http://emedicine.medscape.

com/article/121865-overview

Hyperthyroidism

Author: Stephanie L Lee, MD, PhD, Associate Professor, Department of Medicine,

Boston University School of Medicine; Director of Thyroid Nodule and Cancer Center,
Associate Chief, Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center;
Fellow, Association of Clinical Endocrinology
Coauthor(s): Sonia Ananthakrishnan, MD, Assistant Professor of Medicine, Section of
Endocrinology, Diabetes and Nutrition, Boston University School of Medicine/Boston
Medical Center
Contributor Information and Disclosures

Updated: Apr 26, 2010

Introduction

Background

Thyrotoxicosis is the hypermetabolic condition associated with elevated levels of free

thyroxine (FT4) and/or free triiodothyronine (FT3). Hyperthyroidism includes diseases that
are a subset of thyrotoxicosis, that are caused by excess synthesis and secretion of thyroid
hormone by the thyroid; they are not associated with exogenous thyroid hormone intake
and subacute thyroiditis. Most clinicians, exclusive of endocrinologists, use the terms
hyperthyroidism and thyrotoxicosis interchangeably. This article discusses the causes of
thyrotoxicosis associated with hyperthyroidism (excess synthesis and release of thyroid
hormone) and surreptitious use of thyroid hormone. Subacute thyroiditis is discussed in the
article Subacute Thyroiditis.

The most common forms of hyperthyroidism include diffuse toxic goiter (Graves disease),
toxic multinodular goiter (Plummer disease), and toxic adenoma. Together with subacute
thyroiditis, these conditions constitute 85-90% of all causes of thyrotoxicosis. Table 1
contains a list of hyperthyroid conditions associated with thyrotoxicosis.

Table 1. Common, Less Common, and Uncommon Forms of Thyrotoxicosis and

Hyperthyroidism

Open table in new window

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Table
Common Forms (85-90% of cases) Radioactive iodine uptake
over neck

Diffuse toxic goiter (Graves disease) Increased

Toxic multinodular goiter (Plummer disease) Increased

Thyrotoxic phase of subacute thyroiditis Decreased

Toxic adenoma Increased

Less Common Forms

Iodide-induced thyrotoxicosis Variable

Thyrotoxicosis factitia Decreased

Uncommon Forms

Pituitary tumors producing thyroid-stimulating hormone Increased

Excess human chorionic gonadotropin (molar Increased

pregnancy/choriocarcinoma)

Pituitary resistance to thyroid hormone Increased

Metastatic thyroid carcinoma Decreased

Struma ovarii with thyrotoxicosis Decreased

Common Forms (85-90% of cases) Radioactive iodine uptake

over neck

Diffuse toxic goiter (Graves disease) Increased

Toxic multinodular goiter (Plummer disease) Increased

Thyrotoxic phase of subacute thyroiditis Decreased

Toxic adenoma Increased

Less Common Forms

Iodide-induced thyrotoxicosis Variable

Thyrotoxicosis factitia Decreased

Uncommon Forms

Pituitary tumors producing thyroid-stimulating hormone Increased

Excess human chorionic gonadotropin (molar Increased

pregnancy/choriocarcinoma)

Pituitary resistance to thyroid hormone Increased

Metastatic thyroid carcinoma Decreased

Struma ovarii with thyrotoxicosis Decreased

Pathophysiology

The hypermetabolic effect of thyrotoxicosis affects every organ system. The pituitary gland
stimulates the thyroid to make thyroid hormone, which is released into the circulation to
reach every cell in the body. Thyroid hormone is necessary for normal growth and
development, and it regulates cellular metabolism. Excess thyroid hormone causes an
increase in the metabolic rate that is associated with increased total body heat production
and cardiovascular activity (increased heart contractility, heart rate, vasodilation).

