|Thyrotoxic periodic paralysis|
|Thyrotoxic periodic paralysis occurs when the thyroid gland releases excessive amounts of thyroxine (thyroid hormone).|
Thyrotoxic periodic paralysis (TPP) is a condition featuring attacks of muscle weakness in the presence of hyperthyroidism (overactivity of the thyroid gland). Hypokalemia (a decreased potassium level in the blood) 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 (irregularities in the heart rate).If untreated, it is typically recurrent in nature.
The condition has been linked with genetic mutations in genes that code for certain ion channels that transport electrolytes (sodium and potassium) across cell membranes. The main ones are the L-type calcium channel α1-subunitand potassium inward rectifier 2.6; it is therefore classified as a channelopathy. The abnormality in the channel is thought to lead to shifts of potassium into cells, under conditions of high thyroxine (thyroid hormone) levels, usually with an additional precipitant.
Treatment of the hypokalemia, followed by correction of the hyperthyroidism, leads to complete resolution of the attacks. It occurs predominantly in males of Chinese, Japanese, Vietnamese, Filipino, and Korean descent.TPP is one of several conditions that can cause periodic paralysis.
An attack often begins with muscle pain, cramping, and stiffness.This is followed by weakness or paralysis that tends to develop rapidly, usually in late evening or the early hours of the morning. The weakness is usually symmetrical; the limb muscles closer to the trunk (proximal) are predominantly affected, and weakness tends to start in the legs and spread to the arms. Muscles of the mouth and throat, eyes, and breathing are usually not affected, but occasionally weakness of the respiratory muscles can cause life-threatening respiratory failure. Attacks typically resolve within several hours to several days, even in the absence of treatment. On neurological examination during an attack, flaccid weakness of the limbs is noted; reflexes are usually diminished, but the sensory system is unaffected. Mental status is not affected.
Attacks may be brought on by physical exertion, drinking alcohol, or eating food high in carbohydrates or salt. This may explain why attacks are more common in summer when more people drink sugary drinks and engage in exercise. Exercise-related attacks tend to occur during a period of rest immediately after exercise; exercise may, therefore, be recommended to abort an attack.
There may be symptoms of thyroid overactivity, such as weight loss, a fast heart rate, tremor, and perspiration;but such symptoms occur in only half of all cases. The most common type of hyperthyroidism, Graves' disease, may additionally cause eye problems (Graves' ophthalmopathy) and skin changes of the legs (pretibial myxedema). Thyroid disease may also cause muscle weakness in the form of thyrotoxic myopathy, but this is constant rather than episodic.
Genetic mutations in the L-type calcium channel α1-subunit (Cav1.1) have been described in Southern Chinese with TPP. The mutations are located in a different part of the gene from those described in the related condition familial periodic paralysis. In TPP, the mutations described are single-nucleotide polymorphisms located in the hormone response element responsive to thyroid hormone, implying that transcription of the gene and production of ion channels may be altered by increased thyroid hormone levels. Furthermore, mutations have been reported in the genes coding for potassium voltage-gated channel, Shaw-related subfamily, member 4 (Kv3.4) and sodium channel protein type 4 subunit alpha (Na41.4).
Of people with TPP, 33% from various populations were demonstrated to have mutations in KCNJ18, the gene coding for Kir2.6, an inward-rectifier potassium ion channel. This gene, too, harbors a thyroid response element.
Certain forms of human leukocyte antigen (HLA)—especially B46, DR9, DQB1*0303, A2, Bw22, AW19, B17, and DRW8—are more common in TPP. Linkage to particular forms of HLA, which plays a central role in the immune response, might imply an immune system cause, but it is uncertain whether this directly causes TPP or whether it increases the susceptibility to Graves' disease, a known autoimmune disease.
The most common underlying form of thyroid disease associated with TPP is Graves' disease, a syndrome due to an autoimmune reaction that leads to overproduction of thyroid hormone.TPP has also been described in people with other thyroid problems such as thyroiditis, toxic nodular goiter, toxic adenoma, TSH-producing pituitary adenoma, excessive ingestion of thyroxine or iodine, and amiodarone-induced hyperthyroidism.
