Hyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones (thyroxine or "T4" and/or triiodothyronine or "T3"). Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. It is important to note that hyperthyroidism and thyrotoxicosis are not synonymous. For instance, thyrotoxicosis could instead be caused by ingestion of exogenous thyroid hormone or inflammation of the thyroid gland, causing it to release its stores of thyroid hormones.
There are several causes of hyperthyroidism. Most often, the entire gland is overproducing thyroid hormone. This is called Graves' disease. Less commonly, a single nodule is responsible for the excess hormone secretion, called a "hot" nodule. Thyroiditis (inflammation of the thyroid) can also cause hyperthyroidism. Functional thyroid tissue producing an excess of thyroid hormone occurs in a number of clinical conditions.
The major causes in humans are:
- Graves' disease an autoimmune disease (usually, the most common etiology with 50-80% worldwide, although this varies substantially with location - i.e., 47% in Switzerland (Horst et al., 1987) to 90% in the USA (Hamburger et al. 1981). Thought to be due to varying Iodine in the diet.
- Toxic thyroid adenoma (the most common etiology in Switzerland, 53%, thought to be atypical due to a low level of dietary iodine in this country)
- Toxic multinodular goitre
High blood levels of thyroid hormones (most accurately termed hyperthyroxinemia) can occur for a number of other reasons:
- Inflammation of the thyroid is called thyroiditis. There are several different kinds of thyroiditis including Hashimoto's thyroiditis (immune-mediated), and subacute thyroiditis (DeQuervain's). These may be initially associated with secretion of excess thyroid hormone, but usually progress to gland dysfunction and, thus, to hormone deficiency and hypothyroidism.
- Oral consumption of excess thyroid hormone tablets is possible (surreptitious use of thyroid hormone), as is the rare event of consumption of ground beef contaminated with thyroid tissue, and thus thyroid hormone (termed "hamburger hyperthyroidism").
- Amiodarone, an anti-arhythmic drug is structurally similar to thyroxine and may cause either under- or overactivity of the thyroid.
- Postpartum thyroiditis (PPT) occurs in about 7% of women during the year after they give birth. PPT typically has several phases, the first of which is hyperthyroidism. This form of hyperthyroidism usually corrects itself within weeks or months without the need for treatment.
Hypersecretion of thyroid stimulating hormone (TSH), which in turn is almost always caused by a pituitary adenoma, accounts for much less than 1 percent of hyperthyroidism cases.
Hyperthyroidism may be asymptomatic, but when it is not, symptoms are due to an excess of thyroid hormone. Thyroid hormone is important at a cellular level, affecting nearly every type of tissue in the body. Thyroid hormone functions as a controller of the pace of all of the processes in the body. This pace is called the metabolic rate (see metabolism). If there is too much thyroid hormone, every function of the body tends to speed up. Therefore, some of the symptoms of hyperthyroidism are nervousness, irritability, increased perspiration, heart racing, hand tremors, anxiety, difficulty sleeping, thinning of the skin, fine brittle hair, and muscular weakness—especially in the upper arms and thighs. More frequent bowel movements may occur, but diarrhea is uncommon. Weight loss, sometimes significant, despite a good appetite may occur, vomiting, and, for women, menstrual flow may lighten and menstrual periods may occur less often. Thyroid hormone is critical to normal function of cells. In excess, it both overstimulates metabolism and exacerbates the effect of the sympathetic nervous system, causing "speeding up" of various body systems and symptoms resembling an overdose of epinephrine (adrenaline). These include fast heart beat and symptoms of palpitations, nervous system tremor such as of the hands and anxiety symptoms, digestive system hypermotility, unintended weight loss, and (in "lipid panel" blood tests) a lower and sometimes unusually low serum cholesterol.
Hyperthyroidism usually begins slowly. At first, the symptoms may be mistaken for simple nervousness due to stress. If one has been trying to lose weight by dieting, one may be pleased with weight loss success until the hyperthyroidism, which has quickened the weight loss, causes other problems.
Major clinical signs include weight loss (often accompanied by an increased appetite), anxiety, intolerance to heat, hair loss, muscle aches, weakness, fatigue, hyperactivity, irritability, hypoglycemia, apathy, polyuria, polydipsia, delirium, tremor, pretibial myxedema, and sweating. In addition, patients may present with a variety of symptoms such as palpitations and arrhythmias (the notable ones being atrial fibrillation), shortness of breath (dyspnea), loss of libido, amenorrhea, nausea, vomiting, diarrhea, gynaecomastia and feminization. Long term untreated hyperthyroidism can lead to osteoporosis. These classical symptoms may not be present often in the elderly.
