Gyromitrin
Encyclopedia
Gyromitrin is a toxin
and carcinogen
present in several members of the fungal genus
Gyromitra
, most notably the false morel
G. esculenta. It is unstable and is easily hydrolyzed
to the toxic compound monomethylhydrazine
, a component of some rocket fuels. Monomethylhydrazine acts on the central nervous system
and interferes with the normal use and function of Vitamin B6
. Poisoning results in nausea, stomach cramps, and diarrhea, while severe poisoning can result in convulsion
s, jaundice
, or even coma
or death. Exposure to monomethylhydrazine has been shown to be carcinogenic in small mammals.
, N-methyl-N-formylhydrazone was isolated by German scientists List and Luft and named gyromitrin. Each kilogram of fresh false morel had between 1.2 and 1.6 grams of the compound.
Gyromitrin is a volatile
water-soluble
hydrazine
compound hydrolyzed in the body into monomethylhydrazine
(MMH). Other N-methyl-N-formylhydrazone derivatives have been isolated in subsequent research, although they are present in smaller amounts. These other compounds would also produce monomethylhydrazine when hydrolyzed, although it remains unclear how much each contributes to the false morel's toxicity.
The toxins react with pyridoxal 5-phosphate—the activated form of pyridoxine
—and form a hydrazone
. This reduces production of the neurotransmitter GABA
via decreased activity of glutamic acid decarboxylase, which gives rise to the neurological symptoms. MMH also causes oxidative stress
leading to methemoglobinemia
. Additionally during the metabolism
of MMH, N-methyl-N-formylhydrazine is produced; this then undergoes cytochrome P450 regulated oxidative metabolism which via reactive nitrosamide intermediates leads to formation of methyl radicals which lead to liver necrosis
. Inhibition of diamine oxidase (histaminase) elevates histamine
levels, resulting in headaches, nausea, vomiting, and abdominal pain. Giving pyridoxine to rats poisoned with gyromitrin inhibited seizures, but did not prevent liver damage.
The toxicity of gyromitrin varies greatly according to the animal species being tested. The median lethal dose (LD50) is 244 mg/kg in mice, 50–70 mg/kg in rabbits, and 30–50 mg/kg in humans. The toxicity is largely due to the MMH that is created; about 35% of ingested gyromitrin is transformed to MMH. Based on this conversion, the LD50 of MMH in humans has been estimated to be 1.6–4.8 mg/kg in children, and 4.8–8 mg/kg in adults.
and several steps are available to remove gyromitrin from these mushrooms and allow their consumption. For North America, the toxin has been reliably reported from the species G. esculenta, G. gigas
, and G. fastigiata. Species in which gyromitrin's presence is suspected, but not proven, include G. californica, G. caroliniana
, G. korfi, and G. sphaerospora, in addition to Disciotis venosa
and Sarcosphaera coronaria. The possible presence of the toxin renders these species "suspected, dangerous, or not recommended" for consumption.
Gyromitrin content can differ greatly in different populations of the same species. For example, G. esculenta collected from Europe is "almost uniformly toxic", compared to rarer reports of toxicity from specimens collected from the United States west of the Rocky Mountains. A 1985 study reported that the stems
of G. esculenta contained twice as much gyromitrin than the cap
, and that mushrooms collected at higher altitudes contained less of the toxin than those collected at lower altitudes.
The gyromitrin content in false morels has been reported to be in the range of 40–732 milligrams of gyromitrin per kilogram of mushrooms (wet weight). Gyromitrin is volatile
and water soluble, and can be mostly removed from the mushrooms by cutting them to small pieces and repeatedly boiling them in copious amounts of water under good ventilation. Prolonged periods of air drying also reduces levels of the toxin. In the United States, there are typically between 30 and 100 cases of gyromitrin poisoning requiring medical attention; the mortality rate
for cases worldwide is about 10%.
, or the electrochemical
oxidation of hydrazine. These methods require large amounts of sample, are labor-intensive and unspecific. A 2006 study reported an analytical method
based on gas chromatography-mass spectrometry
with detection levels at the parts per billion level. The method, which involves acid hydrolysis
of gyromitrin followed by derivatization
with pentafluorobenzoyl chloride, has a minimum detectable concentration equivalent to 0.3 microgram
of gyromitrin per gram of dry matter.