The muscle weakness and increased risk of irregular heart beat in TPP result from markedly reduced levels of potassium in the bloodstream. Potassium is not in fact lost from the body, but increased Na+/K+-ATPase activity (the enzyme that moves potassium into cells and keeps sodium in the blood) leads to shift of potassium into tissues, and depletes the circulation. In other types of potassium derangement, the acid-base balance is usually disturbed, with metabolic alkalosis and metabolic acidosis often being present. In TPP, these disturbances are generally absent. Hypokalemia leads to hyperpolarization of muscle cells, making the neuromuscular junction less responsive to normal nerve impulses and leading to decreased contractility of the muscles.
It is not clear how the described genetic defects increase the Na+/K+-ATPase activity, but it is suspected that the enzyme becomes more active due to increased thyroid hormone levels. Hyperthyroidism increases the levels of catecholamines (such as adrenaline) in the blood, increasing Na+/K+-ATPase activity.The enzyme activity is then increased further by the precipitating causes. For instance, increased carbohydrate intake leads to increased insulin levels; this is known to activate Na+/K+-ATPase. Once the precipitant is removed, the enzyme activity returns to normal levels. It has been postulated that male hormones increase Na+/K+-ATPase activity, and that this explains why males are at a higher risk of TPP despite thyroid disease being more common in females.
TPP is regarded as a model for related conditions, known as "channelopathies", which have been linked with mutations in ion channels; the majority of these conditions occurs episodically.
Hypokalemia (low blood potassium levels) commonly occurs during attacks; levels below 3.0 mmol/l are typically encountered. Magnesium and phosphate levels are often found to be decreased. Creatine kinase levels are elevated in two thirds of cases, usually due to a degree of muscle injury; severe elevations suggestive of rhabdomyolysis (muscle tissue destruction) are rare. Electrocardiography (ECG/EKG) may show tachycardia (a fast heart rate) due to the thyroid disease, abnormalities due to cardiac arrhythmia (atrial fibrillation, ventricular tachycardia), and conduction changes associated with hypokalemia (U waves, QRS widening, QT prolongation, and T wave flattening). Electromyography shows changes similar to those encountered in myopathies (muscle diseases), with a reduced amplitude of the compound muscle action potentials (CMAPs); they resolve when treatment has commenced.
TPP is distinguished from other forms of periodic paralysis (especially hypokalemic periodic paralysis) with thyroid function tests on the blood. These are normal in the other forms, and in thyrotoxicosis the levels of thyroxine and triiodothyronine are elevated, with resultant suppression of TSH production by the pituitary gland.Various other investigations are usually performed to separate the different causes of hyperthyroidism.
In the acute phase of an attack, administration of potassium will quickly restore muscle strength and prevent complications. However, caution is advised as the total amount of potassium in the body is not decreased, and it is possible for potassium levels to overshoot ("rebound hyperkalemia"); slow infusions of potassium chloride are therefore recommended while other treatment is commenced.
The effects of excess thyroid hormone typically respond to the administration of a non-selective beta blocker, such as propranolol (as most of the symptoms are driven by increased levels of adrenaline and its effect on the β-adrenergic receptors). Subsequent attacks may be prevented by avoiding known precipitants, such as high salt or carbohydrate intake, until the thyroid disease has been adequately treated.
Treatment of the thyroid disease usually leads to resolution of the paralytic attacks. Depending on the nature of the disease, the treatment may consist of thyrostatics (drugs that reduce production of thyroid hormone), radioiodine, or occasionally thyroid surgery.
TPP occurs predominantly in males of Chinese, Japanese, Vietnamese, Filipino, and Korean descent,as well as Thais, with much lower rates in people of other ethnicities. In Chinese and Japanese people with hyperthyroidism, 1.8–1.9% experience TPP. This is in contrast to North America, where studies report a rate of 0.1–0.2%. Native Americans, who share a genetic background with East Asians, are at an increased risk.
