T3])
every 4 weeks in pregnant women taking antithyroid drugs (ATA Strong recommendation,
every 4-6 weeks after achieving the target value
need for ongoing monitoring of TRAb depends on initial TRAb measurement and use of antithyroid
drugs
if TRAb is elevated in early pregnancy, perform repeat testing of TRAb levels at weeks 18-22
if TRAb is undetectable or low in early pregnancy, consider not retesting levels (ATA Weak
if patient requires antithyroid drugs through midpregnancy, repeat TRAb measurement at
weeks 18-22 (ATA Strong recommendation, Moderate-quality evidence)
if TRAb is elevated during weeks 18-22 or mother is taking antithyroid medication in third
trimester, perform TRAb measurement again in weeks 30-34 to evaluate need for neonatal
and postnatal monitoring (ATA Strong recommendation, High-quality evidence)
fetal monitoring
perform fetal ultrasound (in consultation with experienced obstetrician or maternal-fetal
medicine specialist) in women with ≥ 1 of (ATA Strong recommendation, Moderate-quality
evidence)
uncontrolled hyperthyroidism in second half of pregnancy
thyroid receptor antibody (TRAb) > 3 times upper limit of normal at any time during
pregnancy
fetal ultrasound may be used to assess heart rate, growth, volume of amniotic fluid, and
presence of fetal goiter
umbilical cord blood sampling to determine fetal thyroid status should be reserved for rare
situations and should be performed in appropriate setting; may occasionally be useful when
fetal goiter is detected in a woman taking antithyroid drugs (ATA Weak recommendation,
Reference - Curr Opin Obstet Gynecol 2015 Dec;27(6):406
management of Graves disease in lactating women(6)
treatment decisions should be guided by same considerations applied to nonbreastfeeding women
(ATA Strong recommendation, Low-quality evidence)
no recommendations to treat hyperthyroidism because the impact on lactation is not well understood
(ATA No recommendation, Insufficient evidence)
both MMI and PTU are detected in breast milk of women treated with antithyroid medications;
however, American Thyroid Association (ATA) recommends antithyroid medication for treatment in
lactating women (ATA Strong recommendation, Moderate-quality evidence)
both MMI (≤ 20 mg/day) and PTU (≤ 450 mg/day) can be administered in lactating women
lowest effective doses should be used
do not use of 131 I (radioactive iodine) during lactation (ATA Strong recommendation, Moderate-
quality evidence)
consider (ATA Weak recommendation, Moderate-quality evidence)
monitoring breastfed children of women treated with antithyroid drugs for appropriate growth
and development during routine pediatric health check
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routine assessment of serum thyroid function in child not suggested
Complications and Prognosis

