Thyrotoxic periodic paralysis
Encyclopedia
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 channel
s that transport electrolyte
s (sodium
and potassium
) across cell membrane
s. The main ones are the L-type calcium channel α1-subunit
and 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
.
, 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 carbohydrate
s 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.
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
.
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.
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 catecholamine
s (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.
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 potential
s (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.
s 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.
(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.
Paralysis
Paralysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...
in the presence of hyperthyroidism
Hyperthyroidism
Hyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...
(overactivity of the thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
gland). Hypokalemia
Hypokalemia
Hypokalemia or hypokalaemia , also hypopotassemia or hypopotassaemia , refers to the condition in which the concentration of potassium in the blood is low...
(a decreased potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
level in the blood) is usually present during attacks. The condition may be life-threatening if weakness of the breathing muscles
Muscles of respiration
The various muscles of respiration aid in both inspiration and expiration, which require changes in the pressure within the thoracic cavity. The respiratory muscles work to achieve this by changing the dimensions of the thoracic cavity....
leads to respiratory failure
Respiratory failure
The term respiratory failure, in medicine, is used to describe inadequate gas exchange by the respiratory system, with the result that arterial oxygen and/or carbon dioxide levels cannot be maintained within their normal ranges. A drop in blood oxygenation is known as hypoxemia; a rise in arterial...
, 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 channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s that transport electrolyte
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....
s (sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
and potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
) across cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
s. The main ones are the L-type calcium channel α1-subunit
Cav1.1
Cav1.1 also known as the calcium channel, voltage-dependent, L type, alpha 1S subunit, , is a protein which in humans is encoded by the CACNA1S gene...
and potassium inward rectifier 2.6
Kir2.6
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.- Function :...
; it is therefore classified as a channelopathy
Channelopathy
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 .There are a large number of distinct dysfunctions known to be caused by ion channel...
. The abnormality in the channel is thought to lead to shifts of potassium into cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
, under conditions of high thyroxine
Thyroxine
Thyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones, is the major hormone secreted by the follicular cells of the thyroid gland.-Synthesis and regulation:...
(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
Periodic paralysis
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...
.
Signs and symptoms
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 throatCorticobulbar tract
The corticobulbar tract is a white matter pathway connecting the cerebral cortex to the brainstem. The 'bulb' is an archaic term for the medulla oblongata; in modern clinical usage, it sometimes includes the pons as well...
, eyes
Muscles of orbit
The muscles of the orbit are a group of six muscles that control movement of the eye. Four of the muscles control the movement of the eye in the four cardinal directions: up, down, left and right...
, and breathing
Muscles of respiration
The various muscles of respiration aid in both inspiration and expiration, which require changes in the pressure within the thoracic cavity. The respiratory muscles work to achieve this by changing the dimensions of the thoracic cavity....
are usually not affected, but occasionally weakness of the respiratory muscles can cause life-threatening respiratory failure
Respiratory failure
The term respiratory failure, in medicine, is used to describe inadequate gas exchange by the respiratory system, with the result that arterial oxygen and/or carbon dioxide levels cannot be maintained within their normal ranges. A drop in blood oxygenation is known as hypoxemia; a rise in arterial...
. Attacks typically resolve within several hours to several days, even in the absence of treatment. On neurological examination
Neurological examination
A neurological examination is the assessment of sensory neuron and motor responses, especially reflexes, to determine whether the nervous system is impaired...
during an attack, flaccid weakness
Flaccid paralysis
Flaccid paralysis is a clinical manifestation characterized by weakness or paralysis and reduced muscle tone without other obvious cause .-Polio:...
of the limbs is noted; reflexes
Stretch reflex
The stretch reflex is a muscle contraction in response to stretching within the muscle. It is a monosynaptic reflex which provides automatic regulation of skeletal muscle length....
are usually diminished, but the sensory system
Sensory system
A sensory system is a part of the nervous system responsible for processing sensory information. A sensory system consists of sensory receptors, neural pathways, and parts of the brain involved in sensory perception. Commonly recognized sensory systems are those for vision, hearing, somatic...
is unaffected. Mental status is not affected.
Attacks may be brought on by physical exertion
Physical exercise
Physical exercise is any bodily activity that enhances or maintains physical fitness and overall health and wellness. It is performed for various reasons including strengthening muscles and the cardiovascular system, honing athletic skills, weight loss or maintenance, as well as for the purpose of...
, drinking alcohol
Alcoholic beverage
An alcoholic beverage is a drink containing ethanol, commonly known as alcohol. Alcoholic beverages are divided into three general classes: beers, wines, and spirits. They are legally consumed in most countries, and over 100 countries have laws regulating their production, sale, and consumption...
