Author: Dr Paul W. Ladenson Johns Hopkins University 2008-06-10
1. Introduction
Hyperthyroidism refers to the effects on the body of thyroid hormone excess [see below.], a condition affecting 2% of adults during their lifetimes. Hyperthyroidism can be caused by a number of underlying conditions, some of which are short-lived and resolve spontaneously, and others that persist and progress unless treated definitively. Hyperthyroidism has widespread and disabling health consequences, but it is reversible with prompt diagnosis and treatment. When severe and untreated, however, hyperthyroidism can be life-threatening.
Hyperthyroidism symptoms (i.e., complaints) and signs
(i.e., objective exam findings) are nonspecific, so laboratory tests
and sometimes radionuclide studies are needed to confirm the diagnosis,
define the underlying cause, and monitor its course. 1. Introduction
Hyperthyroidism refers to the effects on the body of thyroid hormone excess [see below.], a condition affecting 2% of adults during their lifetimes. Hyperthyroidism can be caused by a number of underlying conditions, some of which are short-lived and resolve spontaneously, and others that persist and progress unless treated definitively. Hyperthyroidism has widespread and disabling health consequences, but it is reversible with prompt diagnosis and treatment. When severe and untreated, however, hyperthyroidism can be life-threatening.
[The term hyperthyroidism is widely used interchangeably with thyrotoxicosis, but strictly interpreted, hyperthyroidism refers only to forms of thyrotoxicosis due to excessive thyroid hormones production by the thyroid gland itself. In this Knol, the familiar term hyperthyroidism is used to describe this entire class of conditions.]
2. How Common is Hyperthyroidism?
Hyperthyroidism is present in one of every 2,000 adults. Hyperthyroidism can occur in individuals of any age—from newborn children to the very elderly—but the condition most commonly develops between adolescence and 60 years of age. For unknown reasons, hyperthyroidism is more common in women. During their lifetimes, 3 of every 100 women, and 3 of 1000 men will be afflicted with the most common cause of hyperthyroidism, Graves’ disease.
3. What Goes Wrong with the Thyroid Gland and Its Hormones in Hyperthyroidism?
The thyroid gland, a butterfly shaped organ located in the lower front of the neck, normally makes precisely the right amount of its hormones, thyroxine (T4) and triiodothyronine (T3), under the exacting control of the pituitary gland, which is an extension of the brain. Specialized pituitary cells make thyroid stimulating hormone (TSH), which travels in the blood to the thyroid gland, where TSH binds to its own receptors on thyroid cells, prompting them to grow and produce more of the thyroid hormones. Normally, this system is kept in balance by the negative feedback of the thyroid hormones on TSH-secreting pituitary cells (as well as the part of the brain that controls them). When this control system is “short-circuited” or by-passed, hyperthyroidism can be the result. [See attached Hypothalamic-Pituitary-Thyroid Axis animated PowerPoint image: Hyperthyroidism Knol_HPT axis.ppt.]
To
understand hyperthyroidism, it is important to appreciate how thyroid
hormones act and how their production by the thyroid gland is normally
regulated. Thyroid hormones, thyroxine (T4) and triiodothyronine (T3),
are each comprised of a pair of connected amino acids (tyrosines), to
which iodine molecules are attached. Thyroid hormones are delivered by
the blood to tissues throughout the body, where in the nucleus of almost
every cell in the body, they bind to molecules called T3 receptors,
which are attached to segments of DNA that regulate certain genes.
Precise control of how many proteins are made from these genetic
blueprints maintains the normal thyroid (euthyroid) state. Excessive
activation of these genes by abnormally high thyroid hormone levels
causes hyperthyroidism. [If you are seriously interested in how
thyroid hormones work, you can learn much more about thyroid hormones
receptors and the genes regulated by them at the Nuclear Receptor
Signaling Atlas ( NURSA): http://www.nursa.org/molecule.cfm?molType=receptor&molId=1A1.]
4. What are the Consequences of Hyperthyroidism?
Hyperthyroidism typically causes weight loss despite a hearty appetite; discomfort in warm places (heat intolerance); trembling of the hands (tremor); a fast, hard, or irregular heart beat (palpitations); insomnia despite being tired; shortness of breath; sharp short-lived chest pains; frequent bowel movements; muscle weakness, and unexplained anxiety and irritability. However, some patients have uncommon complaints, such as weight gain, nausea and vomiting (especially in pregnant women), headaches, and itching with or without hives. In older people, hyperthyroidism may present solely with droopiness and weight loss (called apathetic thyrotoxicosis). When hyperthyroidism is very mild, symptoms may be absent or barely noticeable, so called subclinical hyperthyroidism. Even then, silent effects of mild hyperthyroidism can lead to osteoporosis or a fast irregular heart rhythm. Conversely, when hyperthyroidism is severe, affected individuals can develop heart failure, become delirious, have high fever, and be at risk of dying from their condition—so called thyroid crisis or storm.
On examination, people with hyperthyroidism typically have a rapid pulse, an elevated systolic blood pressure (the top number), a jittery appearance, warm moist skin, wide staring eyes, a pounding heart that can be felt or seen through the chest wall, trembling hands, and weak thigh muscles. Specific underlying causes of hyperthyroidism can add their own particular findings, as described below under Causes of Hyperthyroidism.