The typical age of onset is 20–40. It is unknown why males are predominantly affected, with rates in males being 17- to 70-fold those in females, despite thyroid overactivity being much more common in women.
After several case reports in the 18th and 19th centuries, periodic paralysis was first described in full by the German neurologist Carl Friedrich Otto Westphal (1833–1890) in 1885.In 1926 the Japanese physician Tetsushiro Shinosaki, from Fukuoka, observed the high rate of thyroid disease in Japanese people with periodic paralysis. The first English-language report, in 1931, originated from Dunlap and Kepler, physicians at the Mayo Clinic; they described the condition in a patient with features of Graves' disease. In 1937 periodic paralysis was linked with hypokalemia, as well as precipitation of attacks with glucose and insulin. This phenomenon has been used as a diagnostic test.
In 1974 it was discovered that propranolol could prevent attacks.The concept of channelopathies and the link with specific ion channel mutations emerged at the end of the 20th century.
Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones 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.
Myotonia is a symptom of a small handful of certain neuromuscular disorders characterized by delayed relaxation of the skeletal muscles after voluntary contraction or electrical stimulation.
Thyroxine-binding globulin (TBG) is a globulin protein that in humans is encoded by the SERPINA7 gene. TBG binds thyroid hormones in circulation. It is one of three transport proteins (along with transthyretin and serum albumin) responsible for carrying the thyroid hormones thyroxine (T4) and triiodothyronine (T3) in the bloodstream. Of these three proteins, TBG has the highest affinity for T4 and T3 but is present in the lowest concentration relative to transthyretin and albumin, which also bind T3 and T4 in circulation. Despite its low concentration, TBG carries the majority of T4 in the blood plasma. Due to the very low concentration of T4 and T3 in the blood, TBG is rarely more than 25% saturated with its ligand. Unlike transthyretin and albumin, TBG has a single binding site for T4/T3. TBG is synthesized primarily in the liver as a 54-kDa protein. In terms of genomics, TBG is a serpin; however, it has no inhibitory function like many other members of this class of proteins.
Primary aldosteronism (PA), also known as primary hyperaldosteronism or Conn's syndrome, refers to the excess production of the hormone aldosterone from the adrenal glands, resulting in low renin levels. This abnormality is caused by hyperplasia or tumors. Many suffer from fatigue, potassium deficiency and high blood pressure which may cause poor vision, confusion or headaches. Symptoms may also include: muscular aches and weakness, muscle spasms, low back and flank pain from the kidneys, trembling, tingling sensations, numbness and excessive urination. Complications include cardiovascular disease such as stroke, myocardial infarction, kidney failure and abnormal heart rhythms.
Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abnormal heart rhythm, which is often too slow and can cause cardiac arrest.
Hyperkalemic periodic paralysis is an inherited autosomal dominant disorder that affects sodium channels in muscle cells and the ability to regulate potassium levels in the blood. It is characterized by muscle hyperexcitability or weakness which, exacerbated by potassium, heat or cold, can lead to uncontrolled shaking followed by paralysis. Onset usually occurs in early childhood, but it still occurs with adults.
Andersen–Tawil syndrome, also called Andersen syndrome and long QT syndrome 7, is a rare genetic disorder affecting several parts of the body. The three predominant features of Andersen–Tawil syndrome include disturbances of the electrical function of the heart characterised by an abnormality seen on an electrocardiogram and a tendency to abnormal heart rhythms, physical characteristics including low-set ears and a small lower jaw, and intermittent periods of muscle weakness known as hypokalaemic periodic paralysis.
Channelopathies are diseases caused by disturbed function of ion channel subunits or the proteins that regulate them. These diseases may be either congenital or acquired.
Myotonia congenita is a congenital neuromuscular channelopathy that affects skeletal muscles. It is a genetic disorder. The hallmark of the disease is the failure of initiated contraction to terminate, often referred to as delayed relaxation of the muscles (myotonia) and rigidity. Symptoms include delayed relaxation of the muscles after voluntary contraction (myotonia), and may also include stiffness, hypertrophy (enlargement), transient weakness in some forms of the disorder, severe masseter spasm, and cramping. The condition is sometimes referred to as fainting goat syndrome, as it is responsible for the eponymous 'fainting' seen in fainting goats when presented with a sudden stimulus. Of note, myotonia congenita has no association with malignant hyperthermia (MH).
