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Hyperthyroidism is a endocrine disease in which the thyroid gland produces excessive amounts of thyroid hormones. Some, however, use the terms interchangeably. Signs and symptoms vary between people and may include irritability, muscle weakness, sleeping problems, a fast heartbeat, heat intolerance, diarrhea, enlargement of the thyroid, hand tremor, and weight loss.

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Graves' disease is the cause of about 50% to 80% of the cases of hyperthyroidism in the United States. Other causes include multinodular goiter, toxic adenoma, inflammation of the thyroid, eating too much iodine, and too much synthetic thyroid hormone. A less common cause is a pituitary adenoma. It occurs between two and ten times more often in women.

left|thumb|[[Exophthalmos seen in Graves' ophthalmopathy]]

The thyroid hormone is critical to the normal function of cells. In excess, it both overstimulates metabolism and disrupts the normal functioning of the sympathetic nervous system, causing speeding up of various body systems and symptoms resembling an overdose of epinephrine (adrenaline). These include fast heartbeat 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.

Major clinical signs of hyperthyroidism include weight loss (often accompanied by an increased appetite), anxiety, heat intolerance, hair loss, muscle aches, weakness, fatigue, hyperactivity, irritability, high blood sugar, In addition, those with hyperthyroidism may present with a variety of physical symptoms such as palpitations and abnormal heart rhythms (the notable ones being atrial fibrillation), shortness of breath (dyspnea), loss of libido, amenorrhea, nausea, vomiting, diarrhea, gynecomastia and feminization. Long term untreated hyperthyroidism can lead to osteoporosis. These classic symptoms may not be present often in the elderly.

Bone loss, which is associated with overt but not subclinical hyperthyroidism, may occur in 10 to 20% of patients. This may be due to an increase in bone remodelling and a decrease in bone density, which increases fracture risk. It is more common in postmenopausal women; less so in younger women and men. Bone disease related to hyperthyroidism was first described by Frederick von Recklinghausen in 1891; he described the bones of a woman who died of hyperthyroidism as appearing "worm-eaten".

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. Thyroid disease, in this condition, is autoimmune in nature, and approximately 5% of people with myasthenia gravis also have hyperthyroidism. Myasthenia gravis rarely improves after thyroid treatment and the relationship between the two entities is becoming better understood over the past 15 years.thumb|Illustration depicting enlarged thyroid that may be associated with hyperthyroidism|255x255pxIn Graves' disease, ophthalmopathy may cause the eyes to look enlarged because the eye muscles swell and push the eye forward. Sometimes, one or both eyes may bulge. Some have swelling of the front of the neck from an enlarged thyroid gland (a goiter).

Minor ocular (eye) signs, which may be present in any type of hyperthyroidism, are eyelid retraction ("stare"), extraocular 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). Extraocular muscle weakness may present with double vision. In lid-lag (von Graefe's sign), when the person 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 exophthalmos 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.

Thyroid storm

Thyroid storm is a severe form of thyrotoxicosis characterized by rapid and often irregular heartbeat, high temperature, vomiting, diarrhea, and mental agitation. Symptoms may not be typical in the young, old, or pregnant.

Causes

thumb|Most common causes of hyperthyroidism by age.

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:

  • Graves' disease. An autoimmune disease (usually, the most common cause 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 levels of iodine in the diet. It is eight times more common in females than males and often occurs in young females, around 20 to 40 years of age.
  • Toxic thyroid adenoma (the most common cause in Switzerland, 53%, thought to be atypical due to a low level of dietary iodine in this country) Pharmacy compounding errors may also be a cause.
  • Amiodarone, an antiarrhythmic 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.
  • A struma ovarii is a rare form of monodermal teratoma that contains mostly thyroid tissue, which leads to hyperthyroidism.
  • Excess iodine consumption, notably from algae such as kelp.

Thyrotoxicosis can also occur after taking too much thyroid hormone in the form of supplements, such as levothyroxine (a phenomenon known as exogenous thyrotoxicosis, alimentary thyrotoxicosis, or occult factitial thyrotoxicosis).

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.

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 T<sub>4</sub> and/or T<sub>3</sub> 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 T<sub>4</sub> and T<sub>3</sub> is still clinically useful. Thyroid scintigraphy should not be performed in those who are pregnant, a thyroid ultrasound with color flow doppler may be obtained as an alternative in these circumstances.