, or eating food high in carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
s or salt
Salt
In chemistry, salts are ionic compounds that result from the neutralization reaction of an acid and a base. They are composed of cations and anions so that the product is electrically neutral...
. 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
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
, and perspiration; but such symptoms occur in only half of all cases. The most common type of hyperthyroidism, Graves' disease
Graves' disease
Graves' disease is an autoimmune disease where the thyroid is overactive, producing an excessive amount of thyroid hormones...
, may additionally cause eye problems (Graves' ophthalmopathy) and skin changes of the legs (pretibial myxedema
Pretibial myxedema
Pretibial myxedema is an infiltrative dermopathy, resulting as a rare complication of Graves' disease, with an incidence rate of about 1-4% in patients.-Presentation:...
). Thyroid disease may also cause muscle weakness in the form of thyrotoxic myopathy
Thyrotoxic Myopathy
Thyrotoxic myopathy 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 of TM may be caused by...
, but this is constant rather than episodic.
Genetics
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 elementHormone response element
A hormone response element is a response element for hormones, a short sequence of DNA within the promoter of a gene that is able to bind a specific hormone receptor complex and therefore regulate transcription...
responsive to thyroid hormone, implying that transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
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
KCNC4
Potassium voltage-gated channel, Shaw-related subfamily, member 4 , also known as Kv3.4, is a human gene.-Further reading:...
(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
Inward-rectifier potassium ion channel
Inwardly rectifying potassium channels are a specific subset of potassium selective ion channels. To date, seven subfamilies have been identified in various mammalian cell types...
. This gene, too, harbors a thyroid response element.
Certain forms of human leukocyte antigen
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
(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
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
, 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
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
.
Thyroid disease
The most common underlying form of thyroid disease associated with TPP is Graves' disease, a syndrome due to an autoimmune reactionAutoimmunity
Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
that leads to overproduction of thyroid hormone. TPP has also been described in people with other thyroid problems such as thyroiditis
Thyroiditis
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.-Classification:...
, toxic nodular goiter, toxic adenoma
Thyroid adenoma
-Types:Almost all thyroid adenomas are follicular adenomas. Follicular adenomas can be described as "cold", "warm" or "hot" depending on their level of function...
, TSH
Thyroid-stimulating hormone
Thyrotrophin-stimulating hormone is a peptide hormone synthesized and secreted by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid gland.- Physiology :...
-producing pituitary adenoma
Pituitary adenoma
Pituitary adenomas are tumors that occur in the pituitary gland, and account for about 15% of intracranial neoplasms. Tumors which exceed 10 mm in size are defined as macroadenomas, and those smaller than 10 mm are referred to as microadenomas...
, excessive ingestion of thyroxine
Thyroxine
Thyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones, is the major hormone secreted by the follicular cells of the thyroid gland.-Synthesis and regulation:...
or iodine
Iodine
Iodine is a chemical element with the symbol I and atomic number 53. The name is pronounced , , or . The name is from the , meaning violet or purple, due to the color of elemental iodine vapor....
, and amiodarone
Amiodarone
Amiodarone is an antiarrhythmic agent used for various types of tachyarrhythmias , both ventricular and supraventricular arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985...
-induced hyperthyroidism.
Mechanism
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+-ATPaseNa+/K+-ATPase
Na+/K+-ATPase is an enzyme located in the plasma membrane in all animals.- Sodium-potassium pumps :Active transport is responsible for cells containing relatively high...
activity (the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that moves potassium into cells and keeps sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
in the blood) leads to shift of potassium into tissues, and depletes the circulation. In other types of potassium derangement, the acid-base balance
Acid-base homeostasis
Acid–base homeostasis is the part of human homeostasis concerning the proper balance between acids and bases, in other words, the pH. The body is very sensitive to its pH level, so strong mechanisms exist to maintain it...
is usually disturbed, with metabolic alkalosis
Metabolic alkalosis
Metabolic alkalosis is a metabolic condition in which the pH of tissue is elevated beyond the normal range . This is the result of decreased hydrogen ion concentration, leading to increased bicarbonate, or alternatively a direct result of increased bicarbonate concentrations.-Terminology:*Alkalosis...
and metabolic acidosis
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
often being present. In TPP, these disturbances are generally absent. Hypokalemia leads to hyperpolarization
Hyperpolarization (biology)
Hyperpolarization is a change in a cell's membrane potential that makes it more negative. It is the opposite of a depolarization.Hyperpolarization is often caused by efflux of K+ through K+ channels, or influx of Cl– through Cl– channels. On the other hand, influx of cations, e.g...
of muscle cells
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
, making the neuromuscular junction
Neuromuscular junction
A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...
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 catecholamine
Catecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...
s (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
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
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
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
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.