, vomiting, and watery diarrhea
which may be bloodstained. Dehydration
may develop if the vomiting or diarrhea is severe. Dizziness, lethargy, vertigo
, tremor, ataxia
, nystagmus, and headaches develop soon after; fever
often occurs, a distinctive feature which does not develop after poisoning by other types of mushrooms. In most cases of poisoning, symptoms do not progress from these initial symptoms, and patients recover after 2–6 days of illness.
In some cases there may be an asymptomatic
phase following the initial symptoms which is then followed by more significant toxicity including kidney damage
, liver damage
, and neurological dysfunction
including seizures and coma. These signs usually develop within 1–3 days in serious cases. The patient develops jaundice
and the liver and spleen
become enlarged, in some cases blood sugar
levels will rise (hyperglycemia
) and then fall (hypoglycemia
) and liver toxicity is seen. Additionally, intravascular hemolysis
causes destruction of red blood cells resulting in increases in free hemoglobin and hemoglobinuria
, which can lead to renal toxicity or renal failure
. Methemoglobinemia
may also occur in some cases. This is where higher than normal levels of methemoglobin—a form of hemoglobin
that can not carry oxygen—are found in the blood. It causes the patient to become short of breath and cyanotic
. Cases of severe poisoning may progress to a terminal neurological phase, with delirium
, muscle fasciculation
s and seizures, and mydriasis
progressing to coma
, circulatory collapse, and respiratory arrest
. Death may occur from five to seven days after consumption.
Toxic effects from gyromitrin may also be accumulated from sub-acute and chronic exposure due to "professional handling"; symptoms include pharyngitis
, bronchitis
, and keratitis
.
; gastric decontamination with activated charcoal may be beneficial if medical attention is sought within a few hours of consumption. However, symptoms often take longer than this to develop, and patients do not usually present for treatment until many hours after ingestion, thus limiting its effectiveness. Patients with severe vomiting or diarrhea can be rehydrated with intravenous
fluids. Monitoring of biochemical parameters such as methemoglobin levels, electrolytes, liver and kidney function, urinalysis
, and complete blood count
is undertaken and any abnormalities are corrected. Dialysis
can be used if kidney function is impaired or the kidneys are failing. Hemolysis may require a blood transfusion
to replace the lost red blood cells, while methemoglobinemia
is treated with intravenous methylene blue
.
Pyridoxine, also known as vitamin B6
, can be used to counteract the inhibition
by MMH on the pyridoxine-dependent step in the synthesis of the neurotransmitter
GABA
. Thus GABA synthesis can continue and symptoms are relieved. Pyridoxine, which is only useful for the neurological symptoms and does not decrease hepatic toxicity, is given at a dose of 25 mg/kg; this can be repeated up to a maximum total of 15 to 30 g daily if symptoms do not improve. Benzodiazepine
s are given to control seizures; as they also modulate GABA receptors they may potentially increase the effect of pyridoxine. Additionally MMH inhibits the chemical transformation of folic acid
into its active form, folinic acid
, this can be treated by folinic acid given at 20–200 mg daily.
ic in experimental animals. Although Gyromitra esculenta has not been observed to cause cancer in humans, it is possible there is a carcinogenic risk for people who ingest these types of mushrooms. The toxins may be cumulative and even small amounts may have a carcinogenic effect. At least 11 different hydrazines have been isolated from Gyromitra esculenta, and it is not known if the potential carcinogens can be completely removed by parboiling.
Toxin
A toxin is a poisonous substance produced within living cells or organisms; man-made substances created by artificial processes are thus excluded...
and carcinogen
Carcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
present in several members of the fungal genus
Genus
In biology, a genus is a low-level taxonomic rank used in the biological classification of living and fossil organisms, which is an example of definition by genus and differentia...
Gyromitra
Gyromitra
Gyromitra is a genus of ascomycete mushrooms found in the northern hemisphere. The most famous member is the controversial false morel ...
, most notably the false morel
False morel
Gyromitra esculenta , one of several species of fungi known as false morels, is an ascomycete fungus from the genus Gyromitra, widely distributed across Europe and North America. It normally sprouts in sandy soils under coniferous trees in spring and early summer...
G. esculenta. It is unstable and is easily hydrolyzed
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
to the toxic compound monomethylhydrazine
Monomethylhydrazine
Monomethylhydrazine is a volatile hydrazine chemical with the chemical formula CH3 NH2. It is used as a rocket propellant in bipropellant rocket engines because it is hypergolic with various oxidizers such as nitrogen tetroxide and nitric acid...
, a component of some rocket fuels. Monomethylhydrazine acts on the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
and interferes with the normal use and function of Vitamin B6
Vitamin B6
Vitamin B6 is a water-soluble vitamin and is part of the vitamin B complex group. Several forms of the vitamin are known, but pyridoxal phosphate is the active form and is a cofactor in many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation...
. Poisoning results in nausea, stomach cramps, and diarrhea, while severe poisoning can result in convulsion
Convulsion
A convulsion is a medical condition where body muscles contract and relax rapidly and repeatedly, resulting in an uncontrolled shaking of the body. Because a convulsion is often a symptom of an epileptic seizure, the term convulsion is sometimes used as a synonym for seizure...
s, jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
, or even coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
or death. Exposure to monomethylhydrazine has been shown to be carcinogenic in small mammals.
History
Poisonings related to consumption of the false morel Gyromitra esculenta, a highly regarded fungus eaten mainly in Finland and by some in parts of Europe and North America, had been reported for at least a hundred years. Experts speculated the reaction was more of an allergic one specific to the consumer, or a misidentification, rather than innate toxicity of the fungus, due to the wide range in effects seen. Some would suffer severely or perish while others exhibited no symptoms after eating similar amounts of mushrooms from the same dish. Yet others would be poisoned after eating the fungus for many years without ill-effects. In 1885, Böhm and Külz described helvellic acid, an oily substance they believed to be responsible for the toxicity of the fungus. The identity of the toxic constituents of Gyromitra species eluded researchers until 1968, when an acetaldehydeAcetaldehyde
Acetaldehyde is an organic chemical compound with the formula CH3CHO or MeCHO. It is one of the most important aldehydes, occurring widely in nature and being produced on a large scale industrially. Acetaldehyde occurs naturally in coffee, bread, and ripe fruit, and is produced by plants as part...
, N-methyl-N-formylhydrazone was isolated by German scientists List and Luft and named gyromitrin. Each kilogram of fresh false morel had between 1.2 and 1.6 grams of the compound.
Mechanism of toxicity
Volatility (chemistry)
In chemistry and physics, volatility is the tendency of a substance to vaporize. Volatility is directly related to a substance's vapor pressure. At a given temperature, a substance with higher vapor pressure vaporizes more readily than a substance with a lower vapor pressure.The term is primarily...
water-soluble
Solubility
Solubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the solute in the solvent. The solubility of a substance fundamentally depends on the used solvent as well as on...
hydrazine
Hydrazine
Hydrazine is an inorganic compound with the formula N2H4. It is a colourless flammable liquid with an ammonia-like odor. Hydrazine is highly toxic and dangerously unstable unless handled in solution. Approximately 260,000 tons are manufactured annually...
compound hydrolyzed in the body into monomethylhydrazine
Monomethylhydrazine
Monomethylhydrazine is a volatile hydrazine chemical with the chemical formula CH3 NH2. It is used as a rocket propellant in bipropellant rocket engines because it is hypergolic with various oxidizers such as nitrogen tetroxide and nitric acid...
(MMH). Other N-methyl-N-formylhydrazone derivatives have been isolated in subsequent research, although they are present in smaller amounts. These other compounds would also produce monomethylhydrazine when hydrolyzed, although it remains unclear how much each contributes to the false morel's toxicity.
The toxins react with pyridoxal 5-phosphate—the activated form of pyridoxine
Pyridoxine
Pyridoxine is one of the compounds that can be called vitamin B6, along with pyridoxal and pyridoxamine. It differs from pyridoxamine by the substituent at the '4' position. It is often used as 'pyridoxine hydrochloride'.-Chemistry:...
—and form a hydrazone
Hydrazone
Hydrazones are a class of organic compounds with the structure R1R2C=NNH2. They are related to ketones and aldehydes by the replacement of the oxygen with the NNH2 functional group...
. This reduces production of the neurotransmitter GABA
Gamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
via decreased activity of glutamic acid decarboxylase, which gives rise to the neurological symptoms. MMH also causes oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
leading to methemoglobinemia
Methemoglobinemia
Methemoglobinemia is a disorder characterized by the presence of a higher than normal level of methemoglobin in the blood. Methemoglobin is an oxidized form of hemoglobin that has an increased affinity for oxygen, resulting in a reduced ability to release oxygen to tissues. The oxygen–hemoglobin...
. Additionally during the metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
of MMH, N-methyl-N-formylhydrazine is produced; this then undergoes cytochrome P450 regulated oxidative metabolism which via reactive nitrosamide intermediates leads to formation of methyl radicals which lead to liver necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
. Inhibition of diamine oxidase (histaminase) elevates histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
levels, resulting in headaches, nausea, vomiting, and abdominal pain. Giving pyridoxine to rats poisoned with gyromitrin inhibited seizures, but did not prevent liver damage.
The toxicity of gyromitrin varies greatly according to the animal species being tested. The median lethal dose (LD50) is 244 mg/kg in mice, 50–70 mg/kg in rabbits, and 30–50 mg/kg in humans. The toxicity is largely due to the MMH that is created; about 35% of ingested gyromitrin is transformed to MMH. Based on this conversion, the LD50 of MMH in humans has been estimated to be 1.6–4.8 mg/kg in children, and 4.8–8 mg/kg in adults.
Occurrence and removal
Several Gyromitra species are traditionally considered very good ediblesEdible mushroom
Edible mushrooms are the fleshy and edible fruiting bodies of several species of fungi. Mushrooms belong to the macrofungi, because their fruiting structures are large enough to be seen with the naked eye. They can appear either below ground or above ground where they may be picked by hand...
and several steps are available to remove gyromitrin from these mushrooms and allow their consumption. For North America, the toxin has been reliably reported from the species G. esculenta, G. gigas
Gyromitra gigas
Gyromitra gigas, commonly known as the snow morel, snow false morel, calf brain, or bull nose, is a fungus and a member of the Ascomycota. G. gigas is found in Europe, western North America where it is common in mountainous areas in coniferous forests, and eastern North America where it is found...
, and G. fastigiata. Species in which gyromitrin's presence is suspected, but not proven, include G. californica, G. caroliniana
Gyromitra caroliniana
Gyromitra caroliniana, known colloquially as big red in Missouri and Kansas, is an ascomycete fungus of the genus Gyromitra, found in the southeastern United States. Growing to large sizes, it is found in spring and is collected and eaten by some. However, there is some suggestion it may contain...
, G. korfi, and G. sphaerospora, in addition to Disciotis venosa
Disciotis venosa
Disciotis venosa, commonly known as the veiny cup fungus, or the cup morel, is a species of fungus in the Morchellaceae family. Fruiting in April and May, they are often difficult to locate because of their nondescript brown color. Found in North America and Europe, they appear to favor banks and...
and Sarcosphaera coronaria. The possible presence of the toxin renders these species "suspected, dangerous, or not recommended" for consumption.
Gyromitrin content can differ greatly in different populations of the same species. For example, G. esculenta collected from Europe is "almost uniformly toxic", compared to rarer reports of toxicity from specimens collected from the United States west of the Rocky Mountains. A 1985 study reported that the stems
Stipe (mycology)
thumb|150px|right|Diagram of a [[basidiomycete]] stipe with an [[annulus |annulus]] and [[volva |volva]]In mycology a stipe refers to the stem or stalk-like feature supporting the cap of a mushroom. Like all tissues of the mushroom other than the hymenium, the stipe is composed of sterile hyphal...
of G. esculenta contained twice as much gyromitrin than the cap
Pileus (mycology)
The pileus is the technical name for the cap, or cap-like part, of a basidiocarp or ascocarp that supports a spore-bearing surface, the hymenium. The hymenium may consist of lamellae, tubes, or teeth, on the underside of the pileus...