Neurological manifestations can include tremors, chorea, myopathy, and in some susceptible individuals (in particular of Asian descent) periodic paralysis. An association between thyroid disease and myasthenia gravis has been recognized. The thyroid disease, in this condition, is autoimmune in nature and approximately 5% of patients with myasthenia gravis also have hyperthyroidism. Myasthenia gravis rarely improves after thyroid treatment and the relationship between the two entities is not well understood.
In Graves disease, which is the most common form or cause of hyperthyroidism, the eyes may look enlarged because the eye muscles swell and push the eye forward. This can only be resolved surgically by orbital decompression. Sometimes, one or both eyes may bulge. Some patients have swelling of the front of the neck from an enlarged thyroid gland (a goiter). Because hyperthyroidism, especially Graves’ disease, may run in families, examinations of the members of a family may reveal other individuals with thyroid problems.
Minor ocular (eye) signs, which may be present in any type of hyperthyroidism, are eyelid retraction ("stare"), extra-ocular muscle weakness, and lid-lag. In hyperthyroid stare (Dalrymple sign) the eyelids are retracted upward more than normal (the normal position is at the superior corneoscleral limbus, where the "white" of the eye begins at the upper border of the iris). Extra-ocular muscle weakness may present with double vision. In lid-lag (von Graefe's sign), when the patient tracks an object downward with their eyes, the eyelid fails to follow the downward moving iris, and the same type of upper globe exposure which is seen with lid retraction occurs, temporarily. These signs disappear with treatment of the hyperthyroidism.
Neither of these ocular signs should be confused with exophthalmos (protrusion of the eyeball), which occurs specifically and uniquely in hyperthyroidism caused by Graves' disease (note that not all exopthalmos is caused by Graves' disease, but when present with hyperthyroidism is diagnostic of Graves' disease). This forward protrusion of the eyes is due to immune-mediated inflammation in the retro-orbital (eye socket) fat. Exophthalmos, when present, may exacerbate hyperthyroid lid-lag and stare.
Measuring the level of thyroid-stimulating hormone (TSH), produced by the pituitary gland (which in turn is also regulated by the hypothalamus's TSH Releasing Hormone) in the blood is typically the initial test for suspected hyperthyroidism. A low TSH level typically indicates that the pituitary gland is being inhibited or "instructed" by the brain to cut back on stimulating the thyroid gland, having sensed increased levels of T4 and/or T3 in the blood. In rare circumstances, a low TSH indicates primary failure of the pituitary, or temporary inhibition of the pituitary due to another illness (euthyroid sick syndrome) and so checking the T4 and T3 is still clinically useful.
Measuring specific antibodies, such as anti-TSH-receptor antibodies in Graves' disease, or anti-thyroid-peroxidase in Hashimoto's thyroiditis — a common cause of hypothyroidism — may also contribute to the diagnosis.
The diagnosis of hyperthyroidism is confirmed by blood tests that show a decreased thyroid-stimulating hormone (TSH) level and elevated T4 and T3 levels. TSH is a hormone made by the pituitary gland in the brain that tells the thyroid gland how much hormone to make. When there is too much thyroid hormone, the TSH will be low. A radioactive iodine uptake test and thyroid scan together characterizes or enables radiologists and doctors to determine the cause of hyperthyroidism. The uptake test uses radioactive iodine injected or taken orally on an empty stomach to measure the amount of iodine absorbed by the thyroid gland. Persons with hyperthyroidism absorb too much iodine. A thyroid scan producing images is typically conducted in connection with the uptake test to allow visual examination of the over-functioning gland.
Thyroid scintigraphy is a useful test to characterize (distinguish between causes of) hyperthyroidism, and this entity from thyroiditis. This test procedure typically involves two tests performed in connection with each other: an iodine uptake test and a scan (imaging) with a gamma camera. The uptake test involves administering a dose of radioactive iodine (radioiodine), typically Iodine-131 or 131I, which is the most suitable isotope of iodine for the diagnostic study of thyroid diseases. I-131 is an almost ideal isotope of iodine for imaging thyroid tissue and thyroid cancer metastasis.
Typical administration involves a pill containing sodium iodide (NaI) taken orally, which contains a small amount of iodine-131, amounting to perhaps less than a grain of salt. A 2-hour fast of no food prior to and for 1 hour after ingesting the pill is required. This low dose of radioiodine is typically tolerated by individuals otherwise allergic to iodine (such as those unable to tolerate contrast mediums containing larger doses of iodine such as used in CT scan, intravenous pyelogram (IVP), and similar imaging diagnostic procedures). Excess radioiodine that does not get absorbed into the thyroid gland is eliminated by the body in urine. Some patients may experience a slight allergic reaction to the diagnostic radioiodine, and may be given an antihistamine. The patient returns 24 hours later to have the level of radioiodine "uptake" (absorbed by the thyroid gland) measured by a device with a metal bar placed against the neck, which measures the radioactivity emitting from the thyroid. This test takes about 4 minutes while the uptake % is accumulated (calculated) by the machine software. A scan is also performed, wherein images (typically a center, left and right angle) are taken of the contrasted thyroid gland with a gamma camera; a radiologist will read and prepare a report indicating the uptake % and comments after examining the images. Hyperthyroid patients will typically "take up" higher than normal levels of radioiodine. Normal ranges for RAI uptake are from 10-30%.
