Thyrotoxic myopathy (TM) is a neuromuscular disorder that develops due to the overproduction of the thyroid hormone thyroxine. Also known as hyperthyroid myopathy, TM is one of many myopathies that lead to muscle weakness and muscle tissue breakdown. Evidence indicates the onset may be caused by hyperthyroidism.There are two known causes of hyperthyroidism that lead to development thyrotoxic myopathy including a multinodular goiter and Graves' disease. Physical symptoms of TM may include muscle weakness, the breakdown of muscle tissue, fatigue, and heat intolerance. Physical acts such as lifting objects and climbing stairs may become increasingly difficult. If untreated, TM can be an extremely debilitating disorder that can, in extreme rare cases, lead to death. If diagnosed and treated properly the effects can be controlled and in most cases reversed leaving no lasting effects.
Myopathy is a disease of the muscle in which the muscle fibers do not function properly. This results in muscular weakness. Myopathy means muscle disease. This meaning implies that the primary defect is within the muscle, as opposed to the nerves or elsewhere. Muscle cramps, stiffness, and spasm can also be associated with myopathy.
Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormone by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism. 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. Symptoms are typically less severe in the elderly and during pregnancy. An uncommon complication is thyroid storm in which an event such as an infection results in worsening symptoms such as confusion and a high temperature and often results in death. The opposite is hypothyroidism, when the thyroid gland does not make enough thyroid hormone.
Graves' disease, also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyroid. Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss. Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy. About 25 to 80% of people with the condition develop eye problems.
Physical symptoms may include:
Symptoms of chronic TM arise slowly. Patients usually cite decreased exercise tolerance, increased fatigue, and difficulty completing certain tasks after six months of onset.If chronic TM goes untreated worse symptoms may develop including difficulty swallowing and respiratory distress. These occurrences are rare since diagnosis of chronic TM usually occurs during the early stages of onset, before these symptoms develop.
Acute TM is rarer than chronic TM and symptoms appear within days of onset. Acute TM degrades muscle fibers rapidly. Due to the rapid degradation of muscle fibers patients usually cite severe muscle cramps and muscle pain. Some acute TM patients may present symptoms of blurred vision and bulging eyes due to eye muscle degradation and inflammation, but documented cases are rare. Acute TM patients usually have very weak respiratory muscles and often severe respiratory failure occurs.
TM is directly related to thyroxine toxicity. It is believed this disorder is a direct result of hyperthyroidism, specifically hyperthyroidism caused by Graves' disease or a multinodular goiter. Both cause the thyroid gland to overproduce thyroxine. A multinodular goiter is a condition where the thyroid develops nodules. Overproduction of thyroxine is due to the enlargement of the thyroid gland. Graves' disease is an autoimmune condition where the immune system attacks the thyroid and induces overproduction of the thyroxine hormone.
Excess thyroxine is believed to bring about the onset of thyrotoxic myopathy and eventually cause the degradation of muscle tissue. Thyroxine is a hormone produced in the thyroid gland that regulates the growth metabolism of the nervous system and regulates basal metabolic rate of many cell types. Scientists agree thyroxine brings about the degradation of muscle fibers specifically at the motor end plates of neuromuscular junctions. There is debate as to whether thyroxine degrades the motor end plates from the muscular side, from the nervous system side, or a combination.
To understand how high levels of thyroxine can be toxic and lead to thyrotoxic myopathy physiologically, consider basic neuromuscular junction function. Under normal circumstances, muscle contraction occurs when electrical impulses travel down descending axons from the brain or spinal cord towards the neuromuscular junction. The axon terminal depolarizes and releases Acetylcholine (ACh), a neurotransmitter, which in turn stimulates the motor end plate (MEP) of the muscle fiber the nerve is innervating. When the MEP depolarizes the muscle fiber releases calcium initiating the process of muscle contraction.
A neuromuscular junction is a chemical synapse formed by the contact between a motor neuron and a muscle fiber. It is at the neuromuscular junction that a motor neuron is able to transmit a signal to the muscle fiber, causing muscle contraction.
Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals, and humans, as a neurotransmitter—a chemical message released by nerve cells to send signals to other cells, such as neurons, muscle cells, and gland cells. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic. Substances that interfere with acetylcholine activity are called anticholinergics.
Neurotransmitters are endogenous chemicals that enable neurotransmission. It is a type of chemical messenger which transmits signals across a chemical synapse, such as a neuromuscular junction, from one neuron to another "target" neuron, muscle cell, or gland cell. Neurotransmitters are released from synaptic vesicles in synapses into the synaptic cleft, where they are received by neurotransmitter receptors on the target cells. Many neurotransmitters are synthesized from simple and plentiful precursors such as amino acids, which are readily available from the diet and only require a small number of biosynthetic steps for conversion. Neurotransmitters play a major role in shaping everyday life and functions. Their exact numbers are unknown, but more than 200 chemical messengers have been uniquely identified.