Graves disease

The most common cause of thyrotoxicosis is Graves disease (50-60%). Graves disease is an
organ-specific autoimmune disorder characterized by a variety of circulating antibodies,
including common autoimmune antibodies, as well as anti-thyroid peroxidase (anti-TPO)
and antithyroglobulin (anti-TG) antibodies. The most important autoantibody is thyroid-
stimulating immunoglobulin (TSI). TSI is directed toward epitopes of the thyroid-
stimulating hormone (TSH) receptor and acts as a TSH-receptor agonist. Similar to TSH,
TSI binds to the TSH receptor on the thyroid follicular cells to activate thyroid hormone
synthesis and release and thyroid 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.
Iodine 123 (123I) nuclear scintigraphy: 123I scans of a normal thyroid gland (A)
and common hyperthyroid conditions with elevated radioiodine uptake, including
Graves disease (B), toxic multinodular goiter (C), and toxic adenoma (D).

Color flow ultrasonogram in a patient with Graves disease. Generalized

hypervascularity is visible throughout the gland, which often can be heard as a
hum or bruit with a stethoscope.

Thyroid hormone levels can be extremely elevated in this condition. Clinical findings
specific to Graves disease include thyroid ophthalmopathy (periorbital edema, chemosis
[conjunctival edema], injection, 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, and
type 1 diabetes mellitus.

Subacute thyroiditis

The next most common cause of thyrotoxicosis is subacute thyroiditis (approximately 15-
20%), a destructive release of preformed thyroid hormone. A typical nuclear scintigraphy
scan shows no radioactive iodine uptake in the thyrotoxic phase of the disease. (See
images below.) Thyroid hormone levels can be extremely elevated in this condition. This
topic is discussed and a typical nuclear scintigraphy scan is shown in the article Subacute
Thyroiditis.

Absence of iodine 123 (123I) radioactive iodine uptake in a patient with

thyrotoxicosis and subacute painless or lymphocytic thyroiditis. Laboratory
studies at the time of the scan demonstrated the following: thyroid-stimulating
hormone (TSH), less than 0.06 mIU/mL; total thyroxine (T4), 21.2 mcg/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/h.
The absence of thyroid uptake, the low T3-to-T4 ratio, and the low ESR confirm the
diagnosis of subacute painless thyroiditis.

Three multinuclear giant cell granulomas observed in a fine-needle aspiration

biopsy of the thyroid from a patient with thyrotoxicosis from subacute painful or
granulomatous thyroiditis.

Toxic multinodular goiter

Toxic multinodular goiter (Plummer disease) occurs in 15-20% of patients with

thyrotoxicosis. It occurs more commonly in elderly individuals, especially in patients with a
long-standing goiter. Thyroid hormone excess develops very slowly over time and often is
only mildly elevated at the time of diagnosis. As discussed below, very high thyroid
hormone levels may occur in this condition after high iodine intake, ie, with contrast or
amiodarone exposure. 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. A typical
nuclear scintigraphy scan of a toxic multinodular goiter is shown in the first image above
and demonstrates an enlarged thyroid gland with areas of increased and decreased
activity. See also the image below.

Scan in a patient with a toxic multinodular goiter. The 5-hour iodine uptake was
elevated at 28%. Note the multiple foci of variably increased tracer uptake.
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Toxic adenoma

Toxic adenoma is caused by a single hyperfunctioning follicular thyroid adenoma. Patients

with a toxic thyroid adenoma comprise approximately 3-5% of patients who are
thyrotoxic. 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. Radioactive iodine uptake 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. See the first image above.

Other causes of thyrotoxicosis

Several rare causes of thyrotoxicosis exist that deserve mention. Iodide-induced

thyrotoxicosis (Jod-Basedow syndrome) occurs in patients with excessive iodine intake,
such as after an iodinated radiocontrast study. It occurs in patients with areas of thyroid
autonomy, such as a multinodular goiter or autonomous nodule. The thyrotoxicosis
appears to be a result of loss of the normal adaptation of the thyroid to iodide excess. It is
treated by cessation of the excess iodine intake and administration of antithyroid
medication. Usually, after depletion of the excess iodine, thyroid functions return to
preexposure levels.

