Megavitamin-B
6 syndrome is a collection of symptoms that can result from chronic supplementation, or acute overdose, of
vitamin B6.
While it is also known as hypervitaminosis B
6, vitamin B
6 toxicity and vitamin B
6 excess, megavitamin-b6 syndrome is the name used in the
ICD-10.
Signs and symptoms
The predominant symptom is
peripheral sensory neuropathy that is experienced as numbness, pins-and-needles and burning sensations (
paresthesia) in a patient's limbs on both sides of their body.
Patients may experience unsteadiness of gait, incoordination (
ataxia
Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
),
involuntary muscle movements (
choreoathetosis
Choreoathetosis is the occurrence of involuntary movements in a combination of chorea (irregular migrating contractions) and athetosis (twisting and writhing).
It is caused by many different diseases and agents. It is a symptom of several diseases ...
)
the sensation of an electric zap in their bodies (
Lhermitte's sign
Lhermitte phenomenon, also called the barber chair phenomenon, is an uncomfortable "electrical" sensation that runs through the back and into the limbs. The sensation can feel like it goes up or down the spine. It is painful for some, although oth ...
),
a heightened sensitivity to sense stimuli including
photosensitivity Photosensitivity is the amount to which an object reacts upon receiving photons, especially visible light. In medicine, the term is principally used for abnormal reactions of the skin, and two types are distinguished, photoallergy and phototoxicit ...
(
hyperesthesia
Hyperesthesia is a condition that involves an abnormal increase in sensitivity to stimuli of the sense. Stimuli of the senses can include sound that one hears, foods that one tastes, textures that one feels, and so forth. Increased touch sensitiv ...
),
impaired skin sensation (
hypoesthesia
Hypoesthesia or numbness is a common side effect of various medical conditions that manifests as a reduced sense of touch or sensation, or a partial loss of sensitivity to sensory stimuli. In everyday speech this is generally referred to as nu ...
),
numbness around the mouth,
and gastrointestinal symptoms such as
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
and
heartburn
Heartburn, also known as pyrosis, cardialgia or acid indigestion, is a burning sensation in the central chest or upper central abdomen. Heartburn is usually due to regurgitation of gastric acid (gastric reflux) into the esophagus. It is the m ...
.
The ability to sense vibrations and to
sense one's position are diminished to a greater degree than pain or temperature.
Skin lesions
A skin condition, also known as cutaneous condition, is any medical condition that affects the integumentary system—the organ system that encloses the body and includes skin, nails, and related muscle and glands. The major function of this s ...
have also been reported.
Megavitamin-B
6 syndrome may also contribute to
burning mouth syndrome
Burning mouth syndrome (BMS) is a burning, tingling or scalding sensation in the mouth, lasting for at least four to six months, with no underlying known dental or medical cause. No related signs of disease are found in the mouth. People with ...
.
Potential psychiatric symptoms range from
anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
,
depression,
agitation, and
cognitive deficit
Cognitive deficit is an inclusive term to describe any characteristic that acts as a barrier to the cognition process.
The term may describe
* deficits in overall intelligence (as with intellectual disabilities),
* specific and restricted defic ...
s to
psychosis
Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...
.
Symptom severity appears to be
dose-dependent (higher doses cause more severe symptoms)
and the duration of supplementation with vitamin B
6 before onset of systems appears to be inversely proportional to the amount taken daily (the smaller the daily dosage, the longer it will take for symptoms to develop).
It is also possible that some individuals are more susceptible to the toxic effects of vitamin B
6 than others.
Megavitamin-B
6 syndrome has been reported in doses as low as 24 mg/day.
Symptoms may also be dependent on the
form of vitamin B6 taken in supplements.
It has been proposed that vitamin B
6 in supplements should be in
pyridoxal
Pyridoxal is one form of vitamin B6.
Some medically relevant bacteria, such as those in the genera ''Granulicatella'' and ''Abiotrophia'', require pyridoxal for growth. This nutritional requirement can lead to the culture phenomenon of satellit ...
or
pyridoxal phosphate
Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent a ...
form rather than
pyridoxine as these are thought to reduce the likelihood of toxicity.
