Pathogenesis of Select Types of Poisoning

Poisoning is an acute pathological state caused by the effects of ingested, inhaled, or otherwise absorbed toxic substances on the body.

Cyanide

Cyanides are a family of hydrocyanic acid salts containing the cyanide anion CN⁻. Especially when they are soluble, they act as rapid, aggressive poisons that block the body's ability to use oxygen by disrupting cellular respiration.[1]

Entry & Sources

Cyanide enters the body by ingestion, inhalation, injection, or absorption through the skin.[1] Symptom onset is quickest with inhalation, usually in the form of hydrogen cyanide gas.[2]

Poisoning caused by direct exposure to cyanide salts is usually linked to potassium and/or sodium cyanide involved in industrial processes. Particular high-risk industries are those involved with the mining of metals, electroplating, and plastic and textile production. Occupational exposures and industrial accidents are considered to be the most significant risks of cyanide poisoning in general, with the potential of causing environmental contamination attributed to improper material handling and waste disposal. Workers of these industries are at an elevated risk of poisoning through inhalation or skin exposure, and workplaces must ensure responsible enforcement of handling protocols and PPE usage.[2]

In household exposure cases, there are two main culprits of cyanide poisoning: hydrogen cyanide in household pesticides/rodenticides and cyanogenic glycosides in some edible plants.[2] The use of hydrogen cyanide as a domestic rodenticide is highly regulated in the EU, and is restricted to professional use under strict conditions: 

Hydrogen cyanide for use #7* shows significant economic and practical disadvantages compared to anticoagulant rodenticides. Products containing hydrogen cyanide are fumigants with very strict use conditions for operators and by-standers. Fumigation is limited to situations where the temperature is above 12 °C. It is expected that the use of hydrogen cyanide would lead to disproportionate costs to mitigate their risks.[3]
Cassava plant

* "Use #7" refers to the usage of rodenticides against house mice, brown rats, and roof rats, which is limited to indoor usage by trained professionals.

Cyanogenic glycosides are plant compounds that, upon hydrolysis by the body's enzymes, can release hydrogen cyanide.[4] Similarly to capsaicin in spicy peppers, these glycosides are an evolutionary defensive mechanism of plants against herbivores to deter consumption. Cyanogenic glycosides are quite common across different plant species, with the largest human agricultural sources being found in the seeds of apples, almonds, flax, apricots, cassava, and many grains such as wheat and barley.[2][4] The most significant of these is the cassava plant, as demonstrated in tropical nations with more plant-based diets where many complications of sub-acute, prolonged cyanide exposure arise. These include konzo disease, mantakassa, and tropical ataxic neuropathy.[4]

Less commonly, cyanide toxicity is the result of intentional criminal acts of targeted poisoning or terrorism.[2]

Pathogenesis

The direct danger of cyanide poisoning is its consequence of histotoxic hypoxia/anoxia and cellular asphyxiation through the blockage of cytochrome c oxidase and, by extension, cellular respiration.[5] Cytochrome c oxidase, also referred to as complex IV of the electron transport chain, is composed of heme groups and copper centers. It uses molecular oxygen as an electron acceptor to oxidize cytochrome c as the last step of the ETC. Cyanide has a high affinity for Fe3+, and irreversibly binds to it in the heme groups of cytochrome c oxidase, disabling it from accepting the electrons of cytochrome c.[6] In this way, the electron transport chain is shut down, and ATP synthesis cannot proceed.

The brain relies almost entirely on aerobic metabolism for its ATP demands, and when it is unable to use oxygen, the cells lose their ability to maintain ion transport, proteosynthesis, and membrane potentials. The consequences of these deficits are cellular swelling and impairment of neuronal signaling/impulse transmission. Similarly, cardiac muscle is heavily dependent on aerobic generation of ATP, and experiences similar consequences of membrane impairment, proteosynthesis deficits, and cellular swelling and damage under the effects of cyanide poisoning. The cellular shift to anaerobic metabolism also leads to excessive production of lactate and the development of metabolic acidosis.[6] These mechanisms directly correspond to the symptoms of cyanide poisoning, which are largely cardiovascular and neurological.