Despite these apparently striking features, the diagnosis of hyperthyroidism not infrequently goes unrecognized by affected individuals, their family and friends, and even good doctors. There are several reasons for this delayed diagnosis. Symptoms of hyperthyroidism are nonspecific, and are often first attributed to life stress or other medical conditions. Only one or two of the classical symptoms may be obvious, and some affected people have no symptoms at all. Finally, most people with hyperthyroidism have previously been healthy, so they may not even seek care until their illness is severe and prolonged.
Hyperthyroidism typically causes weight loss despite a hearty appetite; discomfort in warm places (heat intolerance); trembling of the hands (tremor); a fast, hard, or irregular heart beat (palpitations); insomnia despite being tired; shortness of breath; sharp short-lived chest pains; frequent bowel movements; muscle weakness, and unexplained anxiety and irritability. However, some patients have uncommon complaints, such as weight gain, nausea and vomiting (especially in pregnant women), headaches, and itching with or without hives. In older people, hyperthyroidism may present solely with droopiness and weight loss (called apathetic thyrotoxicosis). When hyperthyroidism is very mild, symptoms may be absent or barely noticeable, so called subclinical hyperthyroidism. Even then, silent effects of mild hyperthyroidism can lead to osteoporosis or a fast irregular heart rhythm. Conversely, when hyperthyroidism is severe, affected individuals can develop heart failure, become delirious, have high fever, and be at risk of dying from their condition—so called thyroid crisis or storm.
On examination, people with hyperthyroidism typically have a rapid pulse, an elevated systolic blood pressure (the top number), a jittery appearance, warm moist skin, wide staring eyes, a pounding heart that can be felt or seen through the chest wall, trembling hands, and weak thigh muscles. Specific underlying causes of hyperthyroidism can add their own particular findings, as described below under Causes of Hyperthyroidism.
Despite these apparently striking features, the diagnosis of hyperthyroidism not infrequently goes unrecognized by affected individuals, their family and friends, and even good doctors. There are several reasons for this delayed diagnosis. Symptoms of hyperthyroidism are nonspecific, and are often first attributed to life stress or other medical conditions. Only one or two of the classical symptoms may be obvious, and some affected people have no symptoms at all. Finally, most people with hyperthyroidism have previously been healthy, so they may not even seek care until their illness is severe and prolonged.
5. Causes of Hyperthyroidism
It is important to determine the underlying cause of hyperthyroidism because the most effective treatment varies depending on which specific condition is responsible. 5.1. Graves disease [see below]
The most common cause of hyperthyroidism is Graves disease, an autoimmune disorder which is more common in women and often runs in families. Graves disease develops when an individual’s immune system make antibodies that bind to and stimulate TSH receptors on thyroid cells—just like TSH itself does, but without the usual regulatory controls. When Graves disease affects a pregnant woman, these antibodies can even cross the placenta to the baby, causing the child to have hyperthyroidism in the womb and for several weeks after their birth.
Although variations in certain genes related to the immune system are more common in people with Graves disease, no genetic test yet exists to identify people at risk. What triggers the onset of Graves disease in someone with a genetic predisposition remains uncertain. Risk factors have include smoking, radiation of the thyroid gland, such as occurs in treating Hodgkins disease, a medication used to treat hepatitis called interferon alpha, and perhaps some sort of infection or stressful life events.
Graves disease typically causes enlargement of the entire thyroid gland (diffuse goiter). The condition also commonly includes inflammation of tissues around the eyes (Graves ophthalmopathy or orbitopathy) and rarely an orange peel-like thickening of the skin over the front of the low leg or foot (pretibial myxedema). These other features of Graves disease usually occur within 6 months of the onset of hyperthyroidism, but they can rarely occur longer before or after hyperthyroidism, or even alone without a thyroid problem. Characteristic features of Graves eye disease can include bulging of the eyes (proptosis or exophthalmos); eye irritation, dryness, itching, redness, and/or increased tearing; puffiness around the eyes (periorbital edema); light sensitivity (photophobia); and double or blurred vision. Sometimes the involvement of Graves disease can be the most serious aspect of the condition. [Graves disease, which named for the physician who first described it in England in 1847, is also called diffuse toxic goiter and, in continental Europe, von Basedow disease.]
5.2. Toxic adenoma and toxic multinodular goiter
Benign tumors of the thyroid, called adenomas, sometimes function on their own, even without TSH stimulation. Once such tumors become sufficiently large and over-functioning, they cause hyperthyroidism. When there is one tumor, the condition is called a toxic adenoma [see below]; when there are more, it is called toxic multinodular goiter.
Genetic and environmental factors have both been implicated in development of this autonomous function. Acquired mutations in genes for the TSH receptor can turn on that cell’s growth and thyroid hormone production even without TSH. Such mutations in the TSH receptor and other key signaling proteins have been found in many over-functioning adenomas. A diet very low in iodine can predispose people to development of toxic adenomas.
On examination, a toxic adenoma may be large enough to see or feel in the front of the neck. A toxic multinodular goiter may be visible or felt as a more generalized, knobbly thyroid enlargement, which rarely can become big enough to interfere with swallowing or breathing.
[Toxic adenomas are also called Plummer disease, which is named for the American doctor who described the condition in the early 20th century.]