, and that mushrooms collected at higher altitudes contained less of the toxin than those collected at lower altitudes.
The gyromitrin content in false morels has been reported to be in the range of 40–732 milligrams of gyromitrin per kilogram of mushrooms (wet weight). Gyromitrin is volatile
Volatile organic compound
Volatile organic compounds are organic chemicals that have a high vapor pressure at ordinary, room-temperature conditions. Their high vapor pressure results from a low boiling point, which causes large numbers of molecules to evaporate or sublimate from the liquid or solid form of the compound and...
and water soluble, and can be mostly removed from the mushrooms by cutting them to small pieces and repeatedly boiling them in copious amounts of water under good ventilation. Prolonged periods of air drying also reduces levels of the toxin. In the United States, there are typically between 30 and 100 cases of gyromitrin poisoning requiring medical attention; the mortality rate
Mortality rate
Mortality rate is a measure of the number of deaths in a population, scaled to the size of that population, per unit time...
for cases worldwide is about 10%.
Detection
The early methods developed for the determination of gyromitrin concentration in mushroom tissue were based on thin-layer chromatography and spectrofluorometryFluorescence spectroscopy
Fluorescence spectroscopy aka fluorometry or spectrofluorometry, is a type of electromagnetic spectroscopy which analyzes fluorescence from a sample. It involves using a beam of light, usually ultraviolet light, that excites the electrons in molecules of certain compounds and causes them to emit...
, or the electrochemical
Electrochemistry
Electrochemistry is a branch of chemistry that studies chemical reactions which take place in a solution at the interface of an electron conductor and an ionic conductor , and which involve electron transfer between the electrode and the electrolyte or species in solution.If a chemical reaction is...
oxidation of hydrazine. These methods require large amounts of sample, are labor-intensive and unspecific. A 2006 study reported an analytical method
Analytical chemistry
Analytical chemistry is the study of the separation, identification, and quantification of the chemical components of natural and artificial materials. Qualitative analysis gives an indication of the identity of the chemical species in the sample and quantitative analysis determines the amount of...
based on gas chromatography-mass spectrometry
Gas chromatography-mass spectrometry
Gas chromatography–mass spectrometry is a method that combines the features of gas-liquid chromatography and mass spectrometry to identify different substances within a test sample. Applications of GC-MS include drug detection, fire investigation, environmental analysis, explosives investigation,...
with detection levels at the parts per billion level. The method, which involves acid hydrolysis
Acid hydrolysis
Acid hydrolysis is a chemical process in which acid is used to convert cellulose or starch to sugar.It implies a chemical mechanism of hydrolysis catalyzed by a Brønsted-Lowry or Arrhenius acid. By contrast, it does not usually imply hydrolysis by direct electrophilic attack—as may originate from...
of gyromitrin followed by derivatization
Derivative (chemistry)
In chemistry, a derivative is a compound that is derived from a similar compound by some chemical or physical process. In the past it was also used to mean a compound that can be imagined to arise from another compound, if one atom is replaced with another atom or group of atoms, but modern...
with pentafluorobenzoyl chloride, has a minimum detectable concentration equivalent to 0.3 microgram
Microgram
In the metric system, a microgram is a unit of mass equal to one millionth of a gram , or 1/1000 of a milligram. It is one of the smallest units of mass commonly used...
of gyromitrin per gram of dry matter.
Symptoms
The symptoms of poisoning are typically gastrointestinal and neurological. Symptoms occur within 6–12 hours of consumption, although cases of more severe poisoning may present sooner—as little as 2 hours after ingestion. Initial symptoms are gastrointestinal, with sudden onset of nauseaNausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, vomiting, and watery diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
which may be bloodstained. Dehydration
Dehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...
may develop if the vomiting or diarrhea is severe. Dizziness, lethargy, vertigo
Vertigo (medical)
Vertigo is a type of dizziness, where there is a feeling of motion when one is stationary. The symptoms are due to a dysfunction of the vestibular system in the inner ear...