Complications
thyroid storm(2)
exacerbation of Graves disease may lead to thyroid storm, an endocrine emergency (can be life-
threatening), that involves severe signs and symptoms of hyperthyroidism and multiorgan
decompensation
mortality reported in 8%-25% of patients with life-threatening thyrotoxicosis or thyroid storm
in patients with previously compensated thyrotoxicosis, precipitants of thyroid storm include
abrupt discontinuation of antithyroid medications
thyroidectomy or nonthyroidal surgery with unrecognized or inadequate treatment of
thyrotoxicosis
acute illnesses unrelated to thyroid disease
radioactive iodine therapy (occasionally)
in patients with unrecognized thyrotoxicosis, precipitants of thyroid storm include
nonthyroid surgery
trauma
infection
iodine exposure due to radiocontrast dye or amiodarone
Reference - J Intensive Care Med 2015 Mar;30(3):131
clinical manifestations of thyroid storm include
diagnose thyroid storm based on clinical manifestations of severe thyrotoxicity and evidence
of systemic decompensation and use diagnostic system to determine use of aggressive therapy
patients with Burch-Wartofsky Point Scale (BWPS) of 45 or Japanese Thyroid
Association categories of thyroid storm 1 or 2 with systemic decompensation require
aggressive therapy
for patients with BWPS of 25-44, use of aggressive therapy is based on clinical
judgement
prevention of thyroid storm include
recognizing and avoiding common precipitants
informing patients of risks associated with abrupt discontinuation of antithyroid
medication
ensuring patients are euthyroid prior to elective surgery, labor and delivery, or other
stressors
high fever (temperature as high as 40-41.1 degrees C [104-106 degrees F] has been reported)
excessive sweating leading to large fluid losses due to high fever (helps differentiate thyroid
storm from thyrotoxicosis)
cardiac manifestations such as
tachycardia that is out of proportion to underlying condition
palpitations
exercise intolerance
dyspnea on exertion
widened pulse pressure
cardiac ischemia
atrial fibrillation
increase in cardiac output and tachyarrhythmia, which may lead to development of
heart failure symptoms and progress to cardiovascular collapse and shock
central nervous system manifestations such as
agitation
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delirium
confusion to stupor
obtundation
coma
gastrointestinal manifestations (leads to volume depletion) such as
nausea
profuse vomiting
severe diarrhea
liver manifestations such as
liver dysfunction
hepatomegaly due to hepatic congestion
hypoperfusion
elderly patients with apathetic hyperthyroidism have a higher tendency to develop thyroid
storm due to delayed diagnosis of hyperthyroidism with apathy, obtundation, and cardiac
failure as symptoms with minimal indication of thyrotoxicosis
jaundice
Reference - J Intensive Care Med 2015 Mar;30(3):131
see also Thyroid storm
complications of hyperthyroidism(1, 3, 4, 5)
atrial fibrillation
rare in patients aged < 60 years but reported to occurs in > 10% of patients aged ≥ 60 years;
risk of atrial fibrillation reported to be 3 times higher among patients ≥ 60 years old compared
to those with healthy thyroid
embolic stroke related to atrial fibrillation
prevalence of embolic stroke secondary to hyperthyroidism reported to be higher
compared to embolic stroke from nonthyroidal causes
use of anticoagulant therapy in patients with hyperthyroidism and atrial fibrillation is
still open for debate
heart failure reported to be the main cause of cardiovascular mortality among patients with
hyperthyroidism and atrial fibrillation may be an independent predictive factor of
development of heart failure
toxic nodular hyperthyroidism, male gender, higher serum free thyroxine concentration
at diagnosis, and older age associated with increased risk atrial fibrillation
3,049 patients (mean age 46.6 years) with hyperthyroidism presenting to
secondary/tertiary clinic for care evaluated for presenting symptoms
1,189 patients (39%) had Graves disease
4.1% had clinical sign of atrial fibrillation at presentation
factors associated with increased risk of atrial fibrillation
toxic nodular hyperthyroidism (adjusted OR 3.12, 95% CI 1.26-7.79)
older age (per year) (adjusted odds ratio [OR] 1.08, 95% CI 1.06-1.1)
higher serum free thyroxine concentrations at diagnosis (per 1 pmol/L) (adjusted
OR 1.01, 95% CI 1-1.02)
female gender associated with decreased risk of atrial fibrillation (adjusted OR 0.59,
95% CI 0.36-0.96)
upper airway or esophageal obstruction due to large goiter leading to dyspnea
hypokalemic periodic paralysis (thyrotoxic periodic paralysis)
reported to be more common among Asian patients; reported incidence 0.2% in North
America and 2% in Japan
characterized by muscle paralysis, acute hypokalemia, and thyrotoxicosis due to potassium
shift into muscle cells
osteopenia, osteoporosis, and fractures
72/83
history of low thyroid stimulating hormone level (≤ 0.1 milliunits/L) and history of
hyperthyroidism might increase risk of vertebral fracture and hip fracture
686 women > 65 years old evaluated for relation of thyroid function and new hip or
vertebral fracture and followed for mean of 3.7 years
relative risks ranged from 2.2 to 4.5 but findings were of borderline statistical
significance
after adjustments for age, body weight, calcaneal bone mineral density
history of low thyroid stimulating hormone associated with risk for new
hip fracture (hazard ratio [HR] 3.6, 95% CI 1-12.9)
vertebral fracture (odds ratio [OR] 4.5, 95% CI 1.3-15.6)
nonspine fracture (HR 2.3, 95% CI 0.8-6.8)
history of hyperthyroidism associated with risk for new
hip fracture (HR 2.2, 95% CI 1-4.4)
vertebral fracture (OR 1.3, 95% CI 0.6-2.9)
nonspine fracture (HR 0.9, 95% CI 0.4-2)
Reference - Ann Intern Med 2001 Apr 3;134(7):561
fatal thyrotoxic cardiomyopathy of young man with hyperthyroid Graves disease in case report
(BMJ 2008 Nov 28;337:a531, commentary can be found in BMJ 2009 Mar 9;338:b955)
hepatitis in 34-year-old woman with hyperthyroid Graves disease in case report (Isr Med Assoc J
2011 Jul;13(7):448 full-text)
cholestasis in 47-year-old man and 67-year-old woman with hyperthyroidism in case series (J Med
Case Rep 2008 Apr 21;2:116 full-text)
complications of ophthalmopathy(1, 4)
corneal ulceration
diplopia and blurred vision
photophobia
reduced visual acuity
optic neuropathy
potential complications of Graves hyperthyroidism associated with pregnancy
maternal complications
pregnancy-induced hypertension (see Hypertensive disorders of pregnancy)
heart failure
thyroid storm
placental abruption
first trimester pregnancy loss
preterm delivery
fetal complications
low birth weight - prematurity, small for gestational age, intrauterine growth restriction
(IUGR)
stillbirth
thyroid dysfunction
fetal hypothyroidism can occur with antithyroid drug therapy
fetal or neonatal hyperthyroidism (neonatal Graves disease) with placental transfer of
TSH receptor-stimulating antibody
Reference - Endocr Pract 2010 Jan-Feb;16(1):118
Prognosis
mortality
hyperthyroidism associated with increased mortality
73/83
systematic review of 6 cohort studies and 1 case-control study evaluating association between
hyperthyroidism and risk of mortality in 31,138 adults
hyperthyroidism associated with increased overall mortality (relative risk 1.21, 95% CI 1.05-
1.38) in analysis of 7 studies with 31,138 patients , results limited by heterogeneity
Reference - Eur J Endocrinol 2011 Oct;165(4):491
remission and relapse(2)
without treatment - up to 30% spontaneous remission reported in mild Graves disease(2)
with antithyroid medications
remission defined by normal serum thyroid-stimulating hormone (TSH), free thyroxine (FT4),
and total tri-iodothyronine (TT3) for 1 year after discontinuation of antithyroid medication
therapy
reported remission rates vary between studies
about 20%-30% of patients were reported to have a lasting remission after 12-18
months of medication
remission rate reported higher in Europe and Japan; long-term study in Europe study
reported 50%-60% remission rate after 5-6 years of treatment and study in Japan
reported 68% remission rate after 2 years of treatment
in pooled analysis of 6 studies with 508 patients on long term (> 24 months) antithyroid
drug treatment for Graves disease, remission reported in 61% (Thyroid 2017
Oct;27(10):1223)
factors that influence treatment response and relapse
in systematic review of 31 studies with 4,364 patients followed for ≥ 12 months after
withdrawal of antithyroid medication
factors associated with increased relapse included
orbitopathy
smoking
greater thyroid volume assessed by ultrasound
larger goiter size
elevated free thyroxine (FT4)
elevated total tri-iodothyronine (TT3)
elevated thyrotropin receptor antibodies
factors not associated with relapse included
age at diagnosis
sex
initial total thyroxine levels
Reference - Eur J Endocrinol 2017 Jan;176(1):87
effect of smoking (current or past smokers) on antithyroid medication treatment
smoking associated with slower response to carbimazole treatment
based on retrospective cohort study without clinical outcomes
59 patients with Graves disease (25 smokers, 34 nonsmokers) were treated
with carbimazole and assessed for thyrotropin receptor antibodies (TRAb),
FT4, and TT3 during first 12 months of therapy
smoking associated with significantly slower reduction in thyroid hormone
receptor antibody, FT4, and T3 levels t (p ≤ 0.02 for each)
no significant differences in TRAb, FT4, and TT3 levels at 12 months, but
higher doses of carbimazole required in patients who smoked (p = 0.04)
Reference - JAMA 2009 Jan 14;301(2):162
presence of thyrotropin receptor antibodies at end of antithyroid drug
treatment and smoking each associated with increased risk of recurrence in
adults with Graves hyperthyroidism
82 adults (mean age 36 years, 85% women) treated with antithyroid drugs
for first episode of Graves hyperthyroidism were randomized to thyroxine
74/83
100 mcg/day vs. placebo for 12 months after discontinuation of antithyroid

