Hyperthyroidism

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. 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. Its opposite is hypothyroidism which is an underproduction of the hormone.

Causes
There are several causes of hyperthyroidism. Most often, the entire gland is overproducing thyroid hormone. 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: High blood levels of thyroid hormones (most accurately termed hyperthyroxinemia) can occur for a number of other reasons:
 * 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
 * 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.

Symptoms and signs
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.

Diagnosis
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), traditionally Iodine-131 or 131I, and more recently Iodine-123 or 123I. Iodine-123 may be the preferred radionuclide in some clinics due to its more favourable radiation dosimetry (i.e. less radiation dose to the patient per unit administered radioactivity) and a gamma photon energy more amenable to imaging with the gamma camera. For the imaging scan, I-123 is considered an almost ideal isotope of iodine for imaging thyroid tissue and thyroid cancer metastasis.

Typical administration involves a pill or liquid 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.

Thyroid storm
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%.

Hypothyroidism
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.

Treatment
The large and generally accepted modalities for treatment of hyperthyroidism in humans involve initial temporary use of suppressive thyrostatics medication (antithyroid drugs), and possibly later use of permanent surgical or radioisotope therapy. All approaches may cause under active thyroid function (hypothyroidism) which is easily managed with levothyroxine or Triiodothyronine supplementation.

Thyrostatics (antithyroid drugs)
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.

Beta-blockers
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.

Permanent treatments
Surgery as an option predates the use of the less invasive radioisotope therapy (radioiodine 131 thyroid ablation), but is still required in cases where the thyroid gland is enlarged and causing compression to the neck structures, or the underlying cause of the hyperthyroidism may be cancerous in origin. Some patients suffering from the related condition of thyroid eye disease leading to diplopia because this condition can be worsened by radiotherapy treatment.

Surgery
Surgery (thyroidectomy to remove the whole thyroid or a part of it) is not extensively used because most common forms of hyperthyroidism are quite effectively treated by the radioactive iodine method, and because there is a risk of also removing the parathyroid glands, and of cutting the recurrent laryngeal nerve, making swallowing difficult, and even simply generalized staph infection as with any major surgery. Some Graves' disease patients, however, that cannot tolerate medicines for one reason or another, patients that are allergic to iodine, or patients that refuse radioiodine may opt for surgical intervention. Also, some surgeons believe that radioiodine treatment is unsafe in patients with unusually large gland, or those whose eyes have begun to bulge from their sockets, fearing that the massive dose of radioiodine 131 needed will only exacerbate the patient's symptoms.

Radioiodine
In iodine-131 (radioiodine) radioisotope therapy, which was first pioneered by Dr. Saul Hertz, radioactive iodine-131 is given orally (either by pill or liquid) on a one-time basis, to severely restrict, or altogether destroy the function of a hyperactive thyroid gland. This isotope of radioactive iodine used for ablative treatment is more potent than diagnostic radioiodine (usually iodine-123 or a very low ammount of iodine-131), which has a biological half life from 8–13 hours. Iodine-131, which also emits beta particles that are far more damaging to tissues at short range, has a half-life of approximately 8 days. Patients not responding sufficiently to the first dose are sometimes given an additional radioiodine treatment, at a larger dose. Iodine-131 in this treatment is picked up by the active cells in the thyroid and destroys them, rendering the thyroid gland mostly or completely inactive. Since iodine is picked more readily (though not exclusively) by thyroid cells, and (more important) is picked up even more readily by over-active thyroid cells, the destruction is local, and there are no widespread side-effects with this therapy. Radioiodine ablation has been used for over 50 years, and the only major reasons for not using it are pregnancy and breast-feeding (breast tissue also picks up and concentrates iodine). Once the thyroid function is reduced, replacement hormone therapy taken orally each day may easily provide the required amount of thyroid hormone the body needs. There is, however, a contrasting study noting increased cancer incidence after radioiodine treatment for hyperthyroidism.

The principal advantage of radioiodine treatment for hyperthyroidism is that it tends to have a much higher success rate than medications. Depending on the dose of radioiodine chosen, and the disease under treatment (Grave's vs. toxic goiter, vs. hot nodule etc.), success rate in achieving definitive resolution of the hyperthyroidism may vary from 75-100%. A major expected side-effect of radioiodine in patients with Graves' disease is the development of lifelong hypothyroidism, requiring daily treatment with thyroid hormone. Also, there are some indications that patients suffering from related eye disease experience a worsening of this condition, and for this reason some patients elect to have a surgical solution. On occasion, some patients may require more than one radioactive treatment, depending on the type of disease present, the size of the thyroid, and the initial dose administered. Many patients are initially unhappy at the thought of having to take a thyroid hormone pill for the rest of their lives. Nevertheless, as thyroid hormone is safe, inexpensive, and easy to take, and is identical to the thyroid hormone normally made by the thyroid, this therapy is, in general, extremely safe and very well tolerated by the vast majority of patients.

As radioactive iodine treatment results in destruction of thyroid tissue, there is often a transient period of several days to weeks when the symptoms of hyperthyroidism may actually worsen following radioactive iodine therapy. In general, this happens as a result of thyroid hormone's being released into the blood following the radioactive iodine-mediated destruction of thyroid cells that contain thyroid hormone. In some patients, treatment with medications such as beta blockers (propranolol, atenolol, etc.) may be useful during this period of time. Many patients are able to tolerate the initial few weeks without any problem whatsoever.