A
tissue culture
Tissue culture is the growth of tissues or cells in an artificial medium separate from the parent organism. This technique is also called micropropagation. This is typically facilitated via use of a liquid, semi-solid, or solid growth medium, su ...
study, however, showed that all B
6 vitamers
Vitamins occur in a variety of related forms known as vitamers. A vitamer () of a particular vitamin is one of several related compounds that performs the functions of said vitamin and prevents the symptoms of deficiency of said vitamin.
Early r ...
that could be converted into active
coenzymes
A cofactor is a non-protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can be considered "helper molecules" that ass ...
(pyridoxal, pyridoxine and
pyridoxamine
Pyridoxamine is one form of vitamin B6. Chemically it is based on a pyridine ring structure, with hydroxyl, methyl, aminomethyl, and hydroxymethyl substituents. It differs from pyridoxine by the substituent at the 4-position. The hydroxyl at ...
) were
neurotoxic
Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specificall ...
at similar
concentrations
In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', ''molar concentration'', ''number concentration'', a ...
.
It has been shown,
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
, that supplementing with pyridoxal or pyridoxal phosphate increases pyridoxine concentrations in humans, meaning there are metabolic pathways from each vitamer of B
6 to the all other forms.
Consuming high amounts of vitamin B
6 from food has not been reported to cause adverse effects.
Early diagnosis and cessation of vitamin B
6 supplementation can reduce the
morbidity
A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
of the syndrome.
Cause
While vitamin B
6 is water-soluble, it has a half-life of 25–33 days and accumulates in the body where it is stored in
muscle,
plasma,
the liver,
red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
s and bound to proteins in tissues.
Potential mechanisms
The common supplemental form of vitamin B
6, pyridoxine, is similar to
pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with a ...
which can be neurotoxic. Pyridoxine has limited transport across the
blood–brain barrier explaining why the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
is spared.
Cell bodies of motor fibers are located within the
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the sp ...
that is also restricted by the blood-brain barrier explaining why motor impairment is rare. The
dorsal root ganglia
A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the dorsal ...
, however, are located outside of the blood-brain barrier making them more susceptible.
Pyridoxine is converted to pyridoxal phosphate via two
enzymes,
pyridoxal kinase and
pyridoxine 5′-phosphate oxidase. High levels of pyridoxine can inhibit these enzymes. As pyridoxal phosphate is the active form of vitamin B
6, this saturation of pyridoxine could mimic a deficiency of vitamin B
6.
Tolerable upper limits
Several government agencies have reviewed the data on vitamin B
6 supplementation and produced consumption upper limits with the desired goal to prevent sensory neuropathy from excessive amounts. Each agency developed its own criteria for usable studies in relation to tolerable upper limits, and as such the recommendations vary by agency. Between agencies, current tolerable upper limit guidelines vary from 10 mg per day to 100 mg per day.
Reviews of vitamin B
6 related neuropathy cautioned that supplementation at doses greater than 50 mg per day for extended periods of time may be harmful and should be discouraged.
In 2008, the Australian Complementary Medicines Evaluation Committee recommended warning statements appear on products containing daily doses of 50 mg or more vitamin B
6 to avoid toxicity.
The relationship between the amount of vitamin B
6 consumed, and serum the levels of those who consume it, varies between individuals.
Some people may have high serum concentrations without symptoms of neuropathy.
It is not known if inhalation of vitamin B
6 while, for example, working with
animal feed containing vitamin B
6 is safe.
Exceptions
High
parenteral
A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body.
Routes of administration are generally classified by the location at which the substance is applied. ...
doses of vitamin B
6 are used to treat
isoniazid
Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the treatment of tuberculosis. For active tuberculosis it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. For la ...
overdose with no adverse effects found,
although a
preservative
A preservative is a substance or a chemical that is added to products such as food products, beverages, pharmaceutical drugs, paints, biological samples, cosmetics, wood, and many other products to prevent decomposition by microbial growth or by ...
in parenteral vitamin B
6 may cause transient worsening of
metabolic acidosis
Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...
.
High doses of vitamin B
6 are used to treat
gyromitra mushroom (
false morel
The name false morel is given to several species of mushroom which bear a resemblance to the highly regarded true morels of the genus ''Morchella''. Like ''Morchella'', false morels are members of the Pezizales, but within that group represent se ...