medication and assessed for recurrence
before randomization, all patients received antithyroid medication for 15
months plus thyroxine (started after becoming euthyroid) for ≥ 12 months
recurrence defined as clinical hyperthyroidism plus low TSH and elevated
free thyroid hormone level after discontinuation of study drug
8 patients with low TSH but borderline elevated FT4 and normal FT3 were
excluded from analysis
recurrence in 31% (23 patients) after antithyroid medication withdrawal
factors associated with recurrence
positive TRAb at end of antithyroid drug treatment (odds ratio 27.7,
95% CI 3-256)
smoking (odds ratio 7, 95% CI 1.4-36)
Reference - Eur J Endocrinol 2001 May;144(5):475
effect of gender on antithyroid mediation treatment and radioactive iodine treatment
99mTc-pertechnetate thyroid uptake ≤ 15.2% and thyroid mass ≤ 40.1 g with
successful radioactive iodine treatment in patients with Graves disease
118 patients (mean age 40 years) with Graves disease were evaluated by
99mTc-pertechnetate thyroid scintigraphy and had thyroid mass evaluated
prior to receiving fixed dose (5 millicurie) of radioactive iodine therapy
all patients came from iodine sufficient areas in east China
follow up was ≥ 12 months after radioactive iodine therapy
successful radioactive iodine therapy defined as achievement of
euthyroidism or hypothyroidism based on thyroid function tests
41.53% patients were euthyroid, 29.6% were hypothyroid and 28.81%
remained hyperthyroid after radioactive iodine as assessed by thyroid
function tests
factors associated with successful treatment in multivariable analysis
99mTc-pertechnetate uptake ≤ 15.2% (odds ratio 4.77, 95% CI 1.53-
14.91)
thyroid mass ≤ 40.1 g (odds ratio 6.35, 95% CI 1.99-20.99)
Reference - Biomed Res Int 2015;2015:974689 full-text
male gender associated with reduced response to antithyroid medication or
radioactive iodine therapy for Graves disease compared to females
536 children and adults (aged 8-77 years, 82.8% female) with Graves
hyperthyroidism evaluated at presentation and after treatment with
antithyroid medication and/or radioactive iodine
outcome assessed in 79% (423 patients)
at baseline, males had higher mean FT3 levels
outcomes for antithyroid medication
treatment success after antithyroid medication (defined as euthyroid
for ≥ 6 months after medication withdrawal) in 37% of 214 patients
taking antithyroid medication as initial therapy
treatment success after antithyroid medication in
19.6% of males vs. 40% of females (p < 0.01)
33% of patients < 40 years old vs. 48% of patients ≥ 40 years
old (p = 0.01)
outcomes for radioactive iodine therapy
cure after 1 dose of radioactive iodine (defined as euthyroid off of all
treatment for 6 months or need for thyroxine replacement therapy) in
75/83
68% of 288 patients treated with radioactive iodine initially or after