Diagnosis
Hypokalaemia (low blood potassiumPotassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
levels) commonly occurs during attacks; levels below 3.0 mmol/l are typically encountered. Magnesium
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...
and phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
levels are often found to be decreased. Creatine kinase
Creatine kinase
Creatine kinase , also known as creatine phosphokinase or phospho-creatine kinase , is an enzyme expressed by various tissues and cell types. CK catalyses the conversion of creatine and consumes adenosine triphosphate to create phosphocreatine and adenosine diphosphate...
levels are elevated in two thirds of cases, usually due to a degree of muscle injury; severe elevations suggestive of rhabdomyolysis
Rhabdomyolysis
Rhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...
(muscle tissue destruction) are rare. Electrocardiography (ECG/EKG) may show tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
(a fast heart rate) due to the thyroid disease, abnormalities due to cardiac arrhythmia (atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
, ventricular tachycardia
Ventricular tachycardia
Ventricular tachycardia is a tachycardia, or fast heart rhythm, that originates in one of the ventricles of the heart...
), and conduction changes associated with hypokalemia (U waves, QRS widening, QT prolongation, and T wave flattening). Electromyography
Electromyography
Electromyography is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an instrument called an electromyograph, to produce a record called an electromyogram. An electromyograph detects the electrical potential generated by muscle...
shows changes similar to those encountered in myopathies
Myopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
(muscle diseases), with a reduced amplitude of the compound muscle action potential
Compound muscle action potential
The compound muscle action potential or compound motor action potential is a electromyography investigation ....
s (CMAPs); they resolve when treatment has commenced.
TPP is distinguished from other forms of periodic paralysis (especially hypokalemic periodic paralysis
Hypokalemic periodic paralysis
Hypokalemic periodic paralysis is a rare channelopathy characterized by muscle weakness or paralysis with a matching fall in potassium levels in the blood...
) with thyroid function tests on the blood. These are normal in the other forms, and in thyrotoxicosis the levels of thyroxine
Thyroxine
Thyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones, is the major hormone secreted by the follicular cells of the thyroid gland.-Synthesis and regulation:...
and triiodothyronine
Triiodothyronine
Triiodothyronine, C15H12I3NO4, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate....
are elevated, with resultant suppression of TSH production by the pituitary gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
. Various other investigations are usually performed to separate the different causes of hyperthyroidism
Hyperthyroidism
Hyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...
.
Treatment
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
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
Hyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...
"); 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
Beta blocker
Beta blockers or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction ,...
, 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.
Epidemiology
TPP occurs predominantly in maleMale
Male refers to the biological sex of an organism, or part of an organism, which produces small mobile gametes, called spermatozoa. Each spermatozoon can fuse with a larger female gamete or ovum, in the process of fertilization...
s of Chinese, Japanese, Vietnamese, Filipino, and Korean descent, as well as Thais
Thailand
Thailand , officially the Kingdom of Thailand , formerly known as Siam , is a country located at the centre of the Indochina peninsula and Southeast Asia. It is bordered to the north by Burma and Laos, to the east by Laos and Cambodia, to the south by the Gulf of Thailand and Malaysia, and to the...
, 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
Native Americans in the United States
Native Americans in the United States are the indigenous peoples in North America within the boundaries of the present-day continental United States, parts of Alaska, and the island state of Hawaii. They are composed of numerous, distinct tribes, states, and ethnic groups, many of which survive as...
, 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.
History
After several case reports in the 18th and 19th centuries, periodic paralysis was first described in full by the German neurologist Carl Friedrich Otto WestphalCarl Friedrich Otto Westphal
Carl Friedrich Otto Westphal was a German neurologist and psychiatrist from Berlin. He was the son of Otto Carl Friedrich Westphal and Karoline Friederike Heine and the father of Alexander Carl Otto Westphal...
(1833–1890) in 1885. In 1926 the Japanese physician Tetsushiro Shinosaki, from Fukuoka
Fukuoka
Fukuoka most often refers to the capital city of Fukuoka Prefecture.It can also refer to:-Locations:* Fukuoka, Gifu, a town in Gifu Prefecture, Japan* Fukuoka, Toyama, a town in Toyama Prefecture, Japan...
, 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
Mayo Clinic
Mayo Clinic is a not-for-profit medical practice and medical research group specializing in treating difficult patients . Patients are referred to Mayo Clinic from across the U.S. and the world, and it is known for innovative and effective treatments. Mayo Clinic is known for being at the top of...
; they described the condition in a patient with features of Graves' disease
Graves' disease
Graves' disease is an autoimmune disease where the thyroid is overactive, producing an excessive amount of thyroid hormones...
. 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.