Struma ovarii is ectopic thyroid tissue associated with dermoid tumors or ovarian teratomas
that can secrete excessive amounts of thyroid hormone and produce thyrotoxicosis.

Metastatic follicular thyroid carcinoma maintains the ability to make thyroid hormone and
can cause thyrotoxicosis in patients with bulky tumors.

Patients with a molar hydatidiform pregnancy or choriocarcinoma have extremely high

levels of beta human chorionic gonadotropin (HCG) that can weakly activate the TSH
receptor. At very high levels of HCG, activation of the TSH receptor occurs that is
sufficient to cause thyrotoxicosis. Physiologic maximum elevation of 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, the FT4 levels usually remain normal or only slightly
above the reference range. As the pregnancy progresses and the HCG plateaus at a lower
level, TSH levels decrease back to normal levels.

Frequency

United States

Graves disease is the most common form of hyperthyroidism. Approximately 60-80% of

cases of thyrotoxicosis are due to Graves disease. The annual incidence of the disease is 0.5
cases per 1000 persons during a 20-year period, with the peak occurrence in people aged
20-40 years. 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 is less than the incidence in areas of the
world with iodine deficiency. Toxic adenoma is the cause of 3-5% of cases of
thyrotoxicosis.

International

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.

Mortality/Morbidity

The clinical manifestations of thyrotoxicosis can be divided into those associated with any
form of thyrotoxicosis and those associated specifically with Graves disease.

Nonspecific changes due to excessive thyroid hormone include weight loss,

nervousness, fatigue, heat intolerance, and rapid heartbeat or palpitations
 sometimes associated with atrial fibrillation and high-output congestive heart
failure (CHF).1
An increase in the rate of bone resorption occurs, but bone loss measured by bone
mineral densitometry has been convincingly shown to occur only in
postmenopausal women with hyperthyroidism.
Thyroid hormone excess causes left ventricular thickening, which is associated with
an increased risk of CHF. Thyrotoxicosis has been associated with dilated
cardiomyopathy, right heart failure with pulmonary hypertension, and diastolic
dysfunction.1
Ophthalmopathy and dermopathy specifically associated with Graves disease
include periorbital edema, chemosis, and proptosis with extraocular muscle
dysfunction and diplopia. The dermopathy, a painless swelling of the pretibial area,
may occur in patients with severe ophthalmopathy.

Race

Autoimmune thyroid disease occurs with the same frequency in Caucasians, Hispanics, and
Asians, and it occurs less frequently in the black population.

Sex

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

Age

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 50 years. Patients with toxic
adenomas present at a younger age than do patients with toxic multinodular goiter.

Clinical

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 more sympathetic activation, such as anxiety, hyperactivity, and
tremor, while older patients have more cardiovascular symptoms, including dyspnea and
atrial fibrillation with unexplained weight loss. The clinical manifestations of
thyrotoxicosis do not always correlate with the extent of the biochemical abnormality.

Common symptoms of thyrotoxicosis include the following:

o Nervousness
 o Anxiety
o Increased perspiration
o Heat intolerance
o Tremor
o Hyperactivity
o Palpitations
o Weight loss despite increased appetite
o Reduction in menstrual flow or oligomenorrhea
Common signs of thyrotoxicosis include the following:
o Hyperactivity
o Tachycardia or atrial arrhythmia
o Systolic hypertension
o Warm, moist, and smooth skin
o Lid lag
o Stare
o Tremor
o Muscle weakness
Generally, a constellation of information, including extent and duration of
symptoms, past medical history, social and family history, and physical
examination, help guide the clinician to the appropriate diagnosis.
Subclinical hyperthyroidism is associated with no clinical symptoms of
thyrotoxicosis. However, certain conditions, such as 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 12% in
the general population.