Symptoms

Typical symptoms of cyanide poisoning include pain or tightness in the chest, dyspnea, brady- or tachypnea, brady- or tachycardia, dizziness, disorientation, weakness, restlessness, headache, nausea, and vomiting. More seriously and in larger doses, the person may experience changes in blood pressure and consciousness, lung injury, seizures, coma, and/or death. Survivors may continue to experience the consequences of cardiac, cerebral, and nerve damage.[7]

While the typical clinical presentation of cyanide poisoning is characterized by symptoms like tonic-clonic seizures, coma, collapse, cardiac symptoms, and the typical odor of almonds, the symptoms developing after exposure are fairly dose-dependent:[5]

Dose-Symptom Relationship in Cyanide Poisoning
Dose Symptoms
Low Tachypnea, weakness, dizziness, nausea, headache
Medium As above, in addition to palpitations, disorientation, dyspnea, vomiting
High Rapid death, usually preceded by coma, convulsions, arrhythmia, and/or respiratory arrest

Treatment

Thiosulfate & Hydroxocobalamin

The mitochondria contain an enzyme called rhodanese, or thiosulfate sulfurtransferase, which catalyzes sulfur donation. Upon intravenous administration of thiosulfate, rhodanese takes the sulfane sulfur atoms and attaches them to cyanide anions. The resulting molecule is called thiocyanate, and is significantly less reactive than cyanide. Thiocyanate is then readily excreted in the urine.[6][8]

Alternatively, hydroxocobalamin (a precursor to vitamin B12) is used. Hydroxocobalamin binds readily to cyanide, and the resulting cyanocobalamin is also known as vitamin B12.[6] As a water-soluble vitamin, excess cyanocobalamin is simply excreted in urine with little to no toxicity.

Nitrites

Clinically, sodium or amyl nitrite can be used to treat cyanide poisoning. These nitrite compounds work by oxidizing the ferrous iron (Fe2+) of hemoglobin into the ferric (Fe3+) form, creating methemoglobin. Cyanide binds more readily to methemoglobin than to cytochrome c oxidase. Methemoglobin consequently binds cyanide before it can block cellular respiration, clearing it from the blood and allowing ATP synthesis to proceed as normal.[6] The resulting cyanomethemoglobin is nontoxic, and the hemoglobin can be recycled by the body once broken down in the liver or spleen. However, this treatment approach is less preferred due to its dose-limiting toxicity, as methemoglobin cannot efficiently carry oxygen in the blood. Nitrite therapy is to be avoided in patients with already diminished oxygen-carrying capacity.[9]

Organophosphates

Organophosphates are potent inhibitors of cholinesterase found commonly in insecticides. They are also used clinically to treat neuromuscular blockade, or in chemical warfare (namely Sarin) as nerve agents.[10]

Entry & Sources

Organophosphate poisoning is usually linked to improper handling of insecticidal preparations and, to a lesser degree, medical interventions or crimes of war and terrorism. Organophosphates can be absorbed through the skin, lungs, and the gastrointestinal tract.[11]

Pathogenesis

Cholinergic receptors are nerve receptors that bind acetylcholine. These are the receptors of cholinergic synapses involved in both the central and peripheral nervous system. They serve both excitatory and inhibitory functions depending on the specific subtype of receptor. Of these, the two main groups are nicotinic and muscarinic. Nicotinic receptors act excitatorily at the neuromuscular junction of skeletal muscle, as well as in autonomic ganglia and the adrenal medulla where catecholamines are secreted. On the other hand, muscarinic receptors are ubiquitous in the body, and as such are divided into 5 subtypes, some of which are inhibitory.

Acetylcholinesterase is an enzyme that catalyzes the hydrolysis of acetylcholine in the nerve synapse:

Pinpoint pupils, typical also for opiate intoxication

Choline is then taken back into the pre-synaptic neuron. Without this crucial reaction, acetylcholine builds up in the synapses and continues to propagate the neuronal impulses.

Organophosphates attach irreversibly to acetylcholinesterase, inhibiting it and allowing acetylcholine to build up. The accumulation of ACh in nerve synapses causes mass activation of both nicotinic and muscarinic cholinergic receptors.[11] The symptomology of organophosphate poisoning consists of the immediate effects of cholinergic overactivation.

Symptoms

The symptoms of acute organophosphate poisoning are divided into two groups, nicotinic and muscarinic, based on the receptor causing the symptom: 

Muscarinic cholinergic symptoms: Salivation, lