3/9/2019 https://emedicine.medscape.

com/article/121865-print

emedicine.medscape.com

Hyperthyroidism and
Thyrotoxicosis
Updated: Mar 15, 2018
Author: Stephanie L Lee, MD, PhD; Chief Editor: Romesh Khardori, MD, PhD, FACP

Overview

Practice Essentials
Hyperthyroidism is a set of disorders that involve excess synthesis and secretion of thyroid hormones by the thyroid gland,
which leads to the hypermetabolic condition of thyrotoxicosis.[1] The most common forms of hyperthyroidism include diffuse
toxic goiter (Graves disease), toxic multinodular goiter (Plummer disease), and toxic adenoma. See the image below.

Bilateral erythematous infiltrative plaques on lower extremities in 42-year-old man with Graves disease are consistent with
pretibial myxedema. Myxedematous changes of skin usually occur in pretibial areas and resemble orange peel in color and
texture.

Signs and symptoms

Common symptoms of thyrotoxicosis include the following:

Nervousness

Anxiety

Increased perspiration

Heat intolerance

Hyperactivity

Palpitations

https://emedicine.medscape.com/article/121865-print 1/33
3/9/2019 https://emedicine.medscape.com/article/121865-print
Common signs of thyrotoxicosis include the following:

Tachycardia or atrial arrhythmia

Systolic hypertension with wide pulse pressure

Warm, moist, smooth skin

Lid lag

Stare

Hand tremor

Muscle weakness

Weight loss despite increased appetite (although a few patients may gain weight, if excessive intake outstrips weight
loss)

Reduction in menstrual flow or oligomenorrhea

Presentation of thyrotoxicosis varies, as follows[2] :

Younger patients tend to exhibit symptoms of sympathetic activation (eg, anxiety, hyperactivity, tremor)

Older patients have more cardiovascular symptoms (eg, dyspnea, atrial fibrillation) and unexplained weight loss

Patients with Graves disease often have more marked symptoms than patients with thyrotoxicosis from other causes

Ophthalmopathy (eg, periorbital edema, diplopia, or proptosis) suggests Graves disease

See Clinical Presentation for more detail.

Diagnosis

Thyroid function tests for hyperthyroidism are as follows:

Thyroid-stimulating hormone (TSH)

Free thyroxine (FT4) or free thyroxine index (FTI—total T4 multiplied by the correction for thyroid hormone binding)

Total triiodothyronine (T3)

Thyroid function study results in hyperthyroidism are as follows:

Thyrotoxicosis is marked by suppressed TSH levels and elevated T3 and T4 levels

Patients with milder thyrotoxicosis may have elevation of T3 levels only

Subclinical hyperthyroidism features decreased TSH and normal T3 and T4 levels

Autoantibody tests for hyperthyroidism are as follows:

Anti–thyroid peroxidase (anti-TPO) antibody - Nonspecific elevation with autoimmune thyroid disease found in 85% of
Graves patients

Thyroid-stimulating antibody (TSab) - Also known as thyroid-stimulating immunoglobulin (TSI), long-acting thyroid
stimulator (LATS), or TSH-receptor antibody (TRab); found in 63-81% of Graves disease; a positive test is diagnostic and
specific for Graves disease

Autoantibody titers in hyperthyroidism are as follows:

Graves disease - Significantly elevated anti-TPO, elevated TSab

Toxic multinodular goiter - Low or absent anti-TPO and TSab

Toxic adenoma - Low or absent anti-TPO and TSab

Patients without active thyroid disease may have mildly positive anti-TPO and TSab

https://emedicine.medscape.com/article/121865-print 2/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

If the etiology of thyrotoxicosis is not clear after physical examination and other laboratory tests, it can be confirmed by
scintigraphy: the degree and pattern of isotope uptake indicates the type of thyroid disorder. Findings are as follows:

Graves disease – Diffuse enlargement of both thyroid lobes, with uniform uptake of isotope and elevated radioactive
iodine uptake

Toxic multinodular goiter -- Irregular areas of relatively diminished and occasionally increased uptake; overall radioactive
iodine uptake is mildly to moderately increased

Subacute thyroiditis –Very low radioactive iodine uptake

See Workup for more detail.

Management

Treatment of hyperthyroidism includes symptom relief, as well as therapy with antithyroid medications, radioactive iodine-131
(131I), or thyroidectomy. Symptomatic treatment is as follows:

Oral rehydration for dehydrated patients

Beta-blockers for relief of neurologic and cardiovascular symptoms

For mild ophthalmopathy, saline eye drops as needed and tight-fitting sunglasses for outdoors

For vision-threatening ophthalmopathy, high-dose glucocorticoids, with consideration for orbital decompression surgery
and ocular radiation therapy

Antithyroid drug treatment is as follows:

Used for long-term control of hyperthyroidism in children, adolescents, and pregnant women

In adult men and nonpregnant women, used to control hyperthyroidism before definitive therapy with radioactive iodine

Methimazole is more potent and longer-acting than propylthiouracil

Propylthiouracil is reserved for use in thyroid storm, first trimester of pregnancy, and methimazole allergy or intolerance

Antithyroid drug doses are titrated every 4 weeks until thyroid functions normalize

Patients with Graves disease may experience remission after treatment for 12-18 months, but recurrences are common
within the following year

Toxic multinodular goiter and toxic adenoma will not go into remission

Radioactive iodine treatment is as follows:

Preferred therapy for hyperthyroidism

Administered orally as a single dose in capsule or liquid form

Causes fibrosis and destruction of the thyroid over weeks to many months

Hypothyroidism is expected

Pregnancy, breast feeding, and recent lactation are contraindications

Radioactive iodine should be avoided in children younger than 5 years[3]

Radioactive iodine is usually not given to patients with severe ophthalmopathy

Thyroidectomy is reserved for special circumstances, including the following:

Severe hyperthyroidism in children

Pregnant women who are noncompliant with or intolerant of antithyroid medication

Patients with very large goiters or severe ophthalmopathy

Patients who refuse radioactive iodine therapy

https://emedicine.medscape.com/article/121865-print 3/33
3/9/2019 https://emedicine.medscape.com/article/121865-print
Refractory amiodarone-induced hyperthyroidism

Patients who require normalization of thyroid functions quickly, such as pregnant women, women who desire pregnancy
in the next 6 months, or patients with unstable cardiac conditions

Guidelines for the management of hyperthyroidism and other causes of thyrotoxicosis were developed by the American Thyroid
Association and the American Association of Clinical Endocrinologists;[3] these were updated in 2016.[4]

See Treatment and Medication for more detail.

Background
Hyperthyroidism is a set of disorders that involve excess synthesis and secretion of thyroid hormones by the thyroid gland. The
resulting elevation in levels of free thyroxine (FT4), free triiodothyronine (FT3), or both leads to the hypermetabolic condition of
thyrotoxicosis.

Thus, although many clinicians (endocrinologists excluded) use the terms hyperthyroidism and thyrotoxicosis interchangeably,
the 2 words have distinct meanings. For example, both exogenous thyroid hormone intake and subacute thyroiditis can cause
thyrotoxicosis, but neither constitutes hyperthyroidism, because the conditions are not associated with new hormone production.

The most common forms of hyperthyroidism include diffuse toxic goiter (Graves disease), toxic multinodular goiter (Plummer
disease), and toxic adenoma (see Etiology). Together with subacute thyroiditis, these conditions constitute 85-90% of all causes
of thyrotoxicosis.

The most reliable screening measure of thyroid function in the healthy ambulatory adult population is the TSH level. The degree
of thyrotoxicosis is determined by measurement of thyroid hormone levels. Autoantibody testing, and nuclear thyroid
scintigraphy in some cases, can provide useful etiologic information. (See Workup.)

Treatment of hyperthyroidism includes symptom relief, as well as therapy with antithyroid medications, radioactive iodine, or
thyroidectomy. However, antithyroid medications are not effective in thyrotoxicosis from subacute thyroiditis, because these
cases result from release of preformed thyroid hormone. (See Treatment.)

For further information, see Pediatric Hyperthyroidism and Subacute Thyroiditis.

Pathophysiology
Normally, the secretion of thyroid hormone is controlled by a complex feedback mechanism involving the interaction of
stimulatory and inhibitory factors (see the image below). Thyrotropin-releasing hormone (TRH) from the hypothalamus
stimulates the pituitary to release TSH.

https://emedicine.medscape.com/article/121865-print 4/33
3/9/2019 https://emedicine.medscape.com/article/121865-print
Hypothalamic-pituitary-thyroid axis feedback. Schematic representation of negative feedback system that regulates thyroid
hormone levels. TRH = thyrotropin-releasing hormone; TSH = thyroid-stimulating hormone.

Binding of TSH to receptors on the thyroid gland leads to the release of thyroid hormones—primarily T4 and to a lesser extent
T3. In turn, elevated levels of these hormones act on the hypothalamus to decrease TRH secretion and thus the synthesis of
TSH.

Synthesis of thyroid hormone requires iodine. Dietary inorganic iodide is transported into the gland by an iodide transporter,
converted to iodine, and bound to thyroglobulin by the enzyme thyroid peroxidase through a process called organification. This
results in the formation of monoiodotyrosine (MIT) and diiodotyrosine (DIT), which are coupled to form T3 and T4; these are
then stored with thyroglobulin in the thyroid’s follicular lumen. The thyroid contains a large supply of its preformed hormones.

Thyroid hormones diffuse into the peripheral circulation. More than 99.9% of T4 and T3 in the peripheral circulation is bound to
plasma proteins and is inactive. Free T3 is 20-100 times more biologically active than free T4. Free T3 acts by binding to
nuclear receptors (DNA-binding proteins in cell nuclei), regulating the transcription of various cellular proteins.

Any process that causes an increase in the peripheral circulation of unbound thyroid hormone can cause thyrotoxicosis.
Disturbances of the normal homeostatic mechanism can occur at the level of the pituitary gland, the thyroid gland, or in the
periphery. Regardless of etiology, the result is an increase in transcription in cellular proteins, causing an increase in the basal
metabolic rate. In many ways, signs and symptoms of hyperthyroidism resemble a state of catecholamine excess, and
adrenergic blockade can improve these symptoms.

In Graves disease, a circulating autoantibody against the thyrotropin receptor provides continuous stimulation of the thyroid
gland. This stimulatory immunoglobulin has been called long-acting thyroid stimulator (LATS), thyroid-stimulating
immunoglobulin (TSI), thyroid-stimulating antibody (TSab), and TSH-receptor antibody (TRab).[5] These antibodies stimulate
the production and release of thyroid hormones and thyroglobulin; they also stimulate iodine uptake, protein synthesis, and
thyroid gland growth. Anti–thyroid peroxidase (anti-TPO) antibody is assessed in a nonspecific test for autoimmune thyroid
disease. Although the anti-TPO antibody is not diagnostic for Graves disease, it is present in 85% of patients with the
disorder and can be quickly measured in local laboratories.[6]

Ophthalmopathy

The underlying pathophysiology of Graves ophthalmopathy (also called thyroid-associated orbitopathy) is not completely
characterized. It most likely involves an antibody reaction against the TSH receptor that results in activation of T cells against
tissues in the retro-orbital space that share antigenic epitopes with thyroid follicular cells.

These immune processes lead to an active phase of inflammation, with lymphocyte infiltration of the orbital tissue and release of
cytokines that stimulate orbital fibroblasts to multiply and produce mucopolysaccharides (glycosaminoglycans), which absorb
water. In consequence, the extraocular muscles thicken and the adipose and connective tissue of the retro-orbit increase in
volume.

Cigarette smoking and a high TSH-receptor autoantibody level are significant risk factors for ophthalmopathy. In addition,
patients who smoke appear to be more likely to experience worsening of their ophthalmopathy if treated with radioactive iodine,
as do patients who have high pretreatment T3 levels and posttherapy hypothyroidism.

Etiology
Genetic factors appear to influence the incidence of thyrotoxicosis. Autoimmune thyroid disease, including Hashimoto
hypothyroidism and Graves disease, often occurs in multiple members of a family.

Several genetic syndromes have been associated with hyperthyroidism, especially autoimmune thyroid disease. McCune-
Albright syndrome is caused by mutations in the GNAS gene. This gene encodes the stimulatory G-protein alpha subunit, which
is a key component of many signal transduction pathways. Patients present with the classic triad of polyostotic fibrous dysplasia,
irregular café-au-lait spots, and precocious puberty. The syndrome may also include facial asymmetry, Cushing syndrome,
hyperthyroidism, and acromegaly.[7]

A number of disorders of thyroid function have been found to be caused by mutations in the TSHR gene, which encodes the
TSH receptor protein. These disorders include the following:

Familial gestational hyperthyroidism

https://emedicine.medscape.com/article/121865-print 5/33
3/9/2019 https://emedicine.medscape.com/article/121865-print
One type of nonimmune hyperthyroidism

Congenital nongoiterous thyrotoxicosis

Toxic thyroid adenoma with somatic mutation

Type II autoimmune polyendocrine syndrome is associated with hyperthyroidism and hypothyroidism, as well as type 1 diabetes
mellitus and adrenal insufficiency. Patients may also have immune deficiency, as manifested by chronic mucosal candidiasis.[8]

Autoimmune thyroid disease has a higher prevalence in patients with human leukocyte antigen (HLA)-DRw3 and HLA-B89.
Graves disease is felt to be an HLA-related, organ-specific defect in suppressor T-cell function. Similarly, subacute painful or
granulomatous thyroiditis occurs more frequently in patients with HLA-Bw35. Like other immune diseases, these thyroid
conditions occur more frequently in women than in men.

With the availability of genome-wide association studies, more than a dozen genes and gene regions have been found to be
associated with an increased risk for development of thyrotoxicosis, particularly Graves disease.[9, 10, 11, 12, 13, 14]
Unsurprisingly, these studies have shown associations between these same genes and the development of other endocrine
autoimmune disorders, such as type 1 diabetes mellitus.

The loci for which specific function can be deduced appear to involve genes related to HLA, non-HLA immune function, and
thyroid function.[13] However, the odds ratios that have been determined generally indicate only a mildly increased risk for
Graves disease.

Most of the genome-wide association studies have focused on diffuse toxic goiter (ie, Graves disease). One study, however,
found an association between development of toxic multinodular goiter (Plummer disease) and a single-nucleotide
polymorphism (SNP) in the TSHR gene.[15] . This SNP was seen in 9.6% of normal patients, 16.3% of patients with Graves
disease, and 33.3% of patients with toxic multinodular goiter.

Iodine intake

Iodine intake also appears to influence the occurrence of thyrotoxicosis. Clearly, patients in borderline iodine-deficient areas of
the world develop nodular goiter, often with areas of thyroid autonomy. When members of this population move to areas of
sufficient iodine intake, thyrotoxicosis occurs. Evidence exists that iodine can act as an immune stimulator, precipitating
autoimmune thyroid disease and acting as a substrate for additional thyroid hormone synthesis.

Graves disease

The most common cause of thyrotoxicosis is Graves disease (50-60% of cases). Graves disease is an organ-specific
autoimmune disorder characterized by a variety of circulating antibodies, including common autoimmune antibodies, as well as
anti-TPO and anti-TG antibodies.

The most important autoantibody is thyroid-stimulating antibody (TSab; also called TSI, LATS, or TRab), which is directed
toward epitopes of the TSH receptor and acts as a TSH-receptor agonist. Like TSH, TSab binds to the TSH receptor on the
thyroid follicular cells to activate thyroid hormone synthesis and release and thyroid gland growth (hypertrophy). This results in
the characteristic picture of Graves thyrotoxicosis, with a diffusely enlarged thyroid, very high radioactive iodine uptake, and
excessive thyroid hormone levels compared with a healthy thyroid (see the images below).

https://emedicine.medscape.com/article/121865-print 6/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

Color flow ultrasonogram in patient with Graves disease. Generalized hypervascularity is visible throughout gland (note red
areas), which often can be heard as hum or bruit with stethoscope.

Iodine 123 (123I) nuclear scintigraphy: 123I scans of normal thyroid gland (A) and common hyperthyroid conditions with
elevated radioiodine uptake, including Graves disease (B), toxic multinodular goiter (C), and toxic adenoma (D).

Thyroid hormone levels can be highly elevated in Graves disease. Clinical findings specific to Graves disease include thyroid
ophthalmopathy (periorbital edema, chemosis [conjunctival edema], injection, or proptosis) and, rarely, dermopathy over the
lower extremities. This autoimmune condition may be associated with other autoimmune diseases, such as pernicious anemia,
myasthenia gravis, vitiligo, adrenal insufficiency, celiac disease, and type 1 diabetes mellitus.

In pregnant women with Graves disease, fetal or neonatal thyrotoxicosis can result from maternal TSH-receptor antibodies
(TRabs) crossing the placenta. A literature review by van Dijk et al indicated that during pregnancy, neonatal thyrotoxicosis is a
risk when the concentration of maternal TRabs reaches 4.4 U/L, a level 3.7 times the upper limit of normal.[16]

Subacute thyroiditis

The next most common cause of thyrotoxicosis is subacute thyroiditis (approximately 15-20% of cases), a destructive release of
preformed thyroid hormone. A typical nuclear scintigraphy scan shows no radioactive iodine uptake (RAIU) in the thyrotoxic
phase of the disease (see the images below). Thyroid hormone levels can be highly elevated in this condition.

https://emedicine.medscape.com/article/121865-print 7/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

Absence of iodine 123 (123I) radioactive iodine uptake in patient with thyrotoxicosis and subacute painless or lymphocytic
thyroiditis. Laboratory studies at time of scan demonstrated the following: thyroid-stimulating hormone (TSH), less than 0.06
mIU/mL; total thyroxine (T4), 21.2 µg/dL (reference range, 4.5-11); total triiodothyronine (T3), 213 ng/dL (reference range, 90-
180); T3-to-T4 ratio, 10; and erythrocyte sedimentation rate (ESR), 10 mm/hr. Absence of thyroid uptake, low T3-to-T4 ratio,
and low ESR confirm diagnosis of subacute painless thyroiditis.

Three multinuclear giant cell granulomas observed in fine-needle aspiration biopsy of thyroid from patient with thyrotoxicosis
from subacute painful or granulomatous thyroiditis.

Toxic multinodular goiter

Toxic multinodular goiter (Plummer disease) accounts for 15-20% of thyrotoxicosis cases (see the image below). It occurs more
commonly in elderly individuals, especially those with a long-standing goiter. Thyroid hormone excess develops very slowly over
time and often is only mildly elevated at the time of diagnosis.

https://emedicine.medscape.com/article/121865-print 8/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

Scan in patient with toxic multinodular goiter. 5-Hour 123I-iodine uptake was elevated at 28% (normal 5-15%). Note multiple
foci of variably increased tracer uptake.

Symptoms of thyrotoxicosis are mild, often because only a slight elevation of thyroid hormone levels is present, and the signs
and symptoms of thyrotoxicosis often are blunted (apathetic hyperthyroidism) in older patients. However, very high thyroid
hormone levels may occur in this condition after high iodine intake (eg, with iodinated radiocontrast or amiodarone exposure).

Toxic adenoma

Toxic adenoma is caused by a single hyperfunctioning follicular thyroid adenoma. This disorder accounts for approximately 3-
5% of thyrotoxicosis cases. The excess secretion of thyroid hormone occurs from a benign monoclonal tumor that usually is
larger than 2.5 cm in diameter. The excess thyroid hormone suppresses TSH levels. RAIU usually is normal, and the radioactive
iodine scan shows only the hot nodule, with the remainder of the normal thyroid gland suppressed because the TSH level is low.

Other causes of thyrotoxicosis

Several rare causes of thyrotoxicosis exist that deserve mention. Struma ovarii is ectopic thyroid tissue associated with dermoid
tumors or ovarian teratomas that can secrete excessive amounts of thyroid hormone and produce thyrotoxicosis.[17]

Iodide-induced thyrotoxicosis (Jod-Basedow syndrome) occurs in patients with excessive iodine intake (eg, from an iodinated
radiocontrast study). The antiarrhythmic drug amiodarone, which is rich in iodine and bears some structural similarity to T4, may
cause thyrotoxicosis (see Thyroid Dysfunction Induced by Amiodarone Therapy). Iodide-induced thyrotoxicosis also occurs in
patients with areas of thyroid autonomy, such as a multinodular goiter or autonomous nodule.

Iodide-induced thyrotoxicosis appears to result from loss of the normal adaptation of the thyroid to iodide excess. It is treated
with cessation of the excess iodine intake and with administration of antithyroid medication. Usually, after depletion of the
excess iodine, thyroid functions return to preexposure levels.

Patients with a molar hydatidiform pregnancy or choriocarcinoma have extremely high levels of beta human chorionic
gonadotropin (β-hCG), which can weakly activate the TSH receptor. At very high levels of β-hCG, activation of the TSH
receptors is sufficient to cause thyrotoxicosis.

Metastatic follicular thyroid carcinoma may also result in thyrotoxicosis. These lesions maintain the ability to make thyroid
hormone, and in patients with bulky tumors, production may be high enough to cause thyrotoxicosis.

Epidemiology
Graves disease is the most common form of hyperthyroidism in the United States, causing approximately 60-80% of cases of
thyrotoxicosis. The annual incidence of Graves disease was found to be 0.5 cases per 1000 population during a 20-year period,
with the peak occurrence in people aged 20-40 years.[18]

https://emedicine.medscape.com/article/121865-print 9/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

Toxic multinodular goiter (15-20% of thyrotoxicosis) occurs more frequently in regions of iodine deficiency. Most persons in the
United States receive sufficient iodine, and the incidence of toxic multinodular goiter in the US population is lower than that in
areas of the world with iodine deficiency. Toxic adenoma is the cause of 3-5% of cases of thyrotoxicosis.

The incidences of Graves disease and toxic multinodular goiter change with iodine intake. Compared with regions of the world
with less iodine intake, the United States has more cases of Graves disease and fewer cases of toxic multinodular goiters.

Race-, sex-, and age-related demographics

Autoimmune thyroid disease occurs with the same frequency in Caucasians, Hispanics, and Asians but at lower rates in African
Americans.

All thyroid diseases occur more frequently in women than in men. Graves autoimmune disease has a male-to-female ratio of
1:5-10. The male-to-female ratio for toxic multinodular goiter and toxic adenoma is 1:2-4. Graves ophthalmopathy is more
common in women than in men.

Autoimmune thyroid diseases have a peak incidence in people aged 20-40 years. Toxic multinodular goiters occur in patients
who usually have a long history of nontoxic goiter and who therefore typically present when they are older than age 50 years.
Patients with toxic adenomas present at a younger age than do patients with toxic multinodular goiter.

Prognosis
Hyperthyroidism from toxic multinodular goiter and toxic adenoma is permanent and usually occurs in adults. After normalization
of thyroid function with antithyroid medications, radioactive iodine ablation usually is recommended as the definitive therapy.
Long-term, high-dose antithyroid medication is not recommended. Toxic multinodular goiters and toxic adenomas probably will
continue to grow slowly in size during antithyroid pharmacotherapy.

Generally, the thyrotoxic areas are ablated, and patients may remain euthyroid. Those who become hypothyroid after
radioactive iodine therapy are easily maintained on thyroid hormone replacement therapy, with T4 taken once daily.

Patients with Graves disease may become hypothyroid in the natural course of their disease, regardless of whether treatment
involves radioactive iodine or surgery. Eye disease may develop at a time distant from the initial diagnosis and therapy.
Generally, after the diagnosis, the ophthalmopathy slowly improves over years.

Thyroid hormone excess causes left ventricular thickening, which is associated with an increased risk of heart failure and
cardiac-related death. Thyrotoxicosis has been associated with dilated cardiomyopathy,[19] right heart failure with pulmonary
hypertension, and diastolic dysfunction and atrial fibrillation.[20]

An increase in the rate of bone resorption occurs. Bone loss, measured by bone mineral densitometry, can be seen in severe
hyperthyroidism at all ages and in both sexes. In mild subclinical disease, however, bone loss has been convincingly shown only
in postmenopausal women.

A study by Zhyzhneuskaya et al of patients with subclinical hyperthyroidism due to Graves disease suggested that
approximately one third will progress to overt hyperthyroidism, about one third will develop normalized thyroid function, and just
under one third will remain in a state of subclinical hyperthyroidism. (One person in the study became hypothyroid.) Multivariate
regression analysis indicated that risk of progression to overt hypothyroidism is greater in patients with older age or a positive
anti–thyroid peroxidase antibody status. The study included 44 patients, with follow-up lasting at least 12 months.[21]

Presentation

History
The presentation of thyrotoxicosis is variable among patients. Thyrotoxicosis leads to an apparent increase in sympathetic
nervous system symptoms. Younger patients tend to exhibit symptoms of sympathetic activation, such as anxiety, hyperactivity,
and tremor, while older patients have more cardiovascular symptoms, including dyspnea and atrial fibrillation with unexplained

https://emedicine.medscape.com/article/121865-print 10/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

weight loss.[2] The clinical manifestations of thyrotoxicosis do not always correlate with the extent of the biochemical
abnormality.

Common symptoms of thyrotoxicosis include the following:

Nervousness

Anxiety

Increased perspiration

Heat intolerance

Hyperactivity

Palpitations

Generally, a constellation of information, including the extent and duration of symptoms, past medical history, and social and
family history, in addition to the information derived from physical examination, help to guide the clinician to the appropriate
diagnosis. For example, Graves disease is an autoimmune disease, and patients often have a family history or past medical
history of autoimmune disease (eg, rheumatoid arthritis, vitiligo, pernicious anemia).

Patients with Graves disease often have more marked symptoms than patients with thyrotoxicosis from other causes, because
thyroid hormone levels usually are the highest with this form of hyperthyroidism. The diagnosis of Graves disease should also
be considered if any evidence of thyroid eye disease exists, including periorbital edema, diplopia, or proptosis.

Toxic multinodular goiters occur in patients who have had a known nontoxic goiter for many years or decades. Often, patients
have emigrated from regions of the world with borderline- low iodine intake or have a strong family history of nontoxic goiter.

Subclinical hyperthyroidism, defined as a low thyroid-stimulating hormone (TSH) level with normal free thyroxine (FT4) and free
triiodothyronine (FT3) levels, is associated with no or minimal clinical symptoms of thyrotoxicosis. However, certain conditions
(eg, atrial fibrillation, osteoporosis, or hypercalcemia) may suggest the possibility of thyrotoxicosis. In fact, subclinical
hyperthyroidism may be associated with a 3-fold increase in the risk of atrial fibrillation. The prevalence of subclinical
hyperthyroidism may be as high as 2% in the general population.

The risk of atrial fibrillation may be elevated even in persons with high-normal thyroid function. In a report from the Netherlands
on 1426 patients whose TSH levels were in the normal range (0.4-4.0 mIU/L), the hazard ratio for atrial fibrillation was 1.94 for
the lowest versus the highest quartile of TSH, after a median follow-up of 8 years.[22]

Radiation exposure increases the risk of benign and malignant nodular thyroid diseases, especially with the higher radiation
levels used in radiation therapy. External radiation therapy is associated with an increase in the incidence of autoimmune
hyperthyroidism when the thyroid is in the radiation field.

The family history should include careful documentation of the following:

Autoimmune disease

Thyroid disease

Emigration from iodine-deficient parts of the world

Review a complete list of medications and dietary supplements. A number of compounds—including expectorants, amiodarone,
iodinated contrast dyes, and health food supplements containing seaweed or thyroid gland extracts—contain large amounts of
iodine that can induce thyrotoxicosis in a patient with thyroid autonomy. Rarely, iodine exposure can cause thyrotoxicosis in a
patient with an apparently healthy thyroid.

Physical Examination
The thyroid is located in the lower anterior neck. The isthmus of the butterfly-shaped gland generally is located just below the
cricoid cartilage of the trachea, with the wings of the gland wrapping around the trachea. Physical examination often can help
the clinician to determine the etiology of thyrotoxicosis.

Common signs of thyrotoxicosis include the following:

https://emedicine.medscape.com/article/121865-print 11/33
3/9/2019 https://emedicine.medscape.com/article/121865-print
Tachycardia or atrial arrhythmia

Systolic hypertension with wide pulse pressure

Warm, moist, smooth skin

Lid lag

Stare

Hand tremor

Muscle weakness

Weight loss despite increased appetite (although a few patients may gain weight, if excessive intake outstrips weight
loss)

Reduction in menstrual flow or oligomenorrhea

Thyroid examination

Thyrotoxicosis from Graves disease is associated with a diffusely enlarged and slightly firm thyroid gland. Sometimes, a thyroid
bruit can be heard by using the bell of the stethoscope.

Toxic multinodular goiters generally occur when the thyroid gland is enlarged to at least 2 to 3 times the normal size. The gland
often is soft, but individual nodules occasionally can be palpated. Because most thyroid nodules cannot be palpated, thyroid
nodules should be documented by thyroid ultrasonography, but overactive thyroid nodules can be demonstrated only by nuclear
thyroid imaging with radioiodine (I-123) or technetium (Tc99m) thyroid scan.

If the thyroid is enlarged and painful, subacute painful or granulomatous thyroiditis is the likely diagnosis. However,
degeneration or hemorrhage into a nodule and suppurative thyroiditis should also be considered.

Ophthalmologic and dermatologic examination

Approximately 50% of patients with Graves thyrotoxicosis have mild thyroid ophthalmopathy. Often, this is manifested only by
periorbital edema, but it also can include conjunctival edema (chemosis), injection, poor lid closure, extraocular muscle
dysfunction (diplopia), and Proptosis (see the image below). Evidence of thyroid eye disease and high thyroid hormone levels
confirms the diagnosis of autoimmune Grave disease.

Severe proptosis, periorbital edema, and eyelid retraction from thyroid-related orbitopathy. This patient also had optic nerve
dysfunction and chemosis (conjunctival edema) from thyroid-related orbitopathy.

In rare instances, Graves disease affects the skin through deposition of glycosaminoglycans in the dermis of the lower leg. This
causes nonpitting edema, which is usually associated with erythema and thickening of the skin, without pain or pruritus (see the
image below).

https://emedicine.medscape.com/article/121865-print 12/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

Bilateral erythematous infiltrative plaques on lower extremities in 42-year-old man with Graves disease are consistent with
pretibial myxedema. Myxedematous changes of skin usually occur in pretibial areas and resemble orange peel in color and
texture.

DDx

Diagnostic Considerations
Diagnostic considerations include factitious hyperthyroidism, which is hyperthyroidism secondary to intentional consumption of
thyroid hormone. In this condition, thyroid hormone consumption causes suppression of thyroglobulin secretion by the thyroid.
Factitious hyperthyroidism is common in medical personnel, who have easy access to medication containing thyroid hormone
and may abuse it for weight loss or an energy boost.

Differential Diagnoses
Diffuse Toxic Goiter (Graves Disease)

Euthyroid Hyperthyroxinemia

Goiter

Graves Disease

Struma Ovarii

Thyrotoxicosis Imaging

Workup

Workup

Approach Considerations
The most reliable screening measure of thyroid function is the thyroid-stimulating hormone (TSH) level. TSH levels usually are
suppressed to unmeasurable levels (< 0.05 µIU/mL) in thyrotoxicosis. The degree of thyrotoxicosis is determined by
measurement of thyroid hormone levels; the severity of clinical manifestations often does not correlate with the degree of thyroid
hormone elevation.

https://emedicine.medscape.com/article/121865-print 13/33
3/9/2019 https://emedicine.medscape.com/article/121865-print
The most specific autoantibody test for autoimmune thyroiditis is an enzyme-linked immunosorbent assay (ELISA) test for anti ̶
thyroid peroxidase (anti-TPO) antibody. The titers usually are significantly elevated in the most common type of hyperthyroidism,
Graves thyrotoxicosis, and usually are low or absent in toxic multinodular goiter and toxic adenoma.

If the etiology of thyrotoxicosis is not clear after physical examination and other laboratory tests, it can be confirmed by means of
scintigraphy. The degree and pattern of isotope uptake indicate the type of thyroid disorder.

Older patients with hyperthyroidism often present with atrial arrhythmias or heart failure. Electrocardiography is recommended if
an irregular or elevated (> 100 beats/min) heart rate or signs of heart failure are noted upon examination.

TSH and Thyroid Hormone Levels

Although measurement of the TSH level is the most reliable screening method for assessing thyroid function, the degree of
thyrotoxicosis cannot be estimated easily in this way. Instead, thyrotoxicosis must be measured using an assay of thyroid
hormone levels in the plasma.

Thyroid hormone circulates as triiodothyronine (T3) and thyroxine (T4), with more than 99.9% of the hormones bound to serum
proteins (especially thyroxine-binding globulin, transthyretin or thyroxine-binding prealbumin, and albumin). Measuring free T4
(FT4) and total T3 is recommended in patients with suspected thyrotoxicosis when TSH is low. Patients with milder
thyrotoxicosis may have elevation of T3 levels only.

Many laboratories do not measure FT4 directly, instead using a calculation to estimate the FT4 level. The free thyroxine index
(FTI) is equal to total T4 multiplied by the correction for thyroid hormone binding, such as the thyroid hormone ̶ binding ratio
(THBR) or T3 resin uptake [T3 RU]). A similar calculation can be used with total T3.

Thyrotoxicosis is marked by TSH levels suppressed below the reference range (usually 0.4-4 mIU/L) and elevated thyroid
hormone levels. Subclinical hyperthyroidism is defined as a decreased but not undetectable TSH level (< 0.5 μIU/mL in many
laboratories) in combination with serum concentrations of T3 and T4 that are within the reference range. Because nonthyroidal
illness will produce temporary suppression of TSH, thyroid function tests should be repeated before therapy is instituted for
subclinical disease.

Hormonal changes in pregnancy can complicate the interpretation of thyroid function tests. Physiologic maximum elevation of
beta human chorionic gonadotropin (β-hCG) at the end of the first trimester of pregnancy is associated with a mirror-image
temporary reduction in TSH. Despite the reduction in TSH, FT4 levels usually remain normal or only slightly above the reference
range. As the pregnancy progresses and β-hCG plateaus at a lower level, TSH levels return to normal.

Autoantibody Studies
The most specific autoantibody test for autoimmune thyroiditis is an ELISA test for anti-TPO antibody. The titers usually are
significantly elevated in the most common type of hyperthyroidism, Graves thyrotoxicosis, and usually are low or absent in toxic
multinodular goiter and toxic adenoma. A significant number of healthy people without active thyroid disease have mildly
positive anti-TPO antibody titers; thus, the test should not be performed for screening purposes.

The thyroid-stimulating immunoglobulin (TSI) level, if elevated, helps to establish the diagnosis of Graves disease. Circulating
antithyroglobulin (anti-TG) antibodies are also present in Graves disease; however, testing for these antibodies should not be
used, because anti-TG antibodies by themselves may be present in persons without other evidence of thyroid dysfunction.[23]

Scintigraphy
If the etiology of thyrotoxicosis is not clear after physical examination and other laboratory tests, it can be confirmed by means of
scintigraphy. Iodine-123 (123 I) or technetium-99m (99m Tc) can be used for thyroid scanning. Normally, the isotope distributes
homogeneously throughout both lobes of the thyroid gland. In patients with hyperthyroidism, the pattern of uptake (eg, diffuse vs
nodular) varies with the underlying disorder.
https://emedicine.medscape.com/article/121865-print 14/33
3/9/2019 https://emedicine.medscape.com/article/121865-print
The overall level of radioactive iodine uptake (RAIU) also varies with different conditions. Normal RAIU is approximately 5-20%
but is modified by the iodine content of the patient’s diet (see Table 1 below).

Table 1. Thyrotoxicosis and Hyperthyroidism (Open Table in a new window)

Common Forms (85-90% of Cases) 24-Hour RAIU Over Neck*

Diffuse toxic goiter (Graves disease) Increased (moderate to high: 40-100%)

Toxic multinodular goiter (Plummer disease) Increased (mild to moderate: 25-60%)

Thyrotoxic phase of subacute thyroiditis Decreased (very low: < 2%)

Toxic adenoma Increased (mild to moderate: 25-60%)

Less Common Forms

Iodide-induced thyrotoxicosis Variable but usually low (< 25%)

Thyrotoxicosis factitia Decreased (very low: < 2%)

Uncommon Forms

Pituitary tumors producing TSH Increased (mild to moderate: 25-60%)

Excess human chorionic gonadotropin (molar pregnancy/choriocarcinoma) Increased (variable: 25-100%)

Pituitary resistance to thyroid hormone Increased (mild to moderate: 25-60%)

Metastatic thyroid carcinoma Decreased

Struma ovarii with thyrotoxicosis Decreased

https://emedicine.medscape.com/article/121865-print 15/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

RAIU = radioactive iodine uptake; TSH = thyroid-stimulating hormone.

* A normal 6-hour RAIU is approximately 2-16%; a 24-hour RAIU is about 8-25% but is modified according to the iodine
content of the patient’s diet. RAIU or scanning should not be performed in a woman who is pregnant (with the exception of
a molar pregnancy) or breastfeeding.

In Graves disease, scintigraphy shows diffuse enlargement of both thyroid lobes, with uniform uptake of isotope (see the image
below). Overall RAIU is elevated.

Iodine 123 (123I) nuclear scintigraphy: 123I scans of normal thyroid gland (A) and common hyperthyroid conditions with
elevated radioiodine uptake, including Graves disease (B), toxic multinodular goiter (C), and toxic adenoma (D).

Toxic multinodular goiters are characterized by irregular areas of relatively diminished and occasionally increased uptake (see
the image below). Overall RAIU is mildly to moderately increased.

https://emedicine.medscape.com/article/121865-print 16/33
3/9/2019 https://emedicine.medscape.com/article/121865-print
Scan in patient with toxic multinodular goiter. 5-Hour 123I-iodine uptake was elevated at 28% (normal 5-15%). Note multiple
foci of variably increased tracer uptake.

The classification of nodules as "hot," "warm," or "cold" is determined by their isotope-concentrating ability relative to the
surrounding normal parenchyma. Autonomously functioning thyroid nodules are "hot" compared with normal thyroid tissue. If a
dominant nodule is found upon examination of a patient with thyrotoxicosis, and scintigraphy shows that the nodule is cold, an
ultrasound-guided fine-needle aspiration (FNA) biopsy of the nodule should be performed to exclude concomitant malignancy.

In subacute thyroiditis (see the image below), radioactive iodine uptake is very low (approximately 1-2%). Occasionally,
Hashimoto hypothyroidism can be associated with normal, elevated, or suppressed radioactive iodine uptake.

Absence of iodine 123 (123I) radioactive iodine uptake in patient with thyrotoxicosis and subacute painless or lymphocytic
thyroiditis. Laboratory studies at time of scan demonstrated the following: thyroid-stimulating hormone (TSH), less than 0.06
mIU/mL; total thyroxine (T4), 21.2 µg/dL (reference range, 4.5-11); total triiodothyronine (T3), 213 ng/dL (reference range, 90-
180); T3-to-T4 ratio, 10; and erythrocyte sedimentation rate (ESR), 10 mm/hr. Absence of thyroid uptake, low T3-to-T4 ratio,
and low ESR confirm diagnosis of subacute painless thyroiditis.

Treatment

Approach Considerations
Treatment of hyperthyroidism includes symptom relief, as well as antithyroid pharmacotherapy, radioactive iodine-131 (131I)
therapy (the preferred treatment of hyperthyroidism among US thyroid specialists), or thyroidectomy. However, antithyroid
medications are not effective in thyrotoxicosis in which scintigraphy shows low uptake of iodine-123 (123I), as in patients with
subacute thyroiditis, because these cases result from release of preformed thyroid hormone.

If a physician treats enough patients who are hyperthyroid, eventually he or she will encounter a patient who develops
agranulocytosis or hepatitis from the antithyroid medications. Discussing these adverse effects with patients before starting
therapy is important; accordingly, patients should be given written or documented verbal instruction to the effect that if they
develop high fever (>100.5°F) or a severe sore throat, they should stop the medication and seek medical attention.

Guidelines for the management of hyperthyroidism and other causes of thyrotoxicosis were developed by the American Thyroid
Association (ATA) and the American Association of Clinical Endocrinologists;[3] these were updated in 2016.[4]

https://emedicine.medscape.com/article/121865-print 17/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

Management of Ophthalmopathy
Although 50% of patients with Graves disease have mild signs and symptoms of thyroid eye disease, only 5% develop severe
ophthalmopathy (eg, diplopia, visual-field deficits, or blurred vision).[3] Less serious ophthalmologic symptoms (eg, photophobia,
irritation, and tearing) are treated with tight-fitting sunglasses, which should be worn at all times when the patient is outside, and
with saline eye drops that are taken as necessary for comfort.

If exposure keratitis is suspected, the patient should be monitored by an ophthalmologist. This condition usually occurs when
eyelid closure is incomplete and the cornea is exposed at night, when the patient does not blink. Typically, patients complain of
irritation and tearing on awakening. Treatment includes administering saline gel or drops and taping eyelids closed with paper
tape before sleep. Some ophthalmologists are concerned about corneal abrasion from the tape and instead recommend that
patients wear goggles at night to keep the eyes moist.

A medical emergency occurs when sufficient orbital edema exists to cause optic nerve compression with early loss of color
vision and orbital pain. Without treatment, continued pressure on the optical nerve may cause permanent vision loss. High-dose
glucocorticoids are administered, with consideration for orbital decompression surgery and ocular radiation therapy.

Management of Dermopathy
Infiltrative dermopathy, usually developing over the lower extremities, is characterized by an accumulation of
glycosaminoglycans and inflammatory cells in the dermis. The skin changes typically include a nonpitting erythematous edema
of the anterior shins. Dermopathy can occur at other sites of repeat trauma. The dermopathy usually occurs only in the presence
of significant ophthalmopathy.

No effective treatment exists. Nightly occlusive wraps of the affected site are recommended, with plastic wrap used after the
application of a high-potency topical steroid cream.

Relief of Symptoms
Many of the neurologic and cardiovascular symptoms of thyrotoxicosis are relieved by beta-blocker therapy. Before such therapy
is initiated, the patient should be examined for signs and symptoms of dehydration that often occur with hyperthyroidism. After
oral rehydration, beta-blocker therapy can be started. Beta-blocker therapy should not be administered to patients with a
significant history of asthma.

Calcium channel blockers (eg, verapamil and diltiazem) can be used for the same purposes when beta-blockers are
contraindicated or poorly tolerated. These therapies should be tapered and stopped once thyroid functions are within the normal
range.

Antithyroid Pharmacotherapy
Antithyroid drugs (eg, methimazole and propylthiouracil) have been used for hyperthyroidism since their introduction in the
1940s. These medications are employed for long-term control of hyperthyroidism in children, adolescents, and pregnant women.
In adult men and nonpregnant women, they are used to control hyperthyroidism before definitive therapy with radioactive iodine.

Antithyroid medications inhibit the formation and coupling of iodotyrosines in thyroglobulin. Because these processes are
necessary for thyroid hormone synthesis, this inhibition induces a gradual reduction in thyroid hormone levels over 2-8 weeks or
longer. A second action of propylthiouracil (but not methimazole) is inhibition of conversion of thyroxine (T4) to triiodothyronine

https://emedicine.medscape.com/article/121865-print 18/33
3/9/2019 https://emedicine.medscape.com/article/121865-print
(T3). T3 is more biologically active than T4; thus, a quick reduction in T3 levels is associated with a clinically significant
improvement in thyrotoxic symptoms.

The antithyroid drug dose should be titrated every 4 weeks until thyroid functions normalize. Some patients with Graves disease
go into a remission after treatment for 12-18 months, and the drug can be discontinued. Notably, half of the patients who go into
remission experience a recurrence of hyperthyroidism within the following year. Nodular forms of hyperthyroidism (ie, toxic
multinodular goiter[24] and toxic adenoma) are permanent conditions and will not go into remission.

Methimazole is more potent than propylthiouracil and has a longer duration of action. In addition, methimazole is taken once
daily, whereas propylthiouracil is taken 2-3 times daily; consequently, patient compliance is often better with methimazole than
with propylthiouracil.

Methimazole is not recommended for use in the first trimester of pregnancy, because it has been associated (albeit rarely) with
cloacal and scalp (cutis aplasia) abnormalities when given during early gestation.[3, 25] Generally, if a nonpregnant woman who
is receiving methimazole desires pregnancy, she should be switched to propylthiouracil before conception. After 12 weeks of
gestation, she can be switched back to methimazole, with frequent monitoring.

Propylthiouracil remains the drug of choice in uncommon situations of life-threatening severe thyrotoxicosis (ie, thyroid storm)
because of the additional benefit of inhibition of T4-to-T3 conversion. In this setting, propylthiouracil should be administered
every 6-8 hours. The reduction in T3, which is 20-100 times more potent than T4, theoretically helps reduce the thyrotoxic
symptoms more quickly than methimazole would. Once thyroid levels have decreased to nearly normal values, the patient can
be switched to methimazole therapy.

Except in thyroid storm, propylthiouracil is considered a second-line drug therapy. It is reserved for use in patients who are
allergic to or intolerant of methimazole and in women who are in the first trimester of pregnancy or planning pregnancy.

Adverse effects of antithyroid medications

The most common adverse effects of antithyroid drugs are allergic reactions manifesting as fever, rash, urticaria, and arthralgia,
which occur in 1-5% of patients, usually within the first few weeks of treatment. Serious adverse effects include agranulocytosis,
aplastic anemia, hepatitis, polyarthritis, and a lupuslike vasculitis. All of these adverse effects, except agranulocytosis, occur
more frequently with propylthiouracil: agranulocytosis occurs in 0.2-0.5% of patients overall and is no more common with one
drug than with the other.

Patients with agranulocytosis usually present with fever and pharyngitis. After the drug is stopped, granulocyte counts usually
start to rise within several days but may not normalize for 10-14 days. Granulocyte colony-stimulating factor (G-CSF) appears to
accelerate recovery in patients with a bone marrow aspiration showing a granulocyte-to-erythrocyte ratio of 1:2 or greater than
0.5.

In 2010, the US Food and Drug Administration (FDA) added a boxed warning, the strongest warning issued by the FDA, to the
prescribing information for propylthiouracil. The warning emphasized the risk for severe liver injury and acute liver failure, some
cases of which have been fatal.[26] Severe liver injury has rarely been reported with methimazole (5 cases, 3 of which resulted
in death).

The FDA recommends the following measures for patients receiving propylthiouracil (for more information, see the FDA Safety
Alert)[26] :

Closely monitor patients for signs and symptoms of liver injury, especially during the first 6 months after initiation of
therapy

For suspected liver injury, promptly discontinue propylthiouracil, evaluate the patient for evidence of liver injury, and
provide supportive care

Counsel patients to contact their health care provider promptly for the following signs or symptoms: fatigue, weakness,
vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin

Other drugs

In severe thyrotoxicosis from Graves disease or subacute thyroiditis, iodine or iodinated contrast agents have been
administered to block the conversion of T4 to T3 and the release of thyroid hormone from the gland. This therapy is reserved for
severe thyrotoxicosis because its use prevents definitive therapy for Graves thyrotoxicosis with radioactive iodine for many
weeks.