failed antithyroid medication therapy
cure after 1 dose of radioactive iodine in 47% of males vs. 74%
females (p < 0.0001)
Reference - J Clin Endocrinol Metab 2000 Mar;85(3):1038
adverse effects on quality-of-life due to somatic and psychiatric symptoms and inability to work(1)
hyperthyroidism in Graves disease associated with increased risk of hospitalization due to
psychiatric illness
3,006 patients with hyperthyroidism and 10,899 patients without hyperthyroidism were
hyperthyroidism in Graves disease associated with increased risk of hospitalization due to
psychiatric diagnosis (odds ratio 2.23 95% CI 1.3-3.83)
Reference - Eur J Endocrinol 2014 Feb;170(2):341, commentary can be found in Nat Rev
Endocrinol 2014 Feb;10(2):65
hyperthyroidism in Graves disease associated with severe work disability and loss of labor
market income
2,526 patients with hyperthyroidism and 8,352 individuals without hyperthyroidism and
hyperthyroidism in Graves disease associated with
increased risk of receiving disability pension (hazard ratio [HR] 1.51, 95% CI 0.87-
2.63)
significant loss of labor market income (p < 0.001)
Reference - Eur J Endocrinol 2015 Nov;173(5):595
Prevention and Screening

Prevention
not applicable
Screening
consider measuring thyroid-stimulating hormone (TSH) in persons > 70 years old with atypical
presentations because typical clinical manifestations and goiter may be absent
anorexia with wasting
atrial fibrillation
heart failure
Reference - Arch Intern Med 2000 Apr 24;160(8):1067
Quality Improvement
Choosing Wisely
American Society for Clinical Pathology recommends against ordering multiple tests in the initial
evaluation of a patient with suspected thyroid disease, and instead recommends ordering thyroid-
stimulating hormone (TSH) and if abnormal following-up with additional evaluation or treatment
depending on the findings (Choosing Wisely 2015 Feb 3)
Choosing Wisely Canada