Most patients do not experience any difficulty after the radioactive iodine treatment, usually given as a small pill. On occasion, neck tenderness or a sore throat may become apparent after a few days, if moderate inflammation in the thyroid develops and produces discomfort in the neck or throat area. This is usually transient, and not associated with a fever, etc.

Women breastfeeding should discontinue breastfeeding for at least a week, and likely longer, following radioactive iodine treatment, as small amounts of radioactive iodine may be found in breast milk even several weeks after the radioactive iodine treatment.

A common outcome following radioiodine is a swing from hyperthyroidism to the easily treatable hypothyroidism, which occurs in 78% of those treated for Graves' thyrotoxicosis and in 40% of those with toxic multinodular goiter or solitary toxic adenoma. Use of higher doses of radioiodine reduces the incidence of treatment failure, with penalty for higher response to treatment consisting mostly of higher rates of eventual hypothyroidism which requires hormone treatment for life.

There is increased sensitivity to radioiodine therapy in thyroids appearing on ultrasound scans as more uniform (hypoechogenic), due to densely packed large cells, with 81% later becoming hypothyroid, compared to just 37% in those with more normal scan appearances (normoechogenic).

Thyroid storm
Thyroid storm presents with extreme symptoms of hyperthyroidism. It is treated aggressively with resuscitation measure along with a combination of the above modalities including: an intravenous beta blockers such as propranolol, followed by a thionamide such as methimazole, an iodinated radiocontrast agent or an iodine solution if the radiocontrast agent is not available, and an intravenous steroid such as hydrocortisone.

Cats
In veterinary medicine, hyperthyroidism is one of the most common endocrine conditions affecting older domesticated felines (cats). Some veterinarians estimate that it occurs in up to 2% of cats over the age of 10. The disease has become significantly more common since the first reports of feline hyperthyroidism in the 1970s. In cats, one cause of hyperthyroidism tends to be benign tumors, but the reason those cats develop such tumors continues to be researched.

However, recent research published in Environmental Science & Technology, a publication of the American Chemical Society, suggests that many cases of feline hyperthyroidism are associated with exposure to environmental contaminants called polybrominated diphenyl ethers (PBDEs), which are present in flame retardants in many household products, in particular, furniture and some electronic products.

The study from which the report was based was conducted jointly by researchers at the EPA's National Health and Environmental Effects Laboratory and Indiana University. In the study, which involved 23 pet cats with feline hyperthyroidism, PDBE blood levels were three times as high as those in younger, non-hyperthyroid cats. In ideal circumstances, PBDE and related endocrine disruptors that seriously damage health would not be present in the blood of any animals or humans.

Mutations of the thyroid-stimulating hormone receptor that cause a constitutive activation of the thyroid gland cells have been discovered recently. Many other factors may play a role in the pathogenesis of the disease such as goitrogens (isoflavones such as genistein, daidzein, and quercertin) and iodine and selenium content in the diet.

The most common presenting symptoms are: rapid weight loss, tachycardia (rapid heart rate), vomiting, diarrhea, increased consumption of fluids (polydipsia) and food, and increased urine production (polyuria). Other symptoms include hyperactivity, possible aggression, heart murmurs, a gallop rhythm, an unkempt appearance, and large, thick nails. About 70% of afflicted cats also have enlarged thyroid glands (goiter).

The same three treatments used with humans are also options in treating feline hyperthyroidism (surgery, radioiodine treatment, and anti-thyroid drugs). Drugs must be given to cats for the remainder of their lives, but may be the least expensive option, especially for very old cats. Radioiodine treatment and surgery often cure hyperthyroidism. Some veterinarians prefer radioiodine treatment over surgery because it does not carry the risks associated with anesthesia. Radioiodine treatment, however, is not available in all areas for cats. The reason is that this treatment requires nuclear radiological expertise and facilities, since the animal's urine, sweat, saliva, and stool are radioactive for several days after the treatment, requiring special inpatient handling and facilities usually for a total of 3 weeks (first week in total isolation and the next two weeks in close confinement). The guidelines for radiation levels vary from state to state; some states such as Massachusetts allow hospitalization for as little as two days before the animal is sent home with care instructions. Surgery tends to be done only when just one of the thyroid glands is affected (unilateral disease); however, following surgery, the remaining gland may become over-active. As in people, one of the most common complications of the surgery is hypothyroidism.

Dogs
Hyperthyroidism is very rare in canines (dogs) (occurring in less than 1 or 2% of dogs), who instead tend to have the opposite problem: hypothyroidism, which can manifest itself in a unhealthy-appearing coat and fertility problems in females. When hyperthyroidism does appear in dogs, it tends to be due to over-supplementation of the thyroid hormone during treatment for hypothyroidism. Symptoms usually disappear when the dose is adjusted.

On occasion, dogs will have functional carcinoma in the thyroid; more often (about 90% of the time), this is a very aggressive tumor that is invasive and easily metastasizes or spreads to other tissues (esp. the lungs), making prognosis very poor. While surgery is possible, it is often very difficult due to the invasiveness of the mass in surrounding tissue including the arteries, the esophagus, and windpipe. It may only be possible to reduce the size of the mass, thus relieving symptoms and also allowing time for other treatments to work.

If a dog does have a benign functional carcinoma (appears in 10% of the cases), treatment and prognosis are no different from those of the cat. The only real difference is that dogs tend to appear to be asymptomatic, with the exception of having an enlarged thyroid gland appearing as a lump on the neck.