A report from the Netherlands on 1426 patients whose TSH levels were in the
normal range (0.4-4.0 mU/L), found evidence, after a median follow-up of 8
years, of an increased risk of atrial fibrillation even in persons with high-normal
thyroid function.2
Radiation exposure, whether due to radiation therapy or to lower-level
radiographic therapy, increases the risk of benign and malignant nodular thyroid
diseases, with an observed increase in the incidence of autoimmune
hyperthyroidism.
The frequency and severity of symptoms of thyrotoxicosis vary from person to
person. Graves disease is an autoimmune disease, and often, a strong family
history or past medical history exists with autoimmune diseases such as with
rheumatoid arthritis, vitiligo, or pernicious anemia.
o The symptoms of Graves disease often are more marked, because thyroid
hormone levels usually are the highest with this form of hyperthyroidism.
o Also consider the diagnosis of Graves disease if any evidence of thyroid eye
disease exists, including periorbital edema, diplopia, or proptosis.
 o 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.
Recording a careful family history of autoimmune disease, thyroid disease, and
emigration from iodine-deficient areas is important.
Review a complete list of medications. A number of compoundsincluding
expectorants, amiodarone, health food supplements containing seaweed, and
iodinated contrast dyescontain 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

Physical examination often can help the clinician determine the etiology of thyrotoxicosis.

Thyroid 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.
o Thyrotoxicosis due to Graves disease is associated with a diffusely enlarged
and slightly firm thyroid gland. Sometimes, a thyroid bruit is audible using
the bell of the stethoscope.
o Toxic multinodular goiters occur when goiters generally are enlarged to at
least 2 to 3 times normal size. The gland often is soft, but individual nodules
occasionally can be palpated.
o A toxic adenoma generally does not cause thyrotoxicosis in a patient until it
is at least 2.5 cm in diameter.
o If the thyroid is enlarged and painful, the diagnosis is likely subacute painful
or granulomatous thyroiditis, but consider degeneration or hemorrhage
into a nodule or suppurative thyroiditis.
Thyroid-specific physical examination - Graves thyrotoxicosis can be associated
with mild thyroid ophthalmopathy in 50% of patients.
o Often, it is manifested only by periorbital edema, but it also can include
conjunctival edema (chemosis), injection, poor lid closure, extraocular
muscle dysfunction (diplopia), and proptosis.
o Evidence of thyroid eye disease and high thyroid hormone levels confirms
the diagnosis of autoimmune Graves disease.
o Graves disease rarely can affect the skin by deposition of
glycosaminoglycans in the dermis of the lower leg. This causes nonpitting
edema, usually associated with erythema and thickening of the skin,
without pain or pruritus.
Signs of thyrotoxicosis - Usually, signs upon physical examination include sinus
tachycardia or atrial fibrillation, systolic hypertension, excessive perspiration,
 palmar erythema and sweating, lid lag, extension tremor, hyperkinesis, large-
muscle weakness, and soft, smooth skin.

Causes

Genetics and iodine intake appear to influence the incidence of thyrotoxicosis.

Genetics - Autoimmune thyroid disease and Graves disease have a higher

prevalence in patients with human leukocyte antigen (HLA)-DRw3 and HLA-B89.
o Graves disease is felt to be an HLA-related, organ-specific defect in
suppressor T-lymphocyte function.
o Observing autoimmune thyroid disease, including Hashimoto
hypothyroidism and Graves disease, in multiple members of a patient's
family is common.
o Similarly, subacute painful or granulomatous thyroiditis occurs more
frequently in patients with HLA-Bw35.
o Similar to other immune diseases, these thyroid conditions occur more
frequently in women than in men.
Iodine intake - Clearly, patients in borderline iodine-deficient areas of the world
develop nodular goiter, often with areas of autonomy. When this population is
moved to areas of sufficient iodine intake, thyrotoxicosis occurs. Evidence that
iodine can act as an immune stimulator exists, precipitating autoimmune thyroid
disease and acting as a substrate for additional thyroid hormone synthesis