A saturated solution of potassium iodide (SSKI) can be administered at a dosage of 10 drops twice daily, with a consequent
rapid reduction in T3 levels. Iopanoic acid/ipodate at a dosage of 1 g/day is also effective; it has not been available in the United
States for several years but is available in some areas of Europe.

https://emedicine.medscape.com/article/121865-print 19/33
3/9/2019 https://emedicine.medscape.com/article/121865-print
These drugs must not be administered to patients with toxic multinodular goiter or toxic adenomas. The autonomous nature of
these conditions can lead to worsening of the thyrotoxicosis in the presence of pharmacologic levels of iodide, a substrate in
thyroid hormone synthesis. This phenomenon typically presents in patients living in iodine deficient areas who relocate to an
iodine sufficient geographical area or upon ingestion of iodine (Jod-Basedow syndrome).

Another drug that might be considered in management of severe thyrotoxicosis would be cholestyramine, a bile salt
sequestrant. It decreases thyroid hormone levels by depleting the pool by enhancing clearance from enterohepatic circulation.
Doses up to 12 grams in 3 divided daily dose have been used for 4 weeks.

Radioactive Iodine Therapy

Radioactive iodine therapy[27] is the most common treatment for Graves disease in adults in the United States. Although its
effect is less rapid than that of antithyroid medication or thyroidectomy, it is effective and safe and does not require
hospitalization.

A literature review by Wang and Qin of randomized, controlled trials indicated that compared with antithyroid drugs, radioiodine
treatment has a higher cure rate for Graves disease and is associated with a lower recurrence rate. However, it was also found
to carry a greater risk for the development or worsening of ophthalmopathy and for hypothyroidism.[28]

Concerns about radiation exposure after therapy have led to the issuance of new recommendations by the ATA. These
recommendations are compliant with Nuclear Regulatory Commission regulations and are a practical guide for patient activity
after radioactive iodine therapy, with the aim of ensuring maximum radiation safety for the family and the public.[29]

Radioactive iodine is administered orally as a single dose in capsule or liquid form. The iodine is quickly absorbed and taken up
by the thyroid. No other tissue or organ in the body is capable of retaining the radioactive iodine; consequently, very few adverse
effects are associated with this therapy. The treatment results in a thyroid-specific inflammatory response, causing fibrosis and
destruction of the thyroid over weeks to many months.

Generally, the dose of 131I administered is 75-200 µCi/g of estimated thyroid tissue divided by the percent of 123I uptake in 24
hours. This dose is intended to render the patient hypothyroid.

Administration of lithium in the weeks following radioactive iodine therapy may extend the retention of radioactive iodine and
increase its efficacy. This may be considered in Graves disease patients with especially large Graves glands (>60 g) or in
patients with extremely high thyroidal iodine uptake (>95% in 4 hours), which is associated with high iodine turnover in the
gland. However, studies have yielded inconsistent results, and the benefits of using lithium with radioactive iodine must be
weighed against the toxicities associated with lithium.

Hypothyroidism is considered by many experts to be the expected goal of radioactive iodine therapy. In several large
epidemiologic studies of radioactive iodine therapy in patients with Graves disease, no evidence indicated that radioactive iodine
therapy caused the development of thyroid carcinoma. There is also no evidence that radioactive iodine therapy for
hyperthyroidism results in increased mortality for any other form of cancer, including leukemia.

Long-term follow-up data of children and adolescents treated with radioactive iodine are lacking. ATA guidelines recommend
avoiding 131I therapy in children younger than 5 years of age. In children 5 to 10 years old, 131I therapy is acceptable if the
calculated activity of administered 131I is less than 10 mCi. In children older than 10 years of age, radioactive iodine therapy is
acceptable if the activity is greater than 150 µCi/g of thyroid tissue.

Radioactive iodine should never be administered to pregnant women, because it can cross the placenta and ablate the fetus’s
thyroid, resulting in hypothyroidism. Similarly, breastfeeding is a contraindication, in that the radioisotope is secreted in breast
milk. Women will continue to receive increased radiation to the breast from radioactive iodine for a few months after ceasing
lactation; accordingly, initiation of this therapy should be delayed.

It is standard practice to check for pregnancy before starting radioactive iodine therapy and to recommend that the patient not
become pregnant for at least 3-6 months after the treatment or until thyroid functions normalize. No excess fetal malformations
or increased miscarriage rates have been found in women previously treated with radioactive iodine for hyperthyroidism.

Radioactive iodine usually is not administered to patients with severe ophthalmopathy, because clinical evidence suggests that
worsening of thyroid eye disease occurs after radioactive iodine therapy. This worsening is usually mild but occasionally severe.
The risk of ophthalmopathy is greater in patients who smoke cigarettes, but it can be reduced by providing glucocorticoid
therapy (prednisone 0.4 mg/kg for 1 month with subsequent taper) after radioactive iodine therapy.

https://emedicine.medscape.com/article/121865-print 20/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

Thyroidectomy
Subtotal thyroidectomy is the oldest form of treatment for hyperthyroidism. Total thyroidectomy and combinations of
hemithyroidectomies and contralateral subtotal thyroidectomies also have been used.[27, 30]

Because of the excellent efficacy of antithyroid medications and radioactive iodine therapy in regulating thyroid function,
thyroidectomy is generally reserved for special circumstances, including the following:

Severe hyperthyroidism in children

Pregnant women who are noncompliant with or intolerant of antithyroid pharmacotherapy

Patients with very large goiters or severe ophthalmopathy

Patients who refuse radioactive iodine therapy

Patients with refractory amiodarone-induced hyperthyroidism

Patients who require normalization of thyroid functions quickly, such as pregnant women, women who desire pregnancy
in the next 6 months, or patients with unstable cardiac conditions

Preparation for thyroidectomy includes antithyroid medication, stable (cold) iodine treatment, and beta-blocker therapy.[30]
Generally, antithyroid drug therapy should be administered until thyroid functions normalize (4-8 weeks). Propranolol is titrated
until the resting pulse rate is lower than 80 beats/min. Finally, iodide is administered as SSKI (1-2 drops twice daily for 10-14
days) before the procedure. Stable iodide therapy both reduces thyroid hormone excretion and decreases thyroid blood flow,
which may help reduce intraoperative blood loss.

A Swiss study found that administration of a single dose of steroid (dexamethasone 8 mg) before thyroidectomy can reduce the
nausea, pain, and vomiting associated with the procedure, as well as improve voice function.[31] Benefits were most
pronounced in the first 16 hours after the operation. Postoperative steroid administration is not considered to be the standard of
care for thyroid surgery in the United States.

With current operative techniques, bilateral subtotal thyroidectomy should have a mortality approaching zero in patients who are
properly prepared. Historically, operative stress was the most common cause of thyroid storm, a physiologic decompensation in
patients who are severely thyrotoxic, with a mortality of about 50%. Adverse effects of thyroidectomy include recurrent laryngeal
nerve damage and hypoparathyroidism from damage to local structures during the procedure.

A literature review by Zhang et al comparing endoscopic with conventional open thyroidectomy for Graves disease reported that
the endoscopic technique offers better cosmetic satisfaction and less blood loss, while open surgery is associated with reduced
operation time. Complication rates for the two techniques with regard to transient recurrent laryngeal nerve palsy, recurrent
hyperthyroidism, hypothyroidism, and transient hypocalcemia were equivalent.[32]

Diet and Activity

No special diet must be followed by patients with thyroid disease. However, some expectorants, radiographic contrast dyes,
seaweed tablets, and health food supplements contain excess amounts of iodide and should be avoided because the iodide
interferes with or complicates the management of antithyroid and radioactive iodine therapies.

Exercise tolerance often is not significantly affected in otherwise healthy patients with mild to moderate hyperthyroidism. For
these patients, no reduction in physical activity is necessary. For patients who are elderly or have cardiopulmonary comorbidities
or severe hyperthyroidism, a decrease in activity is prudent until hyperthyroidism is medically controlled.

With severe thyrotoxicosis, systolic and diastolic cardiac dysfunction often result in dyspnea on exertion. Beta-blocker therapy
often greatly improves exercise tolerance until thyroid hormones levels are reduced by other therapies.

Consultations
https://emedicine.medscape.com/article/121865-print 21/33
3/9/2019 https://emedicine.medscape.com/article/121865-print
Generally, thyrotoxicosis should be evaluated and treated by an endocrinologist. Therapy, including radioactive iodine and
antithyroid medication, requires careful follow-up, which is best performed by a specialist.

Generally, after definitive therapy is completed with radioactive iodine or surgical thyroidectomy, the patient can be cared for by
a primary care physician. These patients may require thyroid hormone replacement therapy.

Patients with Graves thyrotoxicosis should be examined by an ophthalmologist for moderate or symptomatic thyroid eye
disease, which occurs in some form in 50% of patients. Often, the eye disease is subclinical and remits with time. The eye
disease usually occurs within 1 year before or after the diagnosis of hyperthyroidism, but new-onset disease has been detected
decades later. Graves eye disease also can occur without the patient ever having developed hyperthyroidism.

Long-Term Monitoring
Care after initiation of antithyroid medication

After 4-6 weeks, antithyroid medications usually must be reduced; otherwise, the patient becomes hypothyroid. Hypothyroidism
causes the usual symptoms of fatigue and weight gain, and in patients with Graves disease, it has been anecdotally associated
with worsening of thyroid ophthalmopathy. Initially, the patient should have thyroid function tests performed every 4-6 weeks until
thyroid hormone levels are stabilized on a low dosage of antithyroid medication.

Patients with non-Graves hyperthyroidism rarely experience remissions. In patients who are placed on long-term antithyroid
drug therapy with the goal of remission, follow-up tests of thyroid function should be performed at least every 3 months for the
first year.

In patients with Graves disease, antithyroid medication should be stopped or decreased after 12-18 months to determine
whether the patient has gone into remission. In these patients, remission is defined as a normal TSH level after cessation of
antithyroid drug therapy.

Once a patient with Graves hyperthyroidism becomes euthyroid on oral antithyroid medication, other definitive treatment, such
as radioactive iodine therapy or surgery, should be considered. Although a significant fraction of patients with Graves disease go
into remission, as many as 20% become hypothyroid over subsequent years as a consequence of autoimmune destruction of
the gland.

Care after radioactive iodine ablation

Ablation of the gland occurs over 2-5 months after radioactive iodine therapy. Most patients become hypothyroid. Checking
thyroid functions every 4-6 weeks until the patient stabilizes is recommended.

Once the thyroid hormone levels start falling into the low-normal range, it is reasonable to stop antithyroid medications and to
consider starting low-dose thyroid hormone replacement before the patient becomes hypothyroid; however, some physicians
prefer to document persistently elevated TSH values with the patient off antithyroid medication before starting thyroid hormone
replacement.

Starting with partial or low-dose thyroid hormone replacement is recommended (50-75 µg/day, adjusted every 6-8 weeks to
normalize the TSH level). Several weeks after 131I therapy, patients can, in rare cases, become thyrotoxic as a result of
vigorous thyroid destruction and release of preformed hormone. This process often is accompanied by a painful, radiation-
induced thyroiditis that can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids.

In addition, radioablation can cause the release of thyroid antigens and exacerbate the autoimmune thyroid disease process. In
such cases, Graves disease can worsen.

Care after thyroid surgery

Patients whose thyroid functions normalize after surgery require routine follow-up because hypothyroidism (from the chronic
thyroiditis), recurrent hyperthyroidism, or thyroid eye disease may develop at some time in the future. Most patients remain
euthyroid after a lobectomy or lobectomy plus isthmusectomy to treat a toxic adenoma or toxic multinodular goiter with a
dominant nodule. To ensure normal thyroid function, thyroid function tests should be obtained 3-4 weeks after a lobectomy.

After subtotal thyroidectomy for hyperthyroidism and cessation of antithyroid therapy, most patients become hypothyroid,
depending on how much functional tissue is left by the surgeon. Partial replacement (T4 50-75 µg/day) is recommended in these

https://emedicine.medscape.com/article/121865-print 22/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

patients, beginning shortly after the procedure. Thyroid function tests should be monitored 4-8 weeks postoperatively, and the
T4 dosage should be adjusted to maintain a normal TSH level.

Guidelines

Guidelines Summary
In 2016, the American Thyroid Association (ATA) updated the 2011 hyperthyroidism/thyrotoxicosis guidelines it had codeveloped
with the American Association of Clinical Endocrinologists. The following are a sampling of the 124 evidence-based
recommendations included in the guideline update[4] :

Beta-adrenergic blockade is recommended in all patients with symptomatic thyrotoxicosis, especially elderly patients and
thyrotoxic patients with resting heart rates in excess of 90 beats per minute or coexistent cardiovascular disease
Patients with overt Graves hyperthyroidism should be treated with any of the following modalities: radioactive iodine
therapy, antithyroid drugs, or thyroidectomy
If methimazole is chosen as the primary therapy for Graves disease, the medication should be continued for
approximately 12-18 months and then discontinued if the serum thyrotropin and thyrotropin receptor antibody levels are
normal at that time
If surgery is chosen as the primary therapy for Graves disease, near-total or total thyroidectomy is the procedure of
choice
If surgery is chosen as treatment for toxic multinodular goiter, near-total or total thyroidectomy should be performed
If surgery is chosen as the treatment for toxic adenoma, a thyroid sonogram should be done to evaluate the entire thyroid
gland; an ipsilateral thyroid lobectomy (or isthmusectomy, if the adenoma is in the thyroid isthmus), should be performed
for isolated toxic adenomas
Children with Graves disease should be treated with methimazole, radioactive iodine therapy, or thyroidectomy;
radioactive iodine therapy should be avoided in very young children (< 5 years); radioactive iodine therapy in children is
acceptable if the activity is over 150 μCi/g (5.55 MBq/g) of thyroid tissue and for children between ages 5 and 10 years if
the calculated radioactive iodine administered activity is under 10 mCi (< 473 MBq); thyroidectomy should be chosen
when definitive therapy is required, the child is too young for radioactive iodine, and surgery can be performed by a high-
volume thyroid surgeon
If methimazole is chosen as the first-line treatment for Graves disease in children, it may be tapered in those children
requiring low doses after 1-2 years to determine if a spontaneous remission has occurred, or it may be continued until the
child and caretakers are ready to consider definitive therapy, if needed
If surgery is chosen as therapy for Graves disease in children, total or near-total thyroidectomy should be performed
Euthyroidism should be expeditiously achieved and maintained in hyperthyroid patients with Graves orbitopathy or risk
factors for the development of orbitopathy
In patients with Graves hyperthyroidism who have mild active ophthalmopathy and no risk factors for deterioration of their
eye disease, radioactive iodine therapy, antithyroid drugs, and thyroidectomy should be considered equally acceptable
therapeutic options
In Graves disease patients with mild Graves orbitopathy who are treated with radioactive iodine, steroid coverage is
recommended if there are concomitant risk factors for Graves orbitopathy deterioration

In 2017, the American Thyroid Association released guidelines pertaining to the diagnosis and management of thyroid disease
in women during pregnancy and the postpartum period, as well as prior to conception. Recommendations regarding
thyrotoxicosis in pregnancy included the following[33] :

When a suppressed serum TSH is detected in the first trimester (TSH less than the reference range), a medical history,
physical examination, and measurement of maternal serum free thyroxine (FT4) or total thyroxine (T4) concentrations
should be performed; measurement of thyroid-stimulating antibody (TSab) and maternal total triiodothyronine (T3) may
prove helpful in clarifying the etiology of thyrotoxicosis
Radionuclide scintigraphy or radioiodine uptake determination should not be performed in pregnancy
The appropriate management of abnormal maternal thyroid tests attributable to gestational transient thyrotoxicosis and/or
hyperemesis gravidarum includes supportive therapy, management of dehydration, and hospitalization if needed;
antithyroid drugs are not recommended, though beta blockers may be considered
In all women of childbearing age who are thyrotoxic, the possibility of future pregnancy should be discussed; women with
Graves disease seeking future pregnancy should be counseled regarding the complexity of disease management during
future gestation, including the association of birth defects with antithyroid drug use; preconception counseling should
review the risks and benefits of all treatment options and the patient’s desired timeline to conception
Thyrotoxic women should be rendered stably euthyroid before attempting pregnancy; several treatment options exist,
each of which is associated with risks and benefits; these include 131I ablation, surgical thyroidectomy, and antithyroid
https://emedicine.medscape.com/article/121865-print 23/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

drug therapy
Women taking methimazole or propylthiouracil should be instructed to confirm potential pregnancy as soon as possible; if
the pregnancy test is positive, pregnant women should contact their caregiver immediately
In pregnant women with a high risk of developing thyrotoxicosis if antithyroid drugs were to be discontinued, continued
antithyroid medication may be necessary; factors predicting high clinical risk include being currently hyperthyroid or
requirement of >5-10 mg/d methimazole or >100-200 mg/d propylthiouracil to maintain a euthyroid state; in such cases,
propylthiouracil is recommended for the treatment of maternal hyperthyroidism through 16 weeks of pregnancy, and
when shifting from methimazole to propylthiouracil, a dose ratio of approximately 1:20 should be used (e.g., methimazole
5 mg/d = propylthiouracil 50 mg twice daily)
In women being treated with antithyroid drugs in pregnancy, free thyroxine (FT4)/total thyroxine (T4) and TSH should be
monitored approximately every 4 weeks; antithyroid medication during pregnancy should be administered at the lowest
effective dose of methimazole or propylthiouracil, targeting maternal serum free thyroxine (FT4)/total thyroxine (T4) at the
upper limit of or moderately above the reference range.
A combination regimen of levothyroxine (LT4) and an antithyroid drug should not be used in pregnancy, except in the rare
situation of isolated fetal hyperthyroidism
Thyroidectomy in pregnancy may be indicated for unique scenarios; if required, the optimal time for thyroidectomy is in
the second trimester of pregnancy; if maternal thyroid-stimulating antibody (TSab) concentration is high (>3 times the
upper reference for the assay), the fetus should be carefully monitored for development of fetal hyperthyroidism
throughout pregnancy, even if the mother is euthyroid postthyroidectomy
The ATA concurs with the American College of Obstetricians and Gynecologists’ Committee on Obstetric Practice
consensus guidelines (written in 2011 and revised in 2015), which state the following: ‘‘1) A pregnant woman should
never be denied indicated surgery, regardless of trimester. 2) Elective surgery should be postponed until after delivery. 3)
If possible, nonurgent surgery should be performed in the second trimester when preterm contractions and spontaneous
abortion are least likely.’’ In the setting of a patient with Graves disease undergoing urgent, nonthyroid surgery, if the
patient is well controlled on antithyroid medication, no other preparation is needed; beta blockade should also be utilized
if needed
If the patient has a past history of Graves disease treated with ablation (radioiodine or surgery), a maternal serum
determination of thyroid-stimulating antibodies (TSabs) is recommended at initial thyroid function testing during early
pregnancy
If maternal thyroid-stimulating antibody (TSab) concentration is elevated in early pregnancy, repeat testing should occur
at weeks 18-22
If the patient requires treatment with antithyroid drugs for Graves disease through midpregnancy, a repeat determination
of thyroid-stimulating antibody (TSab) concentration is again recommended at weeks 18-22
If elevated thyroid-stimulating antibody (TSab) is detected at weeks 18-22 or the mother is taking antithyroid medication
in the third trimester, a TSab measurement should again be performed in late pregnancy (weeks 30-34) to evaluate the
need for neonatal and postnatal monitoring
Fetal surveillance should be performed in women who have uncontrolled hyperthyroidism in the second half of pregnancy
and in women with high thyroid-stimulating antibody (TSab) levels detected at any time during pregnancy (>3 times the
upper limit of normal); a consultation with an experienced obstetrician or maternal–fetal medicine specialist is
recommended; monitoring may include ultrasonography to assess heart rate, growth, amniotic fluid volume, and the
presence of fetal goiter
If antithyroid drug therapy is given for hyperthyroidism caused by autonomous nodules, the fetus should be carefully
monitored for goiter and signs of hypothyroidism during the second half of pregnancy; a low dose of antithyroid
medication should be administered with the goal of maternal free thyroxine (FT4) or total thyroxine (T4) concentration at
the upper limit of or moderately above the reference range

Medication

Medication Summary
Drug therapy includes medications that reduce the symptoms of thyrotoxicosis and decrease the synthesis and release of
thyroid hormone. In the United States, the most common definitive therapy for hyperthyroidism is ablation of the hyperactive
thyroid with an oral dose of radioactive iodine (131I).

In some cases the patient is treated with antithyroid medication to return thyroid hormone levels to normal. When that is
accomplished, some patients (eg, those with a toxic multinodular goiter or toxic adenoma) are treated immediately with
radioactive iodine, while patients with autoimmune Graves disease may be treated for 12-18 months with antithyroid
medications because of the possibility that the patient will go into remission.

Patients with other forms of hyperthyroidism, including toxic multinodular goiter and toxic adenoma, continue to be thyrotoxic
indefinitely. Remissions with antithyroid medications are not expected.

https://emedicine.medscape.com/article/121865-print 24/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

Antithyroid Agents

Class Summary
Antithyroid agents inhibit the synthesis of thyroxine (T4) and triiodothyronine (T3).

Methimazole (Northyx, Tapazole)

With few exceptions, methimazole should be used in every patient who needs antithyroid drug therapy for hyperthyroidism. The
exceptions are women in the first trimester of pregnancy, patients in thyroid storm, and patients with methimazole allergy or
intolerance. Methimazole is avoided in early pregnancy because of increased placental transfer and risk of a rare fetal condition
(cutis aplasia). Compared with propylthiouracil, it has a higher transfer rate into the milk of lactating women.

Methimazole inhibits thyroid hormone by blocking oxidation of iodine in the thyroid gland. However, it is not known to inhibit
peripheral conversion of thyroid hormone. The drug is available as 5-mg or 10-mg tablets. It is readily absorbed and has a
serum half-life of 6-8 hours. Methimazole is less protein-bound than propylthiouracil is.

Methimazole's duration of action is longer than its half-life, and the drug should be dosed every 12-24 hours. Studies have
shown that rectal suppositories or retention enemas can be used at the same dose as orally administered methimazole for
patients who cannot take oral medications. Usually, after thyroid function improves, the dose must be decreased or the patient
will become hypothyroid.

Propylthiouracil (PropylThyracil, PTU)

Propylthiouracil is a derivative of thiourea that inhibits organification of iodine by the thyroid gland. It blocks oxidation of iodine in
the thyroid gland, thereby inhibiting thyroid hormone synthesis; the drug inhibits T4-to-T3 conversion (and thus has an
advantage over other agents).

Propylthiouracil remains the drug of choice in uncommon situations of life-threatening severe thyrotoxicosis. It may be
preferable during and before the first trimester of pregnancy.

In 2010, the US Food and Drug Administration (FDA) added a boxed warning to the prescribing information for propylthiouracil,
emphasizing the risk for severe liver injury and acute liver failure, some cases of which have been fatal.

Propylthiouracil is available as a 50-mg tablet. It is readily absorbed and has a serum half-life of 1-2 hours. It is highly protein-
bound in the serum. The drug's duration of action is longer than its half-life, and propylthiouracil generally should be dosed every
6-8 hours (though it can also be administered twice daily). If patient compliance is an issue, methimazole may be a better choice
because it can be given as a single daily dose in many cases.