, tremor, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, nystagmus, and headaches develop soon after; fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
often occurs, a distinctive feature which does not develop after poisoning by other types of mushrooms. In most cases of poisoning, symptoms do not progress from these initial symptoms, and patients recover after 2–6 days of illness.
In some cases there may be an asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
phase following the initial symptoms which is then followed by more significant toxicity including kidney damage
Nephrotoxicity
Nephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidneys. There are various forms of toxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the...
, liver damage
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
, and neurological dysfunction
Neurotoxicity
Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neurons, key cells that transmit and process...
including seizures and coma. These signs usually develop within 1–3 days in serious cases. The patient develops jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
and the liver and spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
become enlarged, in some cases blood sugar
Blood sugar
The blood sugar concentration or blood glucose level is the amount of glucose present in the blood of a human or animal. Normally in mammals, the body maintains the blood glucose level at a reference range between about 3.6 and 5.8 mM , or 64.8 and 104.4 mg/dL...
levels will rise (hyperglycemia
Hyperglycemia
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
) and then fall (hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
) and liver toxicity is seen. Additionally, intravascular hemolysis
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
causes destruction of red blood cells resulting in increases in free hemoglobin and hemoglobinuria
Hemoglobinuria
In medicine, hemoglobinuria or haemoglobinuria is a condition in which the oxygen transport protein hemoglobin is found in abnormally high concentrations in the urine. The condition is often associated with hemolytic anemia, in which red blood cells are destroyed, thereby increasing levels of free...
, which can lead to renal toxicity or renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
. Methemoglobinemia
Methemoglobinemia
Methemoglobinemia is a disorder characterized by the presence of a higher than normal level of methemoglobin in the blood. Methemoglobin is an oxidized form of hemoglobin that has an increased affinity for oxygen, resulting in a reduced ability to release oxygen to tissues. The oxygen–hemoglobin...
may also occur in some cases. This is where higher than normal levels of methemoglobin—a form of hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
that can not carry oxygen—are found in the blood. It causes the patient to become short of breath and cyanotic
Cyanosis
Cyanosis is the appearance of a blue or purple coloration of the skin or mucous membranes due to the tissues near the skin surface being low on oxygen. The onset of cyanosis is 2.5 g/dL of deoxyhemoglobin. The bluish color is more readily apparent in those with high hemoglobin counts than it is...
. Cases of severe poisoning may progress to a terminal neurological phase, with delirium
Delirium
Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...
, muscle fasciculation
Fasciculation
A fasciculation , or "muscle twitch", is a small, local, involuntary muscle contraction and relaxation visible under the skin arising from the spontaneous discharge of a bundle of skeletal muscle fibers...
s and seizures, and mydriasis
Mydriasis
Mydriasis is a dilation of the pupil due to disease, trauma or the use of drugs. Normally, the pupil dilates in the dark and constricts in the light to respectively improve vividity at night and to protect the retina from sunlight damage during the day...
progressing to coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
, circulatory collapse, and respiratory arrest
Respiratory arrest
Respiratory arrest is the cessation of breathing. It is a medical emergency and it usually is related to or coincides with a cardiac arrest. Causes include opiate overdose, head injury, anaesthesia, tetanus, or drowning...
. Death may occur from five to seven days after consumption.
Toxic effects from gyromitrin may also be accumulated from sub-acute and chronic exposure due to "professional handling"; symptoms include pharyngitis
Pharyngitis
Pharyngitis is an inflammation of the throat or pharynx. In most cases it is quite painful, and is the most common cause of a sore throat.Like many types of inflammation, pharyngitis can be acute – characterized by a rapid onset and typically a relatively short course – or chronic....
, bronchitis
Bronchitis
Acute bronchitis is an inflammation of the large bronchi in the lungs that is usually caused by viruses or bacteria and may last several days or weeks. Characteristic symptoms include cough, sputum production, and shortness of breath and wheezing related to the obstruction of the inflamed airways...