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Canadian Society of Endocrinology and Metabolism recommends against routinely testing for antithyroid
peroxidase (anti-TPO) antibodies
positive anti-TPO titers are not unusual in the "normal" population
presence of positive anti-TPO titers, in the context of thyroid disease, only assists in indicating that
the pathogenesis is probably autoimmune
as thyroid autoimmunity is a chronic condition, once diagnosed there is rarely a need to remeasure
anti-TPO titers
in euthyroid pregnant patients deemed at high risk of developing thyroid disease, anti-TPO
antibodies may influence the frequency of surveillance for hypothyroidism during the pregnancy
it is uncommon that measurement of anti-TPO antibodies influences patient management
Reference - Choosing Wisely Canada 2014 Oct 29
Guidelines and Resources

Guidelines
International guidelines
American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and
the Postpartum. Thyroid. 2017 Mar;27(3):315-389, editorial can be found in Thyroid 2017 Mar;27(3):309,
commentaries can be found in Thyroid 2017 Sep;27(9):1209, Nat Rev Endocrinol 2017 Apr;13(4):192
Society of Nuclear Medicine and Molecular Imaging (SNMMI) practice guideline on therapy of thyroid
disease with iodine 131 (131I) can be found at SNMMI 2012 Oct PDF or in J Nucl Med 2012
Oct;53(10):1633 full-text, commentary can be found in J Nucl Med 2013 Feb;54(2):327
United States guidelines
American Thyroid Association (ATA) guideline on diagnosis and management of hyperthyroidism and
other causes of thyrotoxicosis. Thyroid 2016 Oct;26(10):1343
American Thyroid Association (ATA) guideline on diagnosis and management of thyroid disease during
pregnancy and postpartum can be found in Thyroid 2017 Mar;27(3):315
American Thyroid Association (ATA) practice recommendation on radiation safety in treatment of patients
with thyroid diseases by radioiodine 131I can be found in Thyroid 2011 Apr;21(4):335 full-text
Endocrine Society clinical practice guideline on management of thyroid dysfunction during pregnancy and
post partum can be found in J Clin Endocrinol Metab 2012 Aug;97(8):2543, editorial can be found in J
Clin Endocrinol Metab 2012 Aug;97(8):2632, commentary can be found in Nat Rev Endocrinol 2012
Nov;8(11):624
American College of Radiology (ACR) Appropriateness Criteria for orbits, vision, and visual loss can be
found at ACR 2017 PDF or in J Am Coll Radiol 2018 May;15(5S):S116
United Kingdom guidelines
British Thyroid Association (BTA) guideline on management of patients with Graves' orbitopathy: initial
assessment, management outside specialised centres and referral pathways can be found in Clin Med
(Lond) 2015 Apr;15(2):173
77/83
Association for Clinical Biochemistry/British Thyroid Association/British Thyroid Foundation

(ACB/BTA/BTF) guideline on use of thyroid function tests can be found at ACB/BTA/BTF 2006 Jul PDF
Canadian guidelines
British Columbia Medical Services Commission (MSC) guideline on diagnoses and monitoring of thyroid
function disorders in adults can be found at MSC 2010 Jan PDF
European guidelines
European Group on Graves Orbitopathy (EUGOGO) consensus statement on management of Graves

orbitopathy can be found in Thyroid 2008 Mar;18(3):333, commentary can be found in Thyroid 2008
Mar;18(3):281
German Association of Endocrine Surgeons (Chirurgischen Arbeitsgemeinschaft für Endokrinologie

[CAEK]) practice guideline on surgical treatment of benign thyroid disease can be found in Langenbecks
Arch Surg 2011 Jun;396(5):639
Polish Society of Endocrinology/Polish Diabetes Association recommendations on management of thyroid