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Subclinical

In overt primary hyperthyroidism, TSH levels are low, and T<sub>4</sub> and T<sub>3</sub> levels are high. Subclinical hyperthyroidism is a milder form of hyperthyroidism characterized by low or undetectable serum TSH level, but with a normal serum free thyroxine level. Although the evidence for doing so is not definitive, treatment of elderly persons having subclinical hyperthyroidism could reduce the number of cases of atrial fibrillation. There is also an increased risk of bone fractures (by 42%) in people with subclinical hyperthyroidism; there is insufficient evidence to say whether treatment with antithyroid medications would reduce that risk.

A 2022 meta-analysis found subclinical hyperthyroidism to be associated with cardiovascular death.

Screening

In those without symptoms who are not pregnant, there is little evidence for or against screening.

Treatment

Antithyroid drugs

Thyrostatics (antithyroid drugs) are drugs that inhibit the production of thyroid hormones, such as carbimazole (used in the UK) and methimazole (used in the US, Germany, and Russia), and propylthiouracil. Thyrostatics are believed to work by inhibiting the iodination of thyroglobulin by thyroperoxidase and, thus, the formation of tetraiodothyronine (T<sub>4</sub>). Propylthiouracil also works outside the thyroid gland, preventing the conversion of (mostly inactive) T<sub>4</sub> to the active form T<sub>3</sub>. 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.

Some minimal effect on thyroid hormone production 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 T<sub>4</sub> to T<sub>3</sub>, providing some, though minimal, therapeutic effect. Other beta-blockers are used to treat only the symptoms associated with hyperthyroidism. Propranolol in the UK, and metoprolol in the US, are most frequently used to augment treatment for people with hyperthyroidism.

Diet

People with autoimmune hyperthyroidism (such as in Graves' disease) should not eat foods high in iodine, such as edible seaweed and seafood.

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 staphylococcal infection as with any major surgery. Some people with Graves' may opt for surgical intervention. This includes those who cannot tolerate medicines for one reason or another, people who are allergic to iodine, or people who refuse radioiodine.

A 2019 systematic review concluded that the available evidence shows no difference between visually identifying the nerve or utilizing intraoperative neuroimaging during surgery, when trying to prevent injury to the recurrent laryngeal nerve during thyroid surgery.

If people have toxic nodules, treatments typically include either the removal or injection of the nodule with alcohol.

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 amount of iodine-131), which has a biological half-life of 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. People 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 up more readily (though not exclusively) by thyroid cells, and (more importantly) is picked up even more readily by overactive 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 breastfeeding (breast tissue also picks up and concentrates iodine). Once the thyroid function is reduced, replacement hormone therapy (levothyroxine) taken each day orally replaces the thyroid hormone that is normally produced by the body.

There is extensive experience, over many years, of the use of radioiodine in the treatment of thyroid overactivity, and this experience does not indicate any increased risk of thyroid cancer following treatment. However, a study from 2007 has reported an increased number of cancer cases after radioiodine treatment for hyperthyroidism.

People with Graves' disease manifesting moderate or severe Graves' ophthalmopathy are cautioned against radioactive iodine-131 treatment, since it has been shown to exacerbate existing thyroid eye disease. People with mild or no ophthalmic symptoms can mitigate their risk with a concurrent six-week course of prednisone. The mechanisms proposed for this side effect involve a TSH receptor common to both thyrocytes and retro-orbital tissue.

As radioactive iodine treatment results in the destruction of thyroid tissue, there is often a transient period of several days to weeks when the symptoms of hyperthyroidism may worsen following radioactive iodine therapy. In general, this happens as a result of thyroid hormones being released into the blood following the radioactive iodine-mediated destruction of thyroid cells that contain thyroid hormone. In some people, treatment with medications such as beta blockers (propranolol, atenolol, etc.) may be useful during this period. Most people 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.

It is recommended that breastfeeding be stopped at least six weeks before radioactive iodine treatment and that it not be resumed, although it can be done in future pregnancies. It also shouldn't be done during pregnancy, and pregnancy should be put off until at least 6–12 months after treatment.

A common outcome following radioiodine is a swing from hyperthyroidism to 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 number of cases of treatment failure, with a 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 measures along with a combination of the above modalities including: intravenous beta blockers such as propranolol, followed by a thioamide 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. Propylthiouracil is the preferred thioamide in thyroid storm as it can prevent the conversion of T4 to the more active T3 in the peripheral tissues in addition to inhibiting thyroid hormone production. Very low quality evidence suggests that traditional Chinese herbal medications may be beneficial when taken along with routine hyperthyroidism medications; however, there is no reliable evidence to determine the effectiveness of Chinese herbal medications for treating hyperthyroidism.