Thyroid hormone levels (thyroid-stimulating hormone [TSH], T4, free thyroxine index [FTI] or free T4, and T3) should be
reassessed in 4-6 weeks after starting propylthiouracil. The dosage is increased if thyroid hormone levels have not significantly
fallen or decreased if thyroid hormone levels have fallen by 50% or more (even if the patient is still thyrotoxic).

Usually, after thyroid function improves, the dosage should be gradually decreased to 50-150 mg/day in divided doses.
Otherwise, the patient will become hypothyroid.

Potassium iodide (SSKI, ThyroSafe, ThyroShield, iOSAT)

Potassium iodide inhibits thyroid hormone secretion. Iodide therapy is primarily used for the treatment of thyroid storm or given
preoperatively, 10-14 days before surgical procedures (including thyroidectomy).

Until high levels of iodine build up in the thyroid follicular cell, however, administration of iodine can increase thyroid hormone
synthesis and lead to higher serum levels of thyroid hormone. Thus, it is usually recommended that iodine not be started until
after antithyroid drug therapy has been initiated. In thyroid storm, iodine should be administered at least 1 hour after
methimazole or propylthiouracil.

Potassium iodide and iodine (Lugol's solution)

https://emedicine.medscape.com/article/121865-print 25/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

Lugol's solution is primarily administered for 10 days before thyroidectomy or during thyrotoxic crisis because high levels of
iodine in the follicular thyroid cell temporarily inhibit thyroid hormone synthesis and secretion. T4 and T3 concentrations can be
reduced for several weeks.

Until high levels of iodine build up in the thyroid follicular cell, however, administration of iodine can increase thyroid hormone
synthesis and lead to higher serum levels of thyroid hormone. Thus, it is usually recommended that iodine not be started until
after antithyroid drug therapy has been initiated.

Sodium iodide 131I (Iodotope, Hicon)

Radioactive iodine is approved by the FDA for treatment of hyperthyroidism in adults. It can also be used with a radioactive
uptake test to evaluate thyroid function. The agent is quickly absorbed and taken up by the thyroid. No other tissue or organ in
the body is capable of retaining radioactive iodine; therefore, few adverse effects develop.

Beta Blockers, Nonselective

Class Summary
Nonselective beta blockers reduce many of the symptoms of thyrotoxicosis, including tachycardia, tremor, and anxiety. Usually,
propranolol is recommended because of central nervous system (CNS) penetration, but some patients prefer longer-acting beta
blockers. Patients note an immediate improvement in tachycardia, anxiety, heat intolerance, and tremor. Calcium channel
blockers for tachycardia are sometimes used when beta blockers are contraindicated or not tolerated.

Propranolol (Inderal, Inderal LA, InnoPran XL)

Propranolol is the drug of choice for treating cardiac arrhythmias resulting from hyperthyroidism. It controls cardiac and
psychomotor manifestations within minutes.

Beta Blockers, Beta1-Selective

Class Summary
Beta blockers diminish hyperthyroid symptoms, such as tachycardia, tremor, and anxiety. Beta1 -selective drugs may be
tolerated better in patients who have relative beta-blockade contraindications.

Atenolol (Tenormin)
Atenolol selectively blocks beta1 receptors, with little or no effect on beta2 types. It is a longer-acting drug that can be more
useful than propranolol for intraoperative and postoperative control.

Questions & Answers

Overview

What is hyperthyroidism?

What are the symptoms of thyrotoxicosis in hyperthyroidism?

What are the signs of thyrotoxicosis in hyperthyroidism?

https://emedicine.medscape.com/article/121865-print 26/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

What is the presentation of thyrotoxicosis in hyperthyroidism?

Which thyroid function tests are performed in the workup of hyperthyroidism?

Which thyroid function study results suggest hyperthyroidism?

Which autoantibody tests are performed in the workup of hyperthyroidism?

Which autoantibody titers suggest hyperthyroidism?

What is the role of scintigraphy in the workup of hyperthyroidism?

What are the treatment options for hyperthyroidism?

What are the indications for antithyroid drug therapy in the treatment of hyperthyroidism?

What is the role of radioactive iodine in the treatment of hyperthyroidism?

What are the indications for thyroidectomy in the treatment of hyperthyroidism?

What organizations have released guidelines for the management of hyperthyroidism?

What is hyperthyroidism?

What are the common forms of hyperthyroidism?

What is the most reliable screening measure of thyroid function in hyperthyroidism?

What are the treatment options for hyperthyroidism?

What is the role of thyrotropin-releasing hormone (TRH) in the pathogenesis of hyperthyroidism?

What is the role of iodine in the pathogenesis of hyperthyroidism?

How are thyroid hormones diffused in the pathophysiology of hyperthyroidism?

Which processes cause thyrotoxicosis in the pathophysiology of hyperthyroidism?

What is the pathogenesis of Graves disease?

What is the pathophysiology of Graves ophthalmopathy (thyroid-associated orbitopathy)?

What are the risk factors for Graves ophthalmopathy?

What are the risk factors for hyperthyroidism?

Which genetic syndromes may cause hyperthyroidism?

Which hyperthyroid disorders are caused by mutations in the TSHR gene?

Which disorder is associated with both hyperthyroidism and hypothyroidism?

Which forms of hyperthyroidism are human leukocyte antigen (HLA)-related?

Which risk factor for hyperthyroidism increases the risk for developing other endocrine autoimmune disorders?

Which genetic loci may increase the risk for Graves disease?

Which gene may be an etiologic agent in toxic multinodular goiter (Plummer disease)?

How does iodine cause hyperthyroidism?

What is the most common cause of thyrotoxicosis?

What is the role of thyroid stimulating antibodies (TSAb) in the etiology of hyperthyroidism?

Which clinical findings suggest Graves disease?

What are the potential fetal or neonatal complications in pregnant women with Graves disease?

https://emedicine.medscape.com/article/121865-print 27/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

After Graves disease, what is the most common cause of thyrotoxicosis?

What is the prevalence of toxic multinodular goiter (Plummer disease) thyrotoxicosis?

What are the signs and symptoms of toxic multinodular goiter (Plummer disease)-related thyrotoxicosis?

What causes toxic adenoma?

What is struma ovarii?

How does iodide-induced thyrotoxicosis (Jod-Basedow syndrome) occur?

What are rare causes of thyrotoxicosis?

What is the most common form of hyperthyroidism and what is its incidence in the US?

What is the incidence of toxic multinodular goiter (Plummer disease in the US?

How does iodine intake affect the incidences of Graves disease and toxic multinodular goiter?

How does the incidence of hyperthyroidism vary among races?

How does the incidence of hyperthyroidism vary between males and females?

How does the incidence of hyperthyroidism vary by age?

What are the treatment options for toxic multinodular goiter and toxic adenoma?

What is the prognosis of hyperthyroidism?

What is the prognosis of Graves disease?

What is the sequelae of hyperthyroidism?

What are possible skeletal complications of hyperthyroidism?

What is the typical disease progression of hyperthyroidism?

Presentation

How does the presentation of thyrotoxicosis vary among age groups?

What are the common symptoms of thyrotoxicosis?

How is hyperthyroidism diagnosed?

When should the diagnosis of Graves disease be considered?

Which factors increase the risk of developing toxic multinodular goiters?

How is subclinical hyperthyroidism defined?

When may the risk of atrial fibrillation be elevated in patients with hyperthyroidism?

What is the role of radiation exposure in the development of hyperthyroidism?

What should be the focus of family history in patients with suspected hyperthyroidism?

Which compounds can induce thyrotoxicosis in patients with thyroid autonomy?

How is the thyroid described in a physical exam for suspected hyperthyroidism?

What are the signs of thyrotoxicosis?

Which physical findings suggest Graves thyrotoxicosis?

Which physical findings suggest toxic multinodular goiters?

Which diagnoses should be considered when the thyroid is enlarged and painful on physical exam for hyperthyroidism?

https://emedicine.medscape.com/article/121865-print 28/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

What is the prevalence of thyroid ophthalmopathy in patients with Graves thyrotoxicosis?

What are the dermatologic manifestations of Graves disease?

DDX

Which conditions should be included in the differential diagnoses for hyperthyroidism?

What are the differential diagnoses for Hyperthyroidism and Thyrotoxicosis?

Workup

What is the most reliable screening measure of thyroid function?

What is the role of anti ? thyroid peroxidase (anti-TPO) antibody testing in the workup of hyperthyroidism?

What is the role of scintigraphy in the workup of hyperthyroidism?

What is the role of electrocardiography (EKG) in the workup of hyperthyroidism?

How is thyrotoxicosis measured in the workup of hyperthyroidism?

What is the role of thyroxine (T4) and triiodothyronine (T3) measurement in the workup of hyperthyroidism?

How is subclinical hyperthyroidism defined?

Which factors may complicate the interpretation of thyroid function tests in the workup of hyperthyroidism?

Is anti ? thyroid peroxidase (anti-TPO) antibody testing used in hyperthyroidism screening?

What is the role of thyroid-stimulating immunoglobulin (TSI) measurement in the workup of hyperthyroidism?

What is role of scintigraphy in the workup of hyperthyroidism?

Which scintigraphy findings suggest Graves disease?

Which scintigraphy findings suggest toxic multinodular goiters?

How are nodules classified in scintigraphy results of hyperthyroidism?

Which scintigraphy findings suggest subacute thyroiditis?

Treatment

What are the treatment options for hyperthyroidism?

What are possible adverse effects of antithyroid medications for hyperthyroidism?

Which organizations have developed guidelines for the management of hyperthyroidism?

How are the ophthalmologic manifestations of hyperthyroidism treated?

What is the treatment for exposure keratitis in patients with hyperthyroidism?

What ophthalmologic emergency may occur in patients with hyperthyroidism?

What is the presentation of dermopathy (dermatologic symptoms) in patients with hyperthyroidism?

How is dermopathy treated in patients with hyperthyroidism?

What is the role of beta-blocker therapy in the treatment of hyperthyroidism?

What is the role of calcium channel blockers in the treatment of hyperthyroidism?

Which drugs are used in the treatment of hyperthyroidism?

How do antithyroid medications work to treat hyperthyroidism?

What is the dosage regimen for antithyroid medication in the treatment of hyperthyroidism?

https://emedicine.medscape.com/article/121865-print 29/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

What is the role of methimazole in the treatment of hyperthyroidism?

What is the role of propylthiouracil in the treatment of hyperthyroidism?

When is propylthiouracil indicated in the treatment of hyperthyroidism?

What are the possible adverse effects of antithyroid drugs in the treatment of hyperthyroidism?

What is the presentation of agranulocytosis in patients with hyperthyroidism?

What is the FDA warning for the use of propylthiouracil in hyperthyroidism treatment?

What are the FDA recommended measures for patients receiving propylthiouracil in the treatment of hyperthyroidism?

What is the role of iodine or iodinated contrast agents in the treatment of hyperthyroidism?

What is the role of cholestyramine in the treatment of hyperthyroidism?

What is the most common treatment for Graves disease in the US?

What are the ATA recommendations for radioactive iodine therapy in the treatment of hyperthyroidism?

How is radioactive iodine administered in the treatment of hyperthyroidism?

What dosage is administered for radioactive iodine therapy for hyperthyroidism?

What is the role of lithium in the treatment of hyperthyroidism?

What is the goal of radioactive iodine therapy in the treatment of hyperthyroidism?

What are the ATA recommendations for use of radioactive iodine therapy in the treatment of hyperthyroidism in children and
adolescents?

What are the contraindications to radioactive iodine therapy for hyperthyroidism?

What is standard practice before starting radioactive iodine therapy for hyperthyroidism?

Can patients with severe ophthalmopathy receive radioactive iodine in the treatment of hyperthyroidism?

What is the oldest form of treatment for hyperthyroidism?

What is the role of thyroidectomy in the treatment of hyperthyroidism?

What is included in the preparation for thyroidectomy in the treatment of hyperthyroidism?

What is the role of dexamethasone in the treatment of hyperthyroidism?