dysfunction in type 1 and type 2 diabetes can be found in Endokrynol Pol 2013;64(1):73
Asian guidelines
Japan Thyroid Association (JTA) guideline on diagnosis of Graves disease can be found at JTA
Review articles
review of management of hyperthyroidism due to Graves disease can be found in J Endocrinol Invest
2016 Oct;39(10):1105
review of antithyroid drug therapy for Graves disease can be found in Int J Endocrinol
2017;2017:3813540 full-text
review of antithyroid drugs can be found in N Engl J Med 2005 Mar 3;352(9):905, commentary can be
found in N Engl J Med 2005 May 26;352(21):2246
review of surgical treatment of Graves disease can be found in World J Surg 2008 Jul;32(7):1269
review of thyrotoxicosis can be found in BMJ 2006 Jun 10;332(7554):1369 full-text
review of diagnosis and treatment of hyperthyroidism can be found in Am Fam Physician 2016 Mar
1;93(5):363 full-text, commentary can be found in Am Fam Physician 2016 Oct 1;94(7):530
review of radioiodine therapy in hyperthyroidism can be found in N Engl J Med 2011 Feb 10;364(6):542,
commentary can be found in N Engl J Med 2011 May 19;364(20):1978, N Engl J Med 2011 May
19;364(20):1978
review of selenium and thyroid disease can be found in Int J Endocrinol 2017;2017:1297658 full-text
thyroid orbitopathy
review of grading severity and activity in thyroid eye disease can be found in Ophthalmic Plast
Reconstr Surg 2018 Jul/Aug;34(4S Suppl 1):S34
review of advances in treatment of mild, moderate, and severe thyroid eye disease (Graves disease)
can be found in Curr Opin Ophthalmol 2017 Sep;28(5):505
review of advanced in pharmacological treatment of Graves orbitopathy can be found in Expert Rev
Clin Pharmacol 2016 Jul;9(7):981
review of Graves ophthalmopathy can be found in N Engl J Med 2010 Feb 25;362(8):726
review of efficacy and safety of orbital radiation therapy for Graves orbitopathy can be found in J
Clin Endocrinol Metab 2012 Nov;97(11):3857
review of Graves ophthalmopathy can be found in N Engl J Med 2009 Mar 5;360(10):994,
correction can be found in N Engl J Med 2011 Feb 24;364(8):785
78/83
review of thyroid eye disease can be found in BMJ 2009 Mar 6;338:b560
thyrotoxic periodic paralysis
review of thyrotoxic periodic paralysis can be found in Mayo Clin Proc 2005 Jan;80(1):99,
commentary can be found in Mayo Clin Proc 2005 Jul;80(7):960
case presentations of thyrotoxic periodic paralysis can be found in
Lancet 2008 Mar 8;371(9615):870
J Am Board Fam Med 2010 Jul-Aug;23(4):551 full-text
CMAJ 2005 Feb 15;172(4):471 full-text
N Engl J Med 2012 Feb 9;366(6):553
review of thyroid disease in pregnancy can be found in Obstet Gynecol 2006 Nov;108(5):1283
MEDLINE search
to search MEDLINE for (Graves disease) with targeted search (Clinical Queries), click therapy, diagnosis,
or prognosis
Patient Information
handout from American Thyroid Association PDF
handout from National Library of Medicine PDF
information from Office on Women's Health, United States Department of Health & Human Services
handout from National Endocrine and Metabolic Diseases Information Service PDF
ICD Codes
ICD-10 codes
E05 thyrotoxicosis [hyperthyroidism]

E05.0 thyrotoxicosis with diffuse goiter
E05.1 thyrotoxicosis with toxic single thyroid nodule
E05.2 thyrotoxicosis with toxic multinodular goiter
E05.3 thyrotoxicosis from ectopic thyroid tissue
E05.4 thyrotoxicosis factitia
E05.5 thyroid crisis or storm
E05.8 other thyrotoxicosis
E05.9 thyrotoxicosis, unspecified
H06.2 dysthyroid exophthalmos
References
General references used
1. Smith TJ, Hegedüs L. Graves' Disease. N Engl J Med. 2016 Oct 20;375(16):1552-1565, commentaries
can be found in N Engl J Med 2017 Jan 12;376(2):184, N Engl J Med 2017 Jan 12;376(2):185
2. Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association Guidelines for Diagnosis
and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016
Oct;26(10):1343-1421, correction can be found in Thyroid 2017 Nov;27(11):1462
3. Burch HB, Cooper DS. Management of Graves Disease: A Review. JAMA. 2015 Dec 15;314(23):2544-
54
4. Menconi F, Marcocci C, Marinò M. Diagnosis and classification of Graves' disease. Autoimmun Rev.
2014 Apr-May;13(4-5):398-402
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5. De Leo S, Lee SY, Braverman LE. Hyperthyroidism. Lancet. 2016 Aug 27;388(10047):906-918 full-
text
6. Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for
the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017
Mar;27(3):315-389, correction can be found in Thyroid 2017 Sep;27(9):1212, editorial can be found in
Thyroid 2017 Mar;27(3):309, commentaries can be found in Thyroid 2017 Sep;27(9):1209, Nat Rev
Endocrinol 2017 Apr;13(4):192
Recommendation grading systems used