) poisoning,
hydrazine exposure and
homocystinuria
Homocystinuria or HCU is an inherited disorder of the metabolism of the amino acid methionine due to a deficiency of cystathionine beta synthase or methionine synthase. It is an inherited autosomal recessive trait, which means a child needs to i ...
Doses of 50 mg to 100 mg per day may also be used to treat
pyridoxine deficient seizures and when patients are taking other medications that reduce vitamin B
6.
Daily doses of 10 mg to 50 mg are recommended for patients undergoing
hemodialysis
Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of waste products such as creatinin ...
.
Outside of rare medical conditions,
placebo-controlled studies
Placebo-controlled studies are a way of testing a medical therapy in which, in addition to a group of subjects that receives the treatment to be evaluated, a separate control group receives a sham "placebo" treatment which is specifically designed ...
have generally failed to show benefits of high doses of vitamin B
6.
Reviews of supplementing with vitamin B
6 have not found it to be effective at reducing swelling, reducing stress, producing energy, preventing neurotoxicity, or treating
asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...
.
A
Diagnosis
The clinical hallmark of megavitamin-B
6 syndrome is ataxia due to sensory
polyneuropathy. Blood tests are performed to rule out other causes and to confirm an elevated level of vitamin B
6 with an absence of
hypophosphatasia
Hypophosphatasia (; also called deficiency of alkaline phosphatase, phosphoethanolaminuria, or Rathbun's syndrome; sometimes abbreviated HPP) is a rare, and sometimes fatal, inherited metabolic bone disease. Clinical symptoms are heterogeneous, ...
.
Examination does not typically show signs of a
motor deficit, dysfunction of the
autonomic nervous system or impairment of the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
,
although in severe cases motor and
autonomic imparement can occur.
When examined, patients typically have diminished reflexes (
hyporeflexia
Hyporeflexia is the reduction or absence of normal bodily reflexes (areflexia). It can be detected through the use of a reflex hammer and is the opposite of hyperreflexia.
Hyporeflexia is generally associated with a deficit in the lower motor n ...
), such as a diminished response when performing an
ankle jerk reflex test.
Nerve conduction studies
A nerve conduction study (NCS) is a medical diagnostic test commonly used to evaluate the function, especially the ability of electrical conduction, of the motor and sensory nerves of the human body. These tests may be performed by medical spec ...
typically show normal motor conduction but decrease in large sensory wave amplitude in the arms and legs.
Needle
electromyography studies generally reveal no signs of
denervation
Denervation is any loss of nerve supply regardless of the cause. If the nerves lost to denervation are part of the neuronal communication to a specific function in the body then altered or a loss of physiological functioning can occur. Denervati ...
.
Classification
Megavitamin-B
6 syndrome is characterized mainly by degeneration of
dorsal root ganglion axons and
cell bodies,
although it also affects the
trigeminal ganglia.
It is classified as a sensory ganglionopathy due to involvement of these
ganglia.
In
electrodiagnostic testing,
it has characteristic non-length-dependent abnormalities of sensory
action potentials
An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells ...
that occur globally, rather than distally decreasing of sensory nerve action potential amplitudes.
Megavitamin-B
6 syndrome is predominately a large fiber neuropathy characterized by sensory loss of joint position, vibration and ataxia.
Although it has characteristics of
small fiber neuropathy in severe cases where there is impairment of pain, temperature, and
autonomic functions.
Treatment
The primary treatment for megavitamin-B
6 syndrome is to stop taking supplemental vitamin B
6.
Physical therapy, including
vestibular rehabilitation
Vestibular rehabilitation (VR), also known as vestibular rehabilitation therapy (VRT), is a specialized form of physical therapy used to treat vestibular disorders or symptoms, characterized by dizziness, vertigo, and trouble with balance, postu ...
, has been used in attempts to improve recovery following cessation of vitamin B
6 supplementation.
Medications such as
amitriptyline
Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat cyclic vomiting syndrome (CVS), major depressive disorder and a variety of pain syndromes from neuropathic pain to fibromyalgi ...
have been used to help with
neuropathic pain
Neuropathic pain is pain caused by damage or disease affecting the somatosensory system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuous ...
.
In experimental tests using animal subjects,
neurotrophic factors
Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their trop ...