History

Caleb Hillier Parry first made the association between the goiter and eye protrusion in 1786; however, he did not publish his findings until 1825. In 1835, Irish doctor Robert James Graves discovered a link between the protrusion of the eyes and goiter, giving his name to the autoimmune disease now known as Graves' Disease.

Pregnancy

Recognizing and evaluating hyperthyroidism in pregnancy is a diagnostic challenge. Thyroid hormones are commonly elevated during the first trimester of pregnancy as the pregnancy hormone human chorionic gonadotropin (hCG) stimulates thyroid hormone production, in a condition known as gestational transient thyrotoxicosis. Such risks include pregnancy-related hypertension, pregnancy loss, low-birth weight, pre-eclampsia, preterm delivery, still birth and behavioral disorders later in the child's life. Nonetheless, high maternal FT4 levels during pregnancy have been associated with impaired brain developmental outcomes of the offspring and this was independent of hCG levels.

Propylthiouracil is the preferred antithyroid medication in the 1st trimester of pregnancy as it is less teratogenic than methimazole. The disease has become significantly more common since the first reports of feline hyperthyroidism in the 1970s. The most common cause of hyperthyroidism in cats is the presence of benign tumors called adenomas. Adenomas cause 98% of cases, but the reason these cats develop such tumors remains under study.

The most common presenting symptoms are: rapid weight loss, tachycardia (rapid heart rate), vomiting, diarrhea, increased consumption of fluids (polydipsia), increased appetite (polyphagia), and increased urine production (polyuria). Other symptoms include hyperactivity, possible aggression, an unkempt appearance, and large, thick claws. Heart murmurs and a gallop rhythm can develop due to secondary hypertrophic cardiomyopathy. About 70% of affected 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). There is also a special low-iodine diet available that will control symptoms, provided no other food is fed; Hill's y/d formula, when given exclusively, decreases T4 production by limiting the amount of iodine needed for thyroid hormone production. It is the only available commercial diet that focuses on managing feline hyperthyroidism. Medical and dietary management using methimazole and Hill's y/d cat food will give hyperthyroid cats an average of 2 years before dying due to secondary conditions such as heart and kidney failure. Drugs used to help manage the symptoms of hyperthyroidism are methimazole and carbimazole. Drug therapy is the least expensive option, even though the drug must be administered daily for the remainder of the cat's life. Carbimazole is only available as a once-daily tablet. Methimazole is available as an oral solution, a tablet, and compounded as a topical gel that is applied using a finger cot to the hairless skin inside a cat's ear. Many cat owners find this gel a good option for cats that do not like being given pills.

Radioiodine treatment, however, is not available in all areas, as this treatment requires nuclear radiological expertise and facilities that not only board the cat, but are specially equipped to manage the cat's urine, sweat, saliva, and stool, which are radioactive for several days after the treatment, usually for a total of 3 weeks (the cat spends the first week in total isolation and the next two weeks in close confinement). In the United States, 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.

Dogs

Hyperthyroidism is much less common in dogs compared to cats. Hyperthyroidism may be caused by a thyroid tumor. This may be a thyroid carcinoma. About 90% of carcinomas are very aggressive; they invade the surrounding tissues and metastasize (spread) to other tissues, particularly the lungs. This has a poor prognosis. Surgery to remove the tumor is often very difficult due to metastasis into arteries, the esophagus, or the windpipe. It may be possible to reduce the size of the tumor, thus relieving symptoms and allowing time for other treatments to work. About 10% of thyroid tumors are benign; these often cause few symptoms.

In dogs treated for hypothyroidism (lack of thyroid hormone), iatrogenic hyperthyroidism may occur as a result of an overdose of the thyroid hormone replacement medication, levothyroxine; in this case, treatment involves reducing the dose of levothyroxine. Dogs which display coprophagy, the consumption of feces, and also live in a household with a dog receiving levothyroxine treatment, may develop hyperthyroidism if they frequently eat the feces from the dog receiving levothyroxine treatment.

Hyperthyroidism may occur if a dog eats an excessive amount of thyroid gland tissue. This has occurred in dogs fed commercial dog food.

See also

  • High-output cardiac failure
  • Jod-Basedow phenomenon
  • Hashitoxicosis

References

Further reading

  • Merck Manual article about hyperthyroidism
  • Hyperthyroidism at MedlinePlus