American Thyroid Association (ATA) grades of recommendation
grades of recommendation
Strong recommendation, High-quality evidence - can be offered to most patients in most
applicable circumstances without reservation
Strong recommendation, Moderate-quality evidence - can be offered to most patients in most
applicable circumstances without reservation
Strong recommendation, Low-quality evidence - can be offered to most patients in most
applicable circumstances; may change when higher-quality evidence becomes available
Weak recommendation, High-quality evidence - best action may differ based on
circumstances or patients’ values
Weak recommendation, Moderate-quality evidence - best action may differ based on
circumstances or patients’ values
Weak recommendation, Low-quality evidence - alternative options may be equally reasonable
Insufficient - insufficient evidence to recommend for or against
levels of evidence
for therapeutic interventions
High-quality evidence - RCT without important limitations or overwhelming evidence
from observational studies
Moderate-quality evidence - RCT with important limitations or strong evidence from
observational studies
Low-quality evidence - observational studies/case studies
Insufficient - evidence is conflicting, of poor quality, or lacking
for diagnostic interventions
High-quality evidence - evidence from ≥ 1 well-designed nonrandomized diagnostic
accuracy studies or systematic reviews/meta-analyses of such observational studies
with no concern about internal validity or external generalizability of the results
Moderate-quality evidence - evidence from nonrandomized diagnostic accuracy studies
with ≥ 1 possible limitations causing minor concern about internal validity or external
generalizability of the results
Low-quality evidence - evidence from nonrandomized diagnostic accuracy studies with
≥ 1 important limitations causing serious concern about internal validity or external
generalizability of the results
Insufficient - evidence may be of such poor quality, conflicting, lacking, or not
externally generalizable to the target clinical population such that the estimate of the
true effect of the test is uncertain and does not permit a reasonable conclusion to be
made
References -
ATA guideline on diagnosis and management of hyperthyroidism and other causes of
thyrotoxicosis (Thyroid 2016 Oct;26(10):1343), correction can be found in Thyroid 2017
Nov;27(11):1462
ATA guideline on diagnosis and management of thyroid disease during pregnancy and the
postpartum (Thyroid 2017 Mar;27(3):315), correction can be found in Thyroid 2017
Sep;27(9):1212, editorial can be found in Thyroid 2017 Mar;27(3):309, commentaries can be
found in Thyroid 2017 Sep;27(9):1209, Nat Rev Endocrinol 2017 Apr;13(4):192
80/83
European Thyroid Association/European Group on Graves' Orbitopathy (ETA/EUGOGO)

recommendations based on Grading of Recommendations, Assessment, Development, and Evaluation
(GRADE)
strength of recommendation
Strong - desirable effects of intervention clearly outweigh undesirable effects, or vice versa
Conditional - uncertainty over whether desirable effects of intervention outweigh undesirable
effects
quality of evidence
High-quality evidence - evidence from well-performed randomized controlled trials (RCTs) or
strong evidence from unbiased observational studies; further research very unlikely to change
confidence in estimate of effect
Moderate-quality evidence - evidence from RCTs with important limitations (inconsistent
results, indirect evidence, methodological flaws), or strong evidence from unbiased
observational studies; further research likely to have important impact on confidence in
estimate of effect; estimate may change
Low-quality evidence - evidence for ≥ 1 observational study, RCTs with serious flaws; further
research very likely to have important impact on confidence in estimate of effect; estimate
will likely change
Very low-quality evidence - evidence for ≥ 1 critical outcome from unsystematic clinical
observations or very indirect evidence; any estimate of effect very uncertain
Reference - ETA/EUGOGO 2016 guideline on management of Graves' orbitopathy (Eur Thyroid J
2016 Mar;5(1):9 full-text)
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We use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to classify
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Strong recommendations are used when, based on the available evidence, clinicians (without
conflicts of interest) consistently have a high degree of confidence that the desirable consequences
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Weak recommendations are used when, based on the available evidence, clinicians believe that
desirable and undesirable consequences are finely balanced, or appreciable uncertainty exists about
the magnitude of expected consequences (benefits and harms). Weak recommendations are used
when clinicians disagree in judgments of relative benefit and harm, or have limited confidence in
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for most patients. Weak recommendations use "consider" or "suggested" phrasing.
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All editorial team members and reviewers have declared that they have no financial or other competing
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DynaMed provides Practice-Changing DynaMed Updates, with support from our partners, McMaster
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Special acknowledgements
Mira Sofia Torres, MD (Program Director, Fellowship in Endocrinology, Diabetes, and Metabolism, and
Associate Professor, Department of Medicine, University of Massachusetts Medical School;
Massachusetts, United States)
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Dr. Torres declares no relevant financial conflicts of interest.
Zbys Fedorowicz, MSc, DPH, BDS, LDSRCS (Director of Bahrain Branch of the United Kingdom
Cochrane Center, The Cochrane Collaboration; Awali, Bahrain)
Dr. Fedorowicz declares no relevant financial conflicts of interest.
Alan Ehrlich, MD (Executive Editor; Associate Professor of Family Medicine, University of