, specifically
neurotrophin-3
Neurotrophin-3 is a protein that in humans is encoded by the ''NTF3'' gene.
The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activi ...
, were shown to potentially reverse the neuropathy caused from the vitamin B
6 toxicity.
With rats and mice, improvement has also been seen with
4-methylcatechol, a specific
chicory
Common chicory (''Cichorium intybus'') is a somewhat woody, perennial herbaceous plant of the family Asteraceae, usually with bright blue flowers, rarely white or pink. Native to the Old World, it has been introduced to North America and Austra ...
extract,
coffee
Coffee is a drink prepared from roasted coffee beans. Darkly colored, bitter, and slightly acidic, coffee has a stimulating effect on humans, primarily due to its caffeine content. It is the most popular hot drink in the world.
Seeds of ...
and
trigonelline.
Prognosis
Other than with extremely high doses of vitamin B
6, neurologic dysfunction improves following cessation of vitamin B
6 supplementation and usually, but not always, resolves within six months.
In cases of acute high doses, for example in people receiving daily doses of 2 grams of vitamin B
6 per kilogram of body weight, symptoms may be irreversible and may additionally cause
pseudoathetosis.
In the immediate 2–6 weeks following discontinuation of vitamin B
6, patients may experience a symptom progression before gradual improvement begins. This is known as ''coasting'' and is encountered in other toxic neuropathies.
A vitamin B
6 substance dependency may exist in daily dosages of 200 mg or more, making a
drug withdrawal
Drug withdrawal, drug withdrawal syndrome, or substance withdrawal syndrome, is the group of symptoms that occur upon the abrupt discontinuation or decrease in the intake of pharmaceutical or recreational drugs.
In order for the symptoms of wit ...
effect possible when discontinued.
See also
*
B vitamins
B vitamins are a class of water-soluble vitamins that play important roles in cell metabolism and synthesis of red blood cells. Though these vitamins share similar names (B1, B2, B3, etc.), they are chemically distinct compounds that often coexi ...
*
Dietary Reference Intake
The Dietary Reference Intake (DRI) is a system of nutrition recommendations from the National Academy of Medicine (NAM) of the National Academies (United States). It was introduced in 1997 in order to broaden the existing guidelines known as Re ...
*
Dietary supplement
*
Hypervitaminosis
Hypervitaminosis is a condition of abnormally high storage levels of vitamins, which can lead to various symptoms as over excitement, irritability, or even toxicity. Specific medical names of the different conditions are derived from the given vit ...
*
Hypervitaminosis A
Hypervitaminosis A refers to the toxic effects of ingesting too much preformed vitamin A (retinyl esters, retinol, and retinal). Symptoms arise as a result of altered bone metabolism and altered metabolism of other fat-soluble vitamins. Hyperv ...
*
Hypervitaminosis D
Vitamin D toxicity, or hypervitaminosis D is the toxic state of an excess of vitamin D. The normal range for blood concentration is 20 to 50 nanograms per milliliter (ng/mL). However, the toxic state is known to be a value of 100 ng/ml or more in ...
*
Megavitamin therapy
Megavitamin therapy is the use of large doses of vitamins, often many times greater than the recommended dietary allowance (RDA) in the attempt to prevent or treat diseases. Megavitamin therapy is typically used in alternative medicine by practit ...
*
Overnutrition
Overnutrition (also known as hyperalimentation) is a form of malnutrition in which the intake of nutrients is oversupplied. The amount of nutrients exceeds the amount required for normal growth, development, and metabolism.
The term can also ref ...
*
Peripheral nervous system
The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...
*
Regulation of alternative medicine
Notes
References
Further reading
* A chapter with a story about a woman experiencing a severe case of Megavitamin-B
6 syndrome titled "The Disembodied Lady" appears in Chapter 3 of ''
The Man Who Mistook His Wife for a Hat'':
* An
ethnographic
Ethnography (from Greek ''ethnos'' "folk, people, nation" and ''grapho'' "I write") is a branch of anthropology and the systematic study of individual cultures. Ethnography explores cultural phenomena from the point of view of the subject ...
study of an online support group for megavitamin B
6 syndrome appears in:
External links
StatPearls - Vitamin B6 Toxicity
{{Poisoning and toxicity
Effects of external causes
Hypervitaminosis
Syndromes