, and keratitis
Keratitis
Keratitis is a condition in which the eye's cornea, the front part of the eye, becomes inflamed. The condition is often marked by moderate to intense pain and usually involves impaired eyesight.-Types:...
.
Treatment
Treatment is mainly supportiveTherapy
This is a list of types of therapy .* Adventure therapy* Animal-assisted therapy* Aquatic therapy* Aromatherapy* Art and dementia* Art therapy* Authentic Movement* Behavioral therapy* Bibliotherapy* Buteyko Method* Chemotherapy...
; gastric decontamination with activated charcoal may be beneficial if medical attention is sought within a few hours of consumption. However, symptoms often take longer than this to develop, and patients do not usually present for treatment until many hours after ingestion, thus limiting its effectiveness. Patients with severe vomiting or diarrhea can be rehydrated with intravenous
Intravenous therapy
Intravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...
fluids. Monitoring of biochemical parameters such as methemoglobin levels, electrolytes, liver and kidney function, urinalysis
Urinalysis
A urinalysis , also known as Routine and Microscopy , is an array of tests performed on urine, and one of the most common methods of medical diagnosis...
, and complete blood count
Complete blood count
A complete blood count , also known as full blood count or full blood exam or blood panel, is a test panel requested by a doctor or other medical professional that gives information about the cells in a patient's blood...
is undertaken and any abnormalities are corrected. Dialysis
Hemodialysis
In medicine, hemodialysis is a method for removing waste products such as creatinine and urea, as well as free water from the blood when the kidneys are in renal failure. Hemodialysis is one of three renal replacement therapies .Hemodialysis can be an outpatient or inpatient therapy...
can be used if kidney function is impaired or the kidneys are failing. Hemolysis may require a blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
to replace the lost red blood cells, while methemoglobinemia
Methemoglobinemia
Methemoglobinemia is a disorder characterized by the presence of a higher than normal level of methemoglobin in the blood. Methemoglobin is an oxidized form of hemoglobin that has an increased affinity for oxygen, resulting in a reduced ability to release oxygen to tissues. The oxygen–hemoglobin...
is treated with intravenous methylene blue
Methylene blue
Methylene blue is a heterocyclic aromatic chemical compound with the molecular formula C16H18N3SCl. It has many uses in a range of different fields, such as biology and chemistry. At room temperature it appears as a solid, odorless, dark green powder, that yields a blue solution when dissolved in...
.
Pyridoxine, also known as vitamin B6
Vitamin B6
Vitamin B6 is a water-soluble vitamin and is part of the vitamin B complex group. Several forms of the vitamin are known, but pyridoxal phosphate is the active form and is a cofactor in many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation...
, can be used to counteract the inhibition
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
by MMH on the pyridoxine-dependent step in the synthesis of the neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
GABA
Gamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
. Thus GABA synthesis can continue and symptoms are relieved. Pyridoxine, which is only useful for the neurological symptoms and does not decrease hepatic toxicity, is given at a dose of 25 mg/kg; this can be repeated up to a maximum total of 15 to 30 g daily if symptoms do not improve. Benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s are given to control seizures; as they also modulate GABA receptors they may potentially increase the effect of pyridoxine. Additionally MMH inhibits the chemical transformation of folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
into its active form, folinic acid
Folinic acid
Folinic acid or leucovorin , generally administered as calcium or sodium folinate , is an adjuvant used in cancer chemotherapy involving the drug methotrexate. It is also used in synergistic combination with the chemotherapy agent 5-fluorouracil.Levofolinic acid and its salts are the enantiopure...
, this can be treated by folinic acid given at 20–200 mg daily.
Carcinogenicity
Monomethylhydrazine, as well as its precursors methylformylhydrazine and gyromitrin and raw Gyromitra esculenta, have been shown to be carcinogenCarcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
ic in experimental animals. Although Gyromitra esculenta has not been observed to cause cancer in humans, it is possible there is a carcinogenic risk for people who ingest these types of mushrooms. The toxins may be cumulative and even small amounts may have a carcinogenic effect. At least 11 different hydrazines have been isolated from Gyromitra esculenta, and it is not known if the potential carcinogens can be completely removed by parboiling.