In addition to testing the TSH levels, many doctors test for T3, Free T3, T4, and/or Free T4 for more detailed results. Typical adult limits for these hormones are: TSH (units): 0.45 - 4.50 uIU/mL; T4 Free/Direct (nanograms): 0.82 - 1.77 ng/dl; and T3 (nanograms): 71 - 180 ng/dl. Persons with hyperthyroidism can easily exhibit levels many times these upper limits for T4 and/or T3. See a complete table of normal range limits for thyroid function at the thyroid gland article.
Thyrotoxic crisis (or thyroid storm) is a rare but severe complication of hyperthyroidism, which may occur when a thyrotoxic patient becomes very sick or physically stressed. Its symptoms can include: an increase in body temperature to over 40 degrees Celsius (104 degrees Fahrenheit), tachycardia, arrhythmia, vomiting, diarrhea, dehydration, coma, and death. Thyroid storm requires emergency treatment and hospitalization. The main treatment is to decrease the circulating thyroid hormone levels and decrease their formation. Propylthiouracil and methimazole are two agents that decrease thyroid hormone synthesis and are usually prescribed in fairly high doses. To inhibit thyroid hormone release from the thyroid gland, sodium iodide, potassium iodide, and/or Lugol's solution can be given. Beta blockers such as propranolol (Inderal, Inderal LA, Innopran XL) can help to control the heart rate, and intravenous steroids may be used to help support the circulation. Earlier in this century, the mortality of thyroid storm approached 100%. However, now, with the use of aggressive therapy as described above, the death rate from thyroid storm is less than 20%.
Hyperthyroidism due to certain types of thryroiditis can eventually lead to hypothyroidism (a lack of thyroid hormone). , as the thyroid gland is damaged. Also, radioiodine treatment of Grave's disease often eventually leads to hypothyroidism. Such hypothyroidism may be avoided by regular thyroid hormone testing and oral thyroid hormone supplementation.
Thyrostatics are drugs that inhibit the production of thyroid hormones, such as carbimazole (used in UK) and methimazole (used in US), and propylthiouracil. Thyrostatics are believed to work by inhibiting the iodination of thyroglobulin by thyroperoxidase, and, thus, the formation of tetra-iodothyronine (T4). Propylthiouracil also works outside the thyroid gland, preventing conversion of (mostly inactive) T4 to the active form T3. Because thyroid tissue usually contains a substantial reserve of thyroid hormone, thyrostatics can take weeks to become effective, and the dose often needs to be carefully titrated over a period of months, with regular doctor visits and blood tests to monitor results.
A very high dose is often needed early in treatment, but, if too high a dose is used persistently, patients can develop symptoms of hypothyroidism. This titrating of the dose is difficult to do accurately, and so sometimes a "block and replace" attitude is taken. In block and replace treatments thyrostatics are taken in sufficient quantities to completely block thyroid hormones, the patient treated as though they have complete hypothyroidism.
Many of the common symptoms of hyperthyroidism such as palpitations, trembling, and anxiety are mediated by increases in beta adrenergic receptors on cell surfaces. Beta blockers, typically used to treat high blood pressure, are a class of drugs that offset this effect, reducing rapid pulse associated with the sensation of palpitations, and decreasing tremor and anxiety. Thus, a patient suffering from hyperthyroidism can often obtain immediate temporary relief until the hyperthyroidism can be characterized with the Radioiodine test noted above and more permanent treatment take place. Note that these drugs do not treat hyperthyroidism or any of its long-term effects if left untreated, but, rather, they treat or reduce only symptoms of the condition. Some minimal effect on thyroid hormone production however also comes with Propranolol - which has two roles in the treatment of hyperthyroidism, determined by the different isomers of propranolol. L-propranolol causes beta-blockade, thus treating the symptoms associated with hyperthyroidism such as tremor, palpitations, anxiety, and heat intolerance. D-propranolol inhibits Thyroxine deiodinase, thereby blocking the conversion of T4 to T3, providing some though minimal therapeutic effect. Other beta blockers are used to treat only the symptoms associated with hyperthyroidism. Propranolol in the US, and Metoprolol in the UK, are most frequently used to augment treatment for hyperthyroid patients.