What are adverse effects of thyroidectomy in the treatment of hyperthyroidism?

How do the benefits of endoscopic thyroidectomy compare to conventional open thyroidectomy in the treatment of Graves
disease?

Which foods, agents, and supplements should be avoided during treatment for hyperthyroidism?

When is a decrease in activity indicated in the treatment of hyperthyroidism?

How can exercise tolerance be improved in patients with severe thyrotoxicosis?

Which specialist consultations are needed in the treatment of thyrotoxicosis?

Who should provide care for patients who have completed definitive therapy for hyperthyroidism?

Which specialist consultations are needed in the treatment of patients with Graves thyrotoxicosis?

What monitoring is needed after the initiation of antithyroid medication for Graves disease?

What monitoring is needed after the initiation of antithyroid medication for non-Graves hyperthyroidism?

When should antithyroid medication for Graves disease be reduced or stopped?

https://emedicine.medscape.com/article/121865-print 30/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

When should definitive treatment be considered for patients with Graves disease?

What monitoring is needed after radioactive iodine therapy for hyperthyroidism?

What monitoring is needed after thyroid surgery for hyperthyroidism?

Guidelines

What are the 2016 ATA guidelines for the management of hyperthyroidism/thyrotoxicosis?

What are the 2017 ATA guidelines for the diagnosis and management of thyroid disease in women during pregnancy, the
postpartum period, and preconception?

Medications

What is the drug therapy for hyperthyroidism?

How are patients with hyperthyroidism treated?

Which patients with hyperthyroidism continue to be thyrotoxic after treatment with antithyroid medications?

Which medications in the drug class Beta Blockers, Beta1-Selective are used in the treatment of Hyperthyroidism and
Thyrotoxicosis?

Which medications in the drug class Beta Blockers, Nonselective are used in the treatment of Hyperthyroidism and
Thyrotoxicosis?

Which medications in the drug class Antithyroid Agents are used in the treatment of Hyperthyroidism and Thyrotoxicosis?

Contributor Information and Disclosures

Author

Stephanie L Lee, MD, PhD Associate Professor, Department of Medicine, Boston University School of Medicine; Director of
Thyroid Health Center, Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center; Fellow, Association of Clinical
Endocrinology

Stephanie L Lee, MD, PhD is a member of the following medical societies: American College of Endocrinology, American
Thyroid Association, Endocrine Society

Disclosure: Nothing to disclose.

Coauthor(s)

Sonia Ananthakrishnan, MD Assistant Professor of Medicine, Section of Endocrinology, Diabetes and Nutrition, Boston
Medical Center, Boston University School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP Professor of Endocrinology, Director of Training Program, Division of Endocrinology,
Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia
Medical School

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical
Endocrinologists, American College of Physicians, American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.

Acknowledgements

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy;
Editor-in-Chief, Medscape Drug Reference

https://emedicine.medscape.com/article/121865-print 31/33
3/9/2019 https://emedicine.medscape.com/article/121865-print

Disclosure: Medscape Salary Employment

Frederick H Ziel, MD Associate Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine;
Physician-In-Charge, Endocrinology/Diabetes Center, Director of Medical Education, Kaiser Permanente Woodland Hills; Chair
of Endocrinology, Co-Chair of Diabetes Complete Care Program, Southern California Permanente Medical Group

Frederick H Ziel, MD is a member of the following medical societies: American Association of Clinical Endocrinologists,
American College of Endocrinology, American College of Physicians, American College of Physicians-American Society of
Internal Medicine, American Diabetes Association, American Federation for Medical Research, American Medical Association,
American Society for Bone and Mineral Research, California Medical Association, Endocrine Society, andInternational Society
for Clinical Densitometry

Disclosure: Nothing to disclose.

References

1. Blick C, Jialal I. Thyroid, Thyrotoxicosis. 2018 Jan. [Medline]. [Full Text].

2. Frost L, Vestergaard P, Mosekilde L. Hyperthyroidism and risk of atrial fibrillation or flutter: a population-based study. Arch Intern
Med. 2004 Aug 9-23. 164(15):1675-8. [Medline].

3. [Guideline] Bahn Chair RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management
guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun. 21(6):593-
646. [Medline].

4. [Guideline] 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. [Medline]. [Full Text].

5. Gupta MK. Thyrotropin-receptor antibodies in thyroid diseases: advances in detection techniques and clinical applications. Clin Chim
Acta. 2000 Mar. 293 (1-2):1-29. [Medline].

6. Feldt-Rasmussen U, Hoier-Madsen M, Bech K, et al. Anti-thyroid peroxidase antibodies in thyroid disorders and non-thyroid
autoimmune diseases. Autoimmunity. 1991. 9 (3):245-54. [Medline].

7. Lumbroso S, Paris F, Sultan C. Activating Gsalpha mutations: analysis of 113 patients with signs of McCune-Albright syndrome--a
European Collaborative Study. J Clin Endocrinol Metab. 2004 May. 89(5):2107-13. [Medline].

8. Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes:
autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev. 2002 Jun. 23(3):327-64.
[Medline].

9. Plagnol V, Howson JM, Smyth DJ, Walker N, Hafler JP, Wallace C, et al. Genome-wide association analysis of autoantibody
positivity in type 1 diabetes cases. PLoS Genet. 2011 Aug. 7(8):e1002216. [Medline]. [Full Text].

10. Chu X, Pan CM, Zhao SX, Liang J, Gao GQ, Zhang XM, et al. A genome-wide association study identifies two new risk loci for
Graves' disease. Nat Genet. 2011 Aug 14. 43(9):897-901. [Medline].

11. Simmonds MJ, Brand OJ, Barrett JC, Newby PR, Franklyn JA, Gough SC. Association of Fc receptor-like 5 (FCRL5) with Graves'
disease is secondary to the effect of FCRL3. Clin Endocrinol (Oxf). 2010 Nov. 73(5):654-60. [Medline]. [Full Text].

12. Newby PR, Pickles OJ, Mazumdar S, Brand OJ, Carr-Smith JD, Pearce SH, et al. Follow-up of potential novel Graves' disease
susceptibility loci, identified in the UK WTCCC genome-wide nonsynonymous SNP study. Eur J Hum Genet. 2010 Sep. 18(9):1021-
6. [Medline]. [Full Text].

13. Nakabayashi K, Shirasawa S. Recent advances in the association studies of autoimmune thyroid disease and the functional
characterization of AITD-related transcription factor ZFAT. Nihon Rinsho Meneki Gakkai Kaishi. 2010. 33(2):66-72. [Medline].

14. Chu X, Dong Y, Shen M, Sun L, Dong C, Wang Y, et al. Polymorphisms in the ADRB2 gene and Graves disease: a case-control
study and a meta-analysis of available evidence. BMC Med Genet. 2009 Mar 13. 10:26. [Medline]. [Full Text].

15. Gabriel EM, Bergert ER, Grant CS, van Heerden JA, Thompson GB, Morris JC. Germline polymorphism of codon 727 of human
thyroid-stimulating hormone receptor is associated with toxic multinodular goiter. J Clin Endocrinol Metab. 1999 Sep. 84(9):3328-35.
[Medline].

16. van Dijk MM, Smits IH, Fliers E, Bisschop PH. Maternal Thyrotropin Receptor Antibody Concentration and the Risk of Fetal and
Neonatal Thyrotoxicosis: A Systematic Review. Thyroid. 2018 Feb. 28 (2):257-64. [Medline].

17. Mittra ES, Niederkohr RD, Rodriguez C, El-Maghraby T, McDougall IR. Uncommon causes of thyrotoxicosis. J Nucl Med. 2008 Feb.
49(2):265-78. [Medline].

https://emedicine.medscape.com/article/121865-print 32/33
3/9/2019 https://emedicine.medscape.com/article/121865-print
18. Davies TF, Larsen PR. Thyrotoxicosis. Larsen PR et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders;
2003. 374-421.

19. White A, Bozso SJ, Moon MC. Thyrotoxicosis induced cardiomyopathy requiring support with extracorporeal membrane
oxygenation. J Crit Care. 2018 Feb 3. 45:140-3. [Medline].

20. Dahl P, Danzi S, Klein I. Thyrotoxic cardiac disease. Curr Heart Fail Rep. 2008 Sep. 5(3):170-6. [Medline].

21. Zhyzhneuskaya S, Addison C, Tsatlidis V, Weaver JU, Razvi S. The Natural History of Subclinical Hyperthyroidism in Graves'
Disease: The Rule of Thirds. Thyroid. 2016 Jun. 26(6):765-9. [Medline].

22. Heeringa J, Hoogendoorn EH, van der Deure WM, et al. High-normal thyroid function and risk of atrial fibrillation: the Rotterdam
study. Arch Intern Med. 2008 Nov 10. 168(20):2219-24. [Medline].

23. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al. Serum TSH, T(4), and thyroid antibodies in
the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol
Metab. 2002 Feb. 87(2):489-99. [Medline]. [Full Text].

24. Porterfield JR Jr, Thompson GB, Farley DR, Grant CS, Richards ML. Evidence-based management of toxic multinodular goiter
(Plummer's Disease). World J Surg. 2008 Jul. 32(7):1278-84. [Medline].

25. [Guideline] De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, et al. Management of thyroid dysfunction during
pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012 Aug. 97(8):2543-65.
[Medline].

26. FDA MedWatch Safety Alerts for Human Medical Products. Propylthiouracil (PTU). US Food and Drug Administration. Accessed:
June 3, 2009. Available at
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm164162.htm.

27. Stalberg P, Svensson A, Hessman O, et al. Surgical treatment of Graves' disease: evidence-based approach. World J Surg. 2008
Jul. 32(7):1269-77. [Medline].

28. Wang J, Qin L. Radioiodine therapy versus antithyroid drugs in Graves' disease: a meta-analysis of randomized controlled trials. Br J
Radiol. 2016 Jun 27. [Medline].

29. Sisson JC, Freitas J, McDougall IR, Dauer LT, Hurley JR, Brierley JD, et al. Radiation safety in the treatment of patients with thyroid
diseases by radioiodine ¹³¹i: practice recommendations of the american thyroid association. Thyroid. 2011 Apr. 21(4):335-46.
[Medline].

30. Shindo M. Surgery for hyperthyroidism. ORL J Otorhinolaryngol Relat Spec. 2008. 70(5):298-304. [Medline].

31. Worni M, Schudel HH, Seifert E, Inglin R, Hagemann M, Vorburger SA, et al. Randomized controlled trial on single dose steroid
before thyroidectomy for benign disease to improve postoperative nausea, pain, and vocal function. Ann Surg. 2008 Dec.
248(6):1060-6. [Medline].

32. Zhang Y, Dong Z, Li J, Yang J, Yang W, Wang C. Comparison of endoscopic and conventional open thyroidectomy for Graves'
disease: A meta-analysis. Int J Surg. 2017 Feb 22. 40:52-9. [Medline].

33. [Guideline] 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):315-89. [Medline]. [Full Text].

34. FDA Drug Safety Communication: New Boxed Warning on severe liver injury with propylthiouracil. US Food and Drug
Administration, April 21, 2010. Available at
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm209023.htm. Accessed: March
6, 2012.

35. Yalamanchi S, Cooper DS. Thyroid disorders in pregnancy. Curr Opin Obstet Gynecol. 2015 Oct 19. [Medline].

36. Burches-Feliciano MJ, Argente-Pla M, Garcia-Malpartida K, Rubio-Almanza M, Merino-Torres JF. Hyperthyroidism induced by topical
iodine. Endocrinol Nutr. 2015 Aug 12. [Medline].

37. Brandt F. The long-term consequences of previous hyperthyroidism. A register-based study of singletons and twins. Dan Med J.
2015 Jun. 62 (6):[Medline].

38. Srinivasan S, Misra M. Hyperthyroidism in children. Pediatr Rev. 2015 Jun. 36 (6):239-48. [Medline].

https://emedicine.medscape.com/article/121865-print 33/33