5.3. Thyroiditis, inflammation of the thyroid gland
It is important to determine the underlying cause of hyperthyroidism because the most effective treatment varies depending on which specific condition is responsible. 5.1. Graves disease [see below]
The most common cause of hyperthyroidism is Graves disease, an autoimmune disorder which is more common in women and often runs in families. Graves disease develops when an individual’s immune system make antibodies that bind to and stimulate TSH receptors on thyroid cells—just like TSH itself does, but without the usual regulatory controls. When Graves disease affects a pregnant woman, these antibodies can even cross the placenta to the baby, causing the child to have hyperthyroidism in the womb and for several weeks after their birth.
Although variations in certain genes related to the immune system are more common in people with Graves disease, no genetic test yet exists to identify people at risk. What triggers the onset of Graves disease in someone with a genetic predisposition remains uncertain. Risk factors have include smoking, radiation of the thyroid gland, such as occurs in treating Hodgkins disease, a medication used to treat hepatitis called interferon alpha, and perhaps some sort of infection or stressful life events.
Graves disease typically causes enlargement of the entire thyroid gland (diffuse goiter). The condition also commonly includes inflammation of tissues around the eyes (Graves ophthalmopathy or orbitopathy) and rarely an orange peel-like thickening of the skin over the front of the low leg or foot (pretibial myxedema). These other features of Graves disease usually occur within 6 months of the onset of hyperthyroidism, but they can rarely occur longer before or after hyperthyroidism, or even alone without a thyroid problem. Characteristic features of Graves eye disease can include bulging of the eyes (proptosis or exophthalmos); eye irritation, dryness, itching, redness, and/or increased tearing; puffiness around the eyes (periorbital edema); light sensitivity (photophobia); and double or blurred vision. Sometimes the involvement of Graves disease can be the most serious aspect of the condition. [Graves disease, which named for the physician who first described it in England in 1847, is also called diffuse toxic goiter and, in continental Europe, von Basedow disease.]
5.2. Toxic adenoma and toxic multinodular goiter
Benign tumors of the thyroid, called adenomas, sometimes function on their own, even without TSH stimulation. Once such tumors become sufficiently large and over-functioning, they cause hyperthyroidism. When there is one tumor, the condition is called a toxic adenoma [see below]; when there are more, it is called toxic multinodular goiter.
Genetic and environmental factors have both been implicated in development of this autonomous function. Acquired mutations in genes for the TSH receptor can turn on that cell’s growth and thyroid hormone production even without TSH. Such mutations in the TSH receptor and other key signaling proteins have been found in many over-functioning adenomas. A diet very low in iodine can predispose people to development of toxic adenomas.
On examination, a toxic adenoma may be large enough to see or feel in the front of the neck. A toxic multinodular goiter may be visible or felt as a more generalized, knobbly thyroid enlargement, which rarely can become big enough to interfere with swallowing or breathing.
[Toxic adenomas are also called Plummer disease, which is named for the American doctor who described the condition in the early 20th century.]
5.3. Thyroiditis, inflammation of the thyroid gland
5.3.1. Subacute thyroiditis (de Quervain thyroiditis)
Subacute
thyroiditis is believed to be caused by a viral infection of the gland.
Fortunately, this presumed infection does not appear to be easily
transmitted from one person to another, and outbreaks with many affected
people have only rarely been described.
Subacute thyroiditis typically has 3 components. The first is a painful enlargement of the thyroid gland, which can sometimes seem to be a sore throat or jaw, or an earache. The gland is very tender to the touch. Second, affected people often feel as though they have the flu, with fatigue, malaise, fever, chills, and night sweats. Third, the inflamed thyroid releases the thyroid hormones stored within it, causing temporary hyperthyroidism that typically lasts from 2 to 8 weeks when the gland’s supply of hormones is exhausted. This can then be followed by a spell of hypothyroidism, an underactive thyroid gland, for a similar period. Almost always, the thyroid’s function then returns to normal and the condition never recurs.
5.3.2. Painless thyroiditis (also known as silent, postpartum, and acute lymphocytic thyroiditis)
As its name implies, this form of thyroid inflammation causes no gland pain or tenderness. Painless thyroiditis almost always occurs in women 2 to 12 months after delivery of a baby or the premature end of a pregnancy. Approximately 1 in 20 women suffer painless thyroiditis during the postpartum period. The condition causes temporary hyperthyroidism that typically lasts from 2 to 8 weeks when the gland’s hormone supply is exhausted. This can then be followed by a time-limited hypothyroidism, an underactive thyroid gland, for a similar period. Sometimes, only hyperthyroidism or hypothyroidism occur. Often, postpartum painless thyroiditis goes unrecognized, and its symptoms of weight loss, sleeplessness, fatigue, nervousness, and depression are chalked up simply to being a new mother. Painless thyroiditis is believed to be an autoimmune disease that temporarily inflames the gland; but in at least one-quarter of people, painless thyroiditis evolves into permanent hypothyroidism due to chronic lymphocytic thyroiditis (or Hashimoto disease).
5.3.3. Unusual kinds of thyroiditis
Subacute thyroiditis typically has 3 components. The first is a painful enlargement of the thyroid gland, which can sometimes seem to be a sore throat or jaw, or an earache. The gland is very tender to the touch. Second, affected people often feel as though they have the flu, with fatigue, malaise, fever, chills, and night sweats. Third, the inflamed thyroid releases the thyroid hormones stored within it, causing temporary hyperthyroidism that typically lasts from 2 to 8 weeks when the gland’s supply of hormones is exhausted. This can then be followed by a spell of hypothyroidism, an underactive thyroid gland, for a similar period. Almost always, the thyroid’s function then returns to normal and the condition never recurs.