Massachusetts Medical School; Massachusetts, United States)
Dr. Ehrlich declares no relevant financial conflicts of interest.
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How to cite
National Library of Medicine, or "Vancouver style" (International Committee of Medical Journal Editors):
DynaMed Plus [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No. T115280,
Graves disease in adults; [updated 2018 Dec 04, cited place cited date here]. Available from
https://www.dynamed.com/topics/dmp~AN~http://www.dynamed.com/login.aspx?
direct=true&site=DynaMed&id=T115280. Registration and login required.
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4/3/2019 DynaMed Plus: Graves disease in adults

Graves disease in adults

GO is suggestive by clinical presentation, assessment of activity and severity of ophthalmopathy using

orbital decompression if poor or no response within 2 weeks

N Engl J Med 2010 Feb 25;362(8):726 full-text

occurs at any age, with peak incidence at age 30-60 years(1, 3)

black men (incidence RR 2.53, 95% CI 2.01-3.18)

alemtuzumab associated with increased thyroid dysfunction compared to interferon-

no significant difference in Holmes-Rahe stress scores

comparing Graves disease vs. controls

thyroid cancer (adjusted hazard ratio 10.4, 95% CI 6.18-17.4)

Etiology and Pathogenesis

Physiology and regulation of thyroid hormones

physiologic effects of thyroid hormones

History and Physical

Organ System Symptoms Signs

optic neuropathy (reported in 6%)

ask about previous intake or current use of(1, 4)

Reference - J Endocrinol Invest 2015 Mar;38(3):283

Past medical history (PMH)

ask about/look for(1, 4)

Family history (FH)

ask about family history of thyroid disorders and autoimmune disease(1, 4)

Social history (SH)

check for physical signs of hyperthyroidism(1, 3, 4)

pain on attempted upward or downward gaze

Graves disease in adults.

check thyroid size, tenderness, symmetry, and nodularity(2)

check for tachypnea(2)

check for signs of(1, 4)

thyroid acropachy (clubbing of fingers and toes)

look for fine tremor, hyperkinesis, and hyperreflexia(1, 2, 3)

other causes of thyrotoxicosis(2, 5, 6)

typically present within the first year after childbirth

References - (3, 4), N Engl J Med 2008 Jun 12;358(24):2594.

Thyroid function tests

Thyroid stimulating hormone (TSH) assay

serum TSH testing(2)

Thyroid hormone assays

free serum thyroxine (FT4) and tri-iodothyroxine (T3) measurements(2, 4, 6)

Assay for thyroid antibodies

thyrotropin receptor antibodies (TRAb)(1, 2, 3, 4)

radioactive iodine/technetium uptake and scanning(2, 3, 4, 6)

Other imaging studies

electrocardiographic (ECG) findings of thyrotoxicosis

increased QRS voltages

Biopsy and pathology

treatment for Graves disease should take into consideration(4)

assess calcium and 25-hydroxyvitamin D levels preoperatively and replete or

Short- term increase of cancer should not

if impact of disease on quality-of-life outweighs risks, consider

Antithyroid medications (thionamide)

failure to achieve euthyroidism is usually due to nonadherence(2)

frequent testing is required, unless block-replacement therapy is used

Antithyroid drugs options and dosing

Monitoring while on antithyroid drugs

clinical and biochemical evaluation(2)

Duration of treatment with antithyroid drugs

Adverse effects of antithyroid drugs

84.6% developed agranulocytosis within 90 days of treatment initiation

activity of radioactive iodine administered

considerations prior to radioactive iodine therapy(2, 3)

NNT 7-19 with 24.6% rate of hypothyroidism in controls