Periodic paralysis is a group of rare genetic diseases that lead to weakness or paralysis from common triggers such as cold, heat, high carbohydrate meals, not eating, stress or excitement and physical activity of any kind. The underlying mechanism of these diseases are malfunctions in the ion channels in skeletal muscle cell membranes that allow electrically charged ions to leak in or out of the muscle cell, causing the cell to depolarize and become unable to move.
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.
Hypokalemic periodic paralysis (hypoKPP), also known as familial hypokalemic periodic paralysis (FHPP), is a rare, autosomal dominant channelopathy characterized by muscle weakness or paralysis when there is a fall in potassium levels in the blood. Not in all cases. Many levels stay the same and should not be used as a guideline for diagnosis of an episode. Individuals with this mutation, attacks sometimes begin in adolescence and most commonly occur with individual triggers such as rest after strenuous exercise, high carbohydrate meals, meals with high sodium content, sudden changes in temperature, and even excitement, noise, flashing lights cold temperatures and stress. Weakness may be mild and limited to certain muscle groups, or more severe full-body paralysis. During an attack reflexes may be decreased or absent. Attacks may last for a few hours or persist for several days. Recovery is usually sudden when it occurs, due to release of potassium from swollen muscles as they recover. Some patients may fall into an abortive attack or develop chronic muscle weakness later in life.
Paramyotonia congenita (PC), is a rare congenital autosomal dominant neuromuscular disorder characterized by “paradoxical” myotonia. This type of myotonia has been termed paradoxical because it becomes worse with exercise whereas classical myotonia, as seen in myotonia congenita, is alleviated by exercise. PC is also distinguished as it can be induced by cold temperatures. Although more typical of the periodic paralytic disorders, patients with PC may also have potassium-provoked paralysis. PC typically presents within the first decade of life and has 100% penetrance. Patients with this disorder commonly present with myotonia in the face or upper extremities. The lower extremities are generally less affected. While some other related disorders result in muscle atrophy, this is not normally the case with PC. This disease can also present as hyperkalemic periodic paralysis and there is debate as to whether the two disorders are actually distinct.
Sodium channel protein type 4 subunit alpha is a protein that in humans is encoded by the SCN4A gene.
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.
Cav1.1 also known as the calcium channel, voltage-dependent, L type, alpha 1S subunit, (CACNA1S), is a protein which in humans is encoded by the CACNA1S gene. It is also known as CACNL1A3 and the dihydropyridine receptor.
Thyroid hormones are two hormones produced and released by the thyroid gland, namely triiodothyronine (T3) and thyroxine (T4). They are tyrosine-based hormones that are primarily responsible for regulation of metabolism. T3 and T4 are partially composed of iodine. A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as simple goitre. The major form of thyroid hormone in the blood is thyroxine (T4), which has a longer half-life than T3. In humans, the ratio of T4 to T3 released into the blood is approximately 14:1. T4 is converted to the active T3 (three to four times more potent than T4) within cells by deiodinases (5′-iodinase). These are further processed by decarboxylation and deiodination to produce iodothyronamine (T1a) and thyronamine (T0a). All three isoforms of the deiodinases are selenium-containing enzymes, thus dietary selenium is essential for T3 production.
The Kir2.6 also known as inward rectifier potassium channel 18 is a protein that in humans is encoded by the KCNJ18 gene. Kir2.6 is an inward-rectifier potassium ion channel.
Louis Ptáček is an American neurologist and professor who contributed greatly to the field of genetics and neuroscience. His chief areas of research include the understanding of inherited Mendelian disorders, and circadian rhythm genes. Currently, Ptáček is a neurology professor and a director of the Division of Neurogenetics in University of California, San Francisco, School of Medicine. His current investigations primarily focus on extensive clinical studies in families with hereditary disorders which include identifying and characterizing the genes responsible for neurological variations.