With the onset of TM due to thyroxine toxicity, there is evidence to suggest that structural changes in MEPs could lead to muscle fiber degradation, weakness, and fatigue. Research indicates that decreased levels of Acetylcholinesterase AChE, an enzyme that breaks down ACh, was observed within the neuromuscular junction.This decrease in AChE blocks degradation of ACh causing ACh to increasingly stimulate the MEP of the muscle fiber. Over stimulation of MEP could cause more muscle contractions which eventually evoke muscle fiber fatigue, weakness, and finally degradation, which are characteristic symptoms of TM. It is believed this decrease in AChE and MEP structural changes could be the result of over stimulation of thyroxin blocking the axoplasmic flow of trophic factors down the axon terminal especially considering thyroxine's role in nervous system growth and metabolism regulation.
Other research indicates muscle fiber fatigue, weakness, and degradation associated with TM is the direct action thyroxine has on the muscle fibers themselves. Research suggests thyroxine directly causes a decrease in protein kinase affinity to cAMP within muscle fibersThis causes an increase in cAMP within the muscle fibers since protein kinases are not inactivating cAMP. Increased levels of cAMP within the muscle fibers cause increased release of Ca2+ from the muscle fiber's sarcoplasmic reticulum which eventually leads to more muscle contractions. Like the nervous system proposal increased muscle contractions eventually evoke muscle fiber fatigue, weakness, and finally degradation, which are characteristic symptoms of TM. There is evidence to support both theories; it has been suggested that toxic levels of thyroxine may ultimately attack muscle fibers directly and indirectly by the motor neurons that innervate the affected muscle fibers.
Thyrotoxic myopathy is usually diagnosed by a neurologist who has extensive experience diagnosing neuromuscular disorders. There are many types of neuromuscular disorders that present similar physical symptoms. Extensive clinical tests are performed first to determine if there is a neuromuscular disorder and then to determine which disorder it is. Electromyography is used to diagnose myopathies by comparing muscle contraction responses to electrical stimulus.For TM results may indicate normal responses or myopathic responses depending on how the disorder has progressed. Early detection may indicate normal contractual responses while highly progressed TM may show a significant decrease in contraction response.
Blood tests are then conducted to determine the specific myopathy. For TM, blood tests reveal increased thyroxine levels. Increased thyroxine levels accompanied with decreased neuromuscular responses together provide best evidence for TM diagnosis. Creatine phosphokinase levels are also examined during the blood tests. Normal or increased levels may be observed with TM depending on the severity of TM's progression. Normal levels indicate possible early stages of progression while increased levels may indicate later stages of thyrotoxic myopathy. Muscle biopsies may also be taken and examined to determine TM's progression with respect to physical degradation. Like measured creatine phosphokinase levels results from the muscle biopsy characteristic of TM typically show normal to severe fiber degradation with respective indications to the severity of progression.
Treatment for TM is typically done with the collaboration of many medical specialists. Usually a neuromuscular specialist, an endocrinologist, a surgeon, and an ophthalmologist will combine their efforts to successfully treat patients with TM. If a patient develops significant to severe muscle degradation as a result of TM, a physical therapist may be consulted for rehabilitation.
Since excess thyroxine leads to onset of TM, the overall goal of treatment is to reduce the overproduction of thyroxine from the thyroid gland and restore normal thyroid homeostasis. This can be accomplished three ways including using medication, radiation, and surgery.
The first choice involves using medications to alleviate the symptoms and reverse the damage by blocking the production of thyroxine from the thyroid gland. Beta-blockers are used to alleviate the symptoms associated with TM. But beta-blockers do not reduce the damage done by excess thyroxine. Medications such as propylthiouracil and methimazole are administered to block the release of thyroxine from the thyroid and to block the damage thyroxine inflicts on muscle fiber tissue.
One treatment option is the use of radioactive iodine which directly destroys the overactive thyroid gland. The thyroid gland naturally uses iodine to produce thyroxine and other hormones. It cannot distinguish between normal iodine and the radioactive version. Administering the radioactive isotope causes the thyroid to take in the lethal iodine and quickly radiation destroys it.Typically overproduction of thyroxine using radio-iodine is blocked with one dose. The drawback to this treatment is the thyroid gland is completely destroyed and patients often develop hypothyroidism. Some do so only a few months after treatment while others may not be affected for 20–30 years. Hypothyroidism patients must begin a lifelong regimen of thyroid replacement hormones. While the onset of hypothyroidism is most common with radio-iodine treatment, the condition has been observed in patients treated with medication series and surgery.
The last option for TM treatment includes surgical removal of portions of the thyroid which can also be performed to restore thyroid homeostasis. This treatment option usually is done when overproduction of TM is caused by multinodular goiters. Since these goiters enlarge the thyroid and can cause the patient to become physically disfigured surgical treatment can alleviate both the aesthetic and physiological effects simultaneously.
TM, with proper diagnosis and effective treatment, can be beaten. Patients who are diagnosed have a normal life expectancy and can ultimately lead healthy lives if proper treatment is administered. Typically, once the over-production of thyroxine is corrected and thyroid function adequately reaches a level of homeostasis, patients begin to regain muscle strength in two to four months. Depending on the severity of the TM progression symptoms may take up to a year to completely reverse the damage done by TM. Untreated TM can eventually cause severe respiratory distress or arrest possible leading to death, yet this is very rarely seen.