5.3.2. Painless thyroiditis (also known as silent, postpartum, and acute lymphocytic thyroiditis)
As its name implies, this form of thyroid inflammation causes no gland pain or tenderness. Painless thyroiditis almost always occurs in women 2 to 12 months after delivery of a baby or the premature end of a pregnancy. Approximately 1 in 20 women suffer painless thyroiditis during the postpartum period. The condition causes temporary hyperthyroidism that typically lasts from 2 to 8 weeks when the gland’s hormone supply is exhausted. This can then be followed by a time-limited hypothyroidism, an underactive thyroid gland, for a similar period. Sometimes, only hyperthyroidism or hypothyroidism occur. Often, postpartum painless thyroiditis goes unrecognized, and its symptoms of weight loss, sleeplessness, fatigue, nervousness, and depression are chalked up simply to being a new mother. Painless thyroiditis is believed to be an autoimmune disease that temporarily inflames the gland; but in at least one-quarter of people, painless thyroiditis evolves into permanent hypothyroidism due to chronic lymphocytic thyroiditis (or Hashimoto disease).
5.3.3. Unusual kinds of thyroiditis
Thyroid
inflammation causing temporary hormone excess and/or deficiency can
also be caused by certain drugs, such as amiodarone used to control
irregular heart rhythms and interferon alpha for hepatitis, bacterial
infections (so called acute thyroiditis) and other very unusual
infections affecting people with a compromised immune system.
5.4. Rare causes of hyperthyroidism
When a person takes too much thyroid hormone medication, thyrotoxicosis occurs. Among patients being prescribed thyroid hormone for an underactive thyroid gland, as many as 1 in 5 has blood test evidence of overtreatment. Rarely, a child accidentally, or a troubled person deliberately takes an overdose of thyroid hormone. Once there was an outbreak of thyrotoxicosis when people ate ground beef that mistakenly contained the thyroid glands of cattle, so called “hamburger hyperthyroidism.”
Over-stimulation of the thyroid gland is the cause of several rare kinds of hyperthyroidism. Certain tumors of the pituitary gland make too much thyroid stimulating hormone (TSH). Excessive production of a hormone called chorionic gonadotropin, which is normally made by the placenta in pregnant women, can cause hyperthyroidism because it is similar to TSH. Chorionic gonadotropin can be overproduced by tumors of the placenta or in some otherwise normal pregnancies, especially when a woman has severe morning sickness.
Among the rarest types of hyperthyroidism are inherited mutations in the genetic blueprint, or gene, for hormone receptors controlling the thyroid system. If the mutant TSH receptor is stuck in the turned-on position, hyperthyroidism begins even before a baby is born. Another rare kind of TSH receptor mutation leads to stimulation of the receptor by even normal amounts of chorionic gonadotropin; this predictably causes hyperthyroidism every time a woman becomes pregnant. When there is an inherited mutation in the thyroid hormone receptor itself, in the pituitary gland, the result can be pituitary resistance to the normal negative feedback of thyroid hormone and excessive TSH production with resulting hyperthyroidism.
Rarely, thyroid hormone may be overproduced outside of the thyroid gland itself, as when thyroid cancer has spread throughout the body and when thyroid tissue oddly develops in a woman’s ovary, a so called struma ovarii.
6. How is the Diagnosis of Hyperthyroidism Made?
In every case, blood tests are essential to confirm or rule out the diagnosis of hyperthyroidism because its symptoms and signs are nonspecific (i.e., they can be caused by many things) and sometimes insensitive (i.e., not present even though hyperthyroidism is). These tests are reliable; their results are typically back in a day or two, if not hours; and the tests are available through almost any doctor’s office, clinic, or hospital.
There are two general blood test strategies. The first approach is measuring TSH, which is suppressed in all common forms of hyperthyroidism; so a normal blood TSH level rules out hyperthyroidism with almost complete certainty. TSH can even be suppressed in mild cases of hyperthyroidism in which the thyroid hormone levels themselves remain within a laboratory’s reference range, but the levels are higher than they should be for that particular person.
The second approach is to measure blood levels of the 2 thyroid hormones, T4 and T3, themselves. A high level of 1 or both thyroid hormones corroborates the significance of a low TSH level, gauges how severe the hyperthyroidism is, and recognizes the very rare kinds of hyperthyroidism in which the TSH level is not low, for example, a TSH-producing pituitary tumor.
7. How is the specific cause of hyperthyroidism determined?
A hyperthyroid patient’s symptoms and signs often provide important clues to the underlying cause of hyperthyroidism, as noted above. In Graves disease, there is often a diffusely enlarged thyroid gland, and bulging eyes occur in no other kind of hyperthyroidism. Seeing or feeling a thyroid nodule can help establish that hyperthyroidism is due to a toxic adenoma. A painful and tender thyroid gland in a patient with a high fever is typical of subacute thyroiditis. Painless thyroiditis affects mainly new mothers.
However, special blood tests often help to nail down the specific cause of a person’s hyperthyroidism. For example, in most patients with Graves disease, antibodies against the TSH receptor can be found in blood, a test called thyroid-stimulating immunoglobulins (TSI). In patients with subacute thyroiditis, a routine blood test for inflammation, called the erythrocyte sedimentation rate can support the diagnosis.