The onset of TM requires toxic levels of the thyroxine hormone due to overproduction by the thyroid gland. Documented cases have only been diagnosed in conjunction with patients with hyperthyroidism. While hyperthyroidism is more common in women, the development of TM was more common among men with hyperthyroidism. Case studies of patients with diagnosed hyperthyroidism showed that only about half of them complained of symptoms characteristic of TM.Further examination as described above indicated that about 75% of the studied patients showed signs of muscle fiber degeneration. This indicates that either at the time of study some patients were in early stages of TM or the symptoms were insignificant patients.
A goitre, or goiter, is a swelling in the neck resulting from an enlarged thyroid gland. A goitre can be associated with a thyroid that is not functioning properly.
The thyroid gland, or simply the thyroid, is an endocrine gland in the neck, consisting of two lobes connected by an isthmus. It is found at the front of the neck, below the Adam's apple. The thyroid gland secretes three hormones, namely the two thyroid hormones (thyroxine/T4 and triiodothyronine/T3), and calcitonin. The thyroid hormones primarily influence the metabolic rate and protein synthesis, but they also have many other effects, including effects on development. Calcitonin plays a role in calcium homeostasis.
Hypothyroidism, also called underactive thyroid or low thyroid, is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as poor ability to tolerate cold, a feeling of tiredness, constipation, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goiter. Untreated hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.
Weakness is a symptom of a number of different conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, including muscular dystrophy and inflammatory myopathy. It occurs in neuromuscular junction disorders, such as myasthenia gravis.
Propylthiouracil (PTU) is a medication used to treat hyperthyroidism. This includes hyperthyroidism due to Graves' disease and toxic multinodular goiter. In a thyrotoxic crisis it is generally more effective than methimazole. Otherwise it is typically only used when methimazole, surgery, and radioactive iodine is not possible. It is taken by mouth.
Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning that it is an endocrine organ. These hormones normally act in the body to regulate energy use, infant development, and childhood development.
Carbimazole is used to treat hyperthyroidism. Carbimazole is a pro-drug as after absorption it is converted to the active form, methimazole. Methimazole prevents thyroid peroxidase enzyme from coupling and iodinating the tyrosine residues on thyroglobulin, hence reducing the production of the thyroid hormones T3 and T4 (thyroxine).
Thyroiditis is the inflammation of the thyroid gland. The thyroid gland is located on the front of the neck below the laryngeal prominence, and makes hormones that control metabolism.
Toxic multinodular goiter is an active multinodular goiter associated with hyperthyroidism.
Thyroid storm is a rare but severe and potentially life-threatening complication of hyperthyroidism. It is characterized by a high fever, fast and often irregular heart beat, elevated blood pressure, vomiting, diarrhea, and agitation. Hypertension with a wide pulse pressure occurs in early to mid crisis, with hypotension accompanying shock occurring in the late stage. Heart failure and heart attack may occur. Death may occur despite treatment. Most episodes occur either in those with known hyperthyroidism whose treatment has been stopped or become ineffective, or in those with untreated mild hyperthyroidism who have developed an intercurrent illness.
De Quervain's thyroiditis, also known as subacute granulomatous thyroiditis or giant cell thyroiditis, is a member of the group of thyroiditis conditions known as resolving thyroiditis. People of all ages and genders may be affected.
A thyroid adenoma is a benign tumor of the thyroid gland, that may be inactive or active as a toxic adenoma.
Autoimmune thyroiditis, is a chronic disease in which the body interprets the thyroid glands and its hormone products T3, T4 and TSH as threats, therefore producing special antibodies that target the thyroid’s cells, thereby destroying it.
Acquired non-inflammatory myopathy (ANIM) is a neurological disorder primarily affecting skeletal muscle, most commonly in the limbs of humans, resulting in a weakness or dysfunction in the muscle. A myopathy refers to a problem or abnormality with the myofibrils, which compose muscle tissue. In general, non-inflammatory myopathies are a grouping of muscular diseases not induced by an autoimmune-mediated inflammatory pathway. These muscular diseases usually arise from a pathology within the muscle tissue itself rather than the nerves innervating that tissue. ANIM has a wide spectrum of causes which include drugs and toxins, nutritional imbalances, acquired metabolic dysfunctions such as an acquired defect in protein structure, and infections.
Thyrotoxic periodic paralysis (TPP) is a condition featuring attacks of muscle weakness in the presence of hyperthyroidism. Hypokalemia is usually present during attacks. The condition may be life-threatening if weakness of the breathing muscles leads to respiratory failure, or if the low potassium levels lead to cardiac arrhythmias. If untreated, it is typically recurrent in nature.
Behavioral endocrinology is the study of hormonal processes and neuroendocrine systems that influence or regulate behavior. Analytical approaches include studies of natural variation among individuals within populations of a single species, sex differences, differences among species, and experimental manipulations of either the endocrine system or behavior itself.