Critical information is sometimes provided by taking special pictures of the thyroid gland after giving radioactive iodine or pertechnetate to determine how much of these radioisotopes are concentrated in the thyroid. In Graves disease, the amount of these radioisotopes captured by the thyroid gland is more than normal, whereas in subacute thyroiditis and painless thyroiditis radioisotope uptake is markedly reduced. How the radioisotope is distributed in the gland also provides important information, with even spread throughout the gland in Graves disease and focal concentration in thyroid nodules in toxic nodular goiter.
8. How is Hyperthyroidism Treated? (Table 1)
There are several effective treatments for hyperthyroidism. Determining which of them is best for a given patient depends on the underlying cause of thyroid gland overactivity, its severity and anticipated course, and the age and general health of the person afflicted.
Beta-adrenergic blocking agents (beta blockers, e.g., propranolol and metoprolol) can promptly control some symptoms of hyperthyroidism, such as trembling hands and palpitations. However, other complaints, such as fatigue, weight loss, and heat intolerance, are not improved. When hyperthyroidism is self-limited, as in subacute or painless thyroiditis, beta blockers may be the sole treatment required. For other forms of hyperthyroidism that are sustained, beta blockers are simply an initial measure to control symptoms while more definitive treatment is carried out. People with asthma, heart failure, and Raynaud phenomenon (blanching of the hands with cold exposure) may have exacerbation of these conditions when taking a beta blocker.
The antithyroid drugs, methimazole (Tapazole®) and propylthiouracil (PTU), block the production of thyroid hormones by the gland. They are appropriate for hyperthyroid conditions in which the gland is actually making too much hormone, like Graves disease and toxic nodular goiter. While these drugs are effective, they can take a number of weeks to control hyperthyroidism because the thyroid hormone supply already made and stored in the gland must be exhausted. Another limitation of their use is that hyperthyroidism returns when antithyroid drug treatment is stopped in the majority of treated patients. In about 5% of people who take them, the antithyroid drugs cause side effects, including rash, itching, joint pain, and fever. Rarely, these drugs can cause a potentially life-threatening loss of white blood cells or hepatitis.
Radioactive iodine (radioiodine, 131-I) brings hyperthyroidism under control by delivering cell-damaging radiation after being concentrated in the thyroid gland. Radioiodine offers a permanent cure for sustained forms of hyperthyroidism, such as toxic nodular goiter and Graves disease. Three-quarters of people are cured by a single dose, which is given as a capsule or liquid taken as an outpatient. Radioiodine typically takes 1 to 2 months to work, so other medications, such as beta blockers and antithyroid drugs, must sometimes be given in the meantime. For a week after treatment, patients should observe certain straightforward precautions to be sure that they do not expose others around them to radioiodine. The only real side effect of radioiodine is development of an underactive thyroid gland, hypothyroidism, which occurs in the majority of the patients who receive it for treatment of hyperthyroidism. However, this can be readily treated with thyroxine medication. Rarely, after radioiodine treatment, there can be mild, short-lived discomfort in the gland. Radioiodine must never be given to pregnant women, as it could damage the developing child’s thyroid, but there is no evidence that previous radioiodine treatment increases a woman’s later risks of infertility, miscarriage, or having a child with birth defects. In a small number of patients, radioiodine treatment seems to worsen Graves eye disease, but this can be prevented or reversed by a course of steroid medication. There is no solid evidence that radioiodine predisposes to later development of thyroid or other cancers.
Several other drugs are less commonly used to treat patients with hyperthyroidism under special circumstances. Nonradioactive iodide is sometimes used along with antithyroid drugs for hyperthyroid patients whose condition is severe or to prepare them for surgery. Lithium, which blocks the release of thyroid hormones from the gland, and perchlorate, which inhibits the gland from taking up iodine, are rarely used. Glucocorticoid medications (steroids), such as prednisone, can help control severe Graves disease more promptly. Cholestyramine, which is usually used to lower cholesterol levels, can accelerate the removal of excess thyroid hormone from the body. For patients with subacute thyroiditis, aspirin or glucocorticoids are used to control gland inflammation.
Surgical thyroidectomy was the first treatment for hyperthyroidism. It remains an effective and relatively quick option, although patients must usually have their hyperthyroidism controlled with medication for a few weeks before the operation is performed. A thyroid operation requires hospitalization and being put to sleep under anesthesia, with its potential complications. Surgery almost always results in hypothyroidism and leaves a small smile-shaped scar in the lower neck. Surgery can also injure structures next to the thyroid. The recurrent laryngeal nerves, which control the voice box, run behind the thyroid; if injured, there can be permanent hoarseness or trouble breathing. The 4 parathyroid glands, which control the blood calcium level, are also right next to the thyroid; and if damaged, may necessitate long-term calcium and vitamin D medication. As a result of all these certain or potential complications, it is uncommon for thyroidectomy to be recommended for treatment of hyperthyroidism anymore; exceptions are hyperthyroid pregnant women with an allergy to antithyroid medication and people who have another problem justifying neck surgery, such as a large nodular goiter, a nodule suspicious for cancer, or overactive parathyroid glands.
5.4. Rare causes of hyperthyroidism
When a person takes too much thyroid hormone medication, thyrotoxicosis occurs. Among patients being prescribed thyroid hormone for an underactive thyroid gland, as many as 1 in 5 has blood test evidence of overtreatment. Rarely, a child accidentally, or a troubled person deliberately takes an overdose of thyroid hormone. Once there was an outbreak of thyrotoxicosis when people ate ground beef that mistakenly contained the thyroid glands of cattle, so called “hamburger hyperthyroidism.”
Over-stimulation of the thyroid gland is the cause of several rare kinds of hyperthyroidism. Certain tumors of the pituitary gland make too much thyroid stimulating hormone (TSH). Excessive production of a hormone called chorionic gonadotropin, which is normally made by the placenta in pregnant women, can cause hyperthyroidism because it is similar to TSH. Chorionic gonadotropin can be overproduced by tumors of the placenta or in some otherwise normal pregnancies, especially when a woman has severe morning sickness.
Among the rarest types of hyperthyroidism are inherited mutations in the genetic blueprint, or gene, for hormone receptors controlling the thyroid system. If the mutant TSH receptor is stuck in the turned-on position, hyperthyroidism begins even before a baby is born. Another rare kind of TSH receptor mutation leads to stimulation of the receptor by even normal amounts of chorionic gonadotropin; this predictably causes hyperthyroidism every time a woman becomes pregnant. When there is an inherited mutation in the thyroid hormone receptor itself, in the pituitary gland, the result can be pituitary resistance to the normal negative feedback of thyroid hormone and excessive TSH production with resulting hyperthyroidism.
Rarely, thyroid hormone may be overproduced outside of the thyroid gland itself, as when thyroid cancer has spread throughout the body and when thyroid tissue oddly develops in a woman’s ovary, a so called struma ovarii.
6. How is the Diagnosis of Hyperthyroidism Made?
In every case, blood tests are essential to confirm or rule out the diagnosis of hyperthyroidism because its symptoms and signs are nonspecific (i.e., they can be caused by many things) and sometimes insensitive (i.e., not present even though hyperthyroidism is). These tests are reliable; their results are typically back in a day or two, if not hours; and the tests are available through almost any doctor’s office, clinic, or hospital.
There are two general blood test strategies. The first approach is measuring TSH, which is suppressed in all common forms of hyperthyroidism; so a normal blood TSH level rules out hyperthyroidism with almost complete certainty. TSH can even be suppressed in mild cases of hyperthyroidism in which the thyroid hormone levels themselves remain within a laboratory’s reference range, but the levels are higher than they should be for that particular person.
The second approach is to measure blood levels of the 2 thyroid hormones, T4 and T3, themselves. A high level of 1 or both thyroid hormones corroborates the significance of a low TSH level, gauges how severe the hyperthyroidism is, and recognizes the very rare kinds of hyperthyroidism in which the TSH level is not low, for example, a TSH-producing pituitary tumor.
7. How is the specific cause of hyperthyroidism determined?
A hyperthyroid patient’s symptoms and signs often provide important clues to the underlying cause of hyperthyroidism, as noted above. In Graves disease, there is often a diffusely enlarged thyroid gland, and bulging eyes occur in no other kind of hyperthyroidism. Seeing or feeling a thyroid nodule can help establish that hyperthyroidism is due to a toxic adenoma. A painful and tender thyroid gland in a patient with a high fever is typical of subacute thyroiditis. Painless thyroiditis affects mainly new mothers.
However, special blood tests often help to nail down the specific cause of a person’s hyperthyroidism. For example, in most patients with Graves disease, antibodies against the TSH receptor can be found in blood, a test called thyroid-stimulating immunoglobulins (TSI). In patients with subacute thyroiditis, a routine blood test for inflammation, called the erythrocyte sedimentation rate can support the diagnosis.
Critical information is sometimes provided by taking special pictures of the thyroid gland after giving radioactive iodine or pertechnetate to determine how much of these radioisotopes are concentrated in the thyroid. In Graves disease, the amount of these radioisotopes captured by the thyroid gland is more than normal, whereas in subacute thyroiditis and painless thyroiditis radioisotope uptake is markedly reduced. How the radioisotope is distributed in the gland also provides important information, with even spread throughout the gland in Graves disease and focal concentration in thyroid nodules in toxic nodular goiter.
8. How is Hyperthyroidism Treated? (Table 1)
There are several effective treatments for hyperthyroidism. Determining which of them is best for a given patient depends on the underlying cause of thyroid gland overactivity, its severity and anticipated course, and the age and general health of the person afflicted.
Beta-adrenergic blocking agents (beta blockers, e.g., propranolol and metoprolol) can promptly control some symptoms of hyperthyroidism, such as trembling hands and palpitations. However, other complaints, such as fatigue, weight loss, and heat intolerance, are not improved. When hyperthyroidism is self-limited, as in subacute or painless thyroiditis, beta blockers may be the sole treatment required. For other forms of hyperthyroidism that are sustained, beta blockers are simply an initial measure to control symptoms while more definitive treatment is carried out. People with asthma, heart failure, and Raynaud phenomenon (blanching of the hands with cold exposure) may have exacerbation of these conditions when taking a beta blocker.
The antithyroid drugs, methimazole (Tapazole®) and propylthiouracil (PTU), block the production of thyroid hormones by the gland. They are appropriate for hyperthyroid conditions in which the gland is actually making too much hormone, like Graves disease and toxic nodular goiter. While these drugs are effective, they can take a number of weeks to control hyperthyroidism because the thyroid hormone supply already made and stored in the gland must be exhausted. Another limitation of their use is that hyperthyroidism returns when antithyroid drug treatment is stopped in the majority of treated patients. In about 5% of people who take them, the antithyroid drugs cause side effects, including rash, itching, joint pain, and fever. Rarely, these drugs can cause a potentially life-threatening loss of white blood cells or hepatitis.
Radioactive iodine (radioiodine, 131-I) brings hyperthyroidism under control by delivering cell-damaging radiation after being concentrated in the thyroid gland. Radioiodine offers a permanent cure for sustained forms of hyperthyroidism, such as toxic nodular goiter and Graves disease. Three-quarters of people are cured by a single dose, which is given as a capsule or liquid taken as an outpatient. Radioiodine typically takes 1 to 2 months to work, so other medications, such as beta blockers and antithyroid drugs, must sometimes be given in the meantime. For a week after treatment, patients should observe certain straightforward precautions to be sure that they do not expose others around them to radioiodine. The only real side effect of radioiodine is development of an underactive thyroid gland, hypothyroidism, which occurs in the majority of the patients who receive it for treatment of hyperthyroidism. However, this can be readily treated with thyroxine medication. Rarely, after radioiodine treatment, there can be mild, short-lived discomfort in the gland. Radioiodine must never be given to pregnant women, as it could damage the developing child’s thyroid, but there is no evidence that previous radioiodine treatment increases a woman’s later risks of infertility, miscarriage, or having a child with birth defects. In a small number of patients, radioiodine treatment seems to worsen Graves eye disease, but this can be prevented or reversed by a course of steroid medication. There is no solid evidence that radioiodine predisposes to later development of thyroid or other cancers.
Several other drugs are less commonly used to treat patients with hyperthyroidism under special circumstances. Nonradioactive iodide is sometimes used along with antithyroid drugs for hyperthyroid patients whose condition is severe or to prepare them for surgery. Lithium, which blocks the release of thyroid hormones from the gland, and perchlorate, which inhibits the gland from taking up iodine, are rarely used. Glucocorticoid medications (steroids), such as prednisone, can help control severe Graves disease more promptly. Cholestyramine, which is usually used to lower cholesterol levels, can accelerate the removal of excess thyroid hormone from the body. For patients with subacute thyroiditis, aspirin or glucocorticoids are used to control gland inflammation.
Surgical thyroidectomy was the first treatment for hyperthyroidism. It remains an effective and relatively quick option, although patients must usually have their hyperthyroidism controlled with medication for a few weeks before the operation is performed. A thyroid operation requires hospitalization and being put to sleep under anesthesia, with its potential complications. Surgery almost always results in hypothyroidism and leaves a small smile-shaped scar in the lower neck. Surgery can also injure structures next to the thyroid. The recurrent laryngeal nerves, which control the voice box, run behind the thyroid; if injured, there can be permanent hoarseness or trouble breathing. The 4 parathyroid glands, which control the blood calcium level, are also right next to the thyroid; and if damaged, may necessitate long-term calcium and vitamin D medication. As a result of all these certain or potential complications, it is uncommon for thyroidectomy to be recommended for treatment of hyperthyroidism anymore; exceptions are hyperthyroid pregnant women with an allergy to antithyroid medication and people who have another problem justifying neck surgery, such as a large nodular goiter, a nodule suspicious for cancer, or overactive parathyroid glands.
Table 1. Main Treatment Options for Common Forms of Hyperthyroidism
Treatment
|
Main Mechanism of Action
|
Advantages and Uses
|
Disadvantages
|
Beta Blockers
|
Controls
some symptoms of hyperthyroidism by interfering with the actions of
excess thyroid hormone on the nervous system and heart
|
Fast acting symptom control
Does not permanently damage the thyroid gland
Best choice for transient forms of hyperthyroidism, e.g., thyroiditis
|
Does not control all symptoms
Does not treat underlying cause of hyperthyroidism
Can worsen asthma or heart failure
|
Antithyroid Drugs
|
Blocks further overproduction of thyroid hormones by the gland
|
Effective in controlling gland overactivity while taken
Low risk of permanent hypothyroidism
Usually best initial option for pregnant women, children, and people with severe hyperthyroidism
|
Takes 1-2 months to work
Must take medication faithfully
Not a permanent cure for toxic nodular goiter or most Graves patients
Potential side effects: rash, itching, joint pains, fever, low white blood cells, hepatitis
|
Radioiodine
|
Controls hyperthyroidism by damaging thyroid tissue with radiation
|
Effective cure for toxic nodular goiter and Graves disease
Simple outpatient medication by mouth, with one dose for most patients
|
Later development of an underactive thyroid gland, requiring lifelong thyroxine treatment
Not safe during pregnancy
|
Surgery
|
Controls hyperthyroidism by removing the overactive thyroid tissue
|
Effective in curing most patients
Quickest permanent cure
Relatively safe in pregnancy
|
Must be hospitalized and have general anesthesia
Temporary postoperative pain and permanent small neck scar
Rare injury to the nearby voice box nerves and/or parathyroid glands
|
MORE INFORMATION ABOUT HYPERTHYROIDISM
Web Resources
American Thyroid Association: http://www.thyroid.org/patients/brochures/Hyper_brochure.pdf
UptoDate Patient Information: http://patients.uptodate.com/topic.asp?file=endocrin/7775
Hormone Foundation: Spanish Language Patient Fact Sheet on Graves' Disease: http://www.hormone.org/Spanish/index.cfm
Books
Wood LC, Cooper DS, Ridgway EC. Your Thyroid: A Home Reference., Ballantine Books, New York, 1995
Surks MI. The Thyroid Book. Consumer Reports Books, Yonkers, New York, 1993
Garber J, White SS. Harvard Medical School Guide to Overcoming Thyroid Problems. McGraw-Hill, 2005
Wood LC, Cooper DS, Ridgway EC. Your Thyroid: A Home Reference., Ballantine Books, New York, 1995
Surks MI. The Thyroid Book. Consumer Reports Books, Yonkers, New York, 1993
Garber J, White SS. Harvard Medical School Guide to Overcoming Thyroid Problems. McGraw-Hill, 2005
Patient Support Organizations
Thyroid Foundation of America, Inc.
One Longfellow Place Suite 1518
Boston, MA 02114
phone (toll-free) 800 832-8321
phone 617 534-1500
fax 617 534-1515
e-mail info@allthyroid.org
web www.allthyroid.org
One Longfellow Place Suite 1518
Boston, MA 02114
phone (toll-free) 800 832-8321
phone 617 534-1500
fax 617 534-1515
e-mail info@allthyroid.org
web www.allthyroid.org
National Graves' Disease Foundation
P. O. Box 1969
Brevard, NC 28712
phone 828-877-5251
Toll free 877-NGDF 123
FAx 828-698-8244
email: nancyngdf@bellsouth.net or nancyngdf@yahoo.com
web www.ngdf.org
P. O. Box 1969
Brevard, NC 28712
phone 828-877-5251
Toll free 877-NGDF 123
FAx 828-698-8244
email: nancyngdf@bellsouth.net or nancyngdf@yahoo.com
web www.ngdf.org
Cutting Edge Hyperthyroidism Research
Clinical trials in progress: http://www.clinicaltrials.gov/ct2/results?term=hyperthyroidism
Recently published clinical research:
References
1. Pearce EN. Diagnosis and management of thyrotoxicosis. BMJ. 2006 Jun 10;332(7554):1369-73. PMID: 16763249
2. Cooper DS. Hyperthyroidism. Lancet. 2003 Aug 9;362(9382):459-68.
PMID: 12927435
3. Abalovich M, Amino N, Barbour LA, Cobin RH, De Groot LJ, Glinoer D, Mandel SJ, Stagnaro-Green A. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2007 Aug;92(8 Suppl):S1-47. PMID: 17948378
4. Klein I, Danzi S. Thyroid disease and the heart. Circulation. 2007 Oct 9;116(15):1725-35. PMID: 17923583
5. Garrity JA, Bahn RS. Pathogenesis of graves ophthalmopathy: implications for prediction, prevention, and treatment. Am J Ophthalmol. 2006 Jul;142(1):147-153. PMID: 16815265
6. Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med. 2003 Jun 26;348(26):2646-55. 12826640
7. Singer PA, Cooper DS, Levy EG, Ladenson PW, Braverman LE, Daniels G, Greenspan FS, McDougall IR, Nikolai TF. Treatment guidelines for patients with hyperthyroidism and hypothyroidism. Standards of Care Committee, American Thyroid Association. JAMA. 1995 Mar 8;273(10):808-12. PMID: 7532241
8. American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002 Nov-Dec;8(6):457-69. PMID: 15260011
9. Weetman AP. Radioiodine treatment for benign thyroid diseases. Clin Endocrinol (Oxf). 2007 Jun;66(6):757-64. PMID: 17466000
10. Cooper DS. Antithyroid drugs. N Engl J Med. 2005 Mar 3;352(9):905-17. PMID: 15745981
2. Cooper DS. Hyperthyroidism. Lancet. 2003 Aug 9;362(9382):459-68.
PMID: 12927435
3. Abalovich M, Amino N, Barbour LA, Cobin RH, De Groot LJ, Glinoer D, Mandel SJ, Stagnaro-Green A. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2007 Aug;92(8 Suppl):S1-47. PMID: 17948378
4. Klein I, Danzi S. Thyroid disease and the heart. Circulation. 2007 Oct 9;116(15):1725-35. PMID: 17923583
5. Garrity JA, Bahn RS. Pathogenesis of graves ophthalmopathy: implications for prediction, prevention, and treatment. Am J Ophthalmol. 2006 Jul;142(1):147-153. PMID: 16815265
6. Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med. 2003 Jun 26;348(26):2646-55. 12826640
7. Singer PA, Cooper DS, Levy EG, Ladenson PW, Braverman LE, Daniels G, Greenspan FS, McDougall IR, Nikolai TF. Treatment guidelines for patients with hyperthyroidism and hypothyroidism. Standards of Care Committee, American Thyroid Association. JAMA. 1995 Mar 8;273(10):808-12. PMID: 7532241
8. American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002 Nov-Dec;8(6):457-69. PMID: 15260011
9. Weetman AP. Radioiodine treatment for benign thyroid diseases. Clin Endocrinol (Oxf). 2007 Jun;66(6):757-64. PMID: 17466000
10. Cooper DS. Antithyroid drugs. N Engl J Med. 2005 Mar 3;352(9):905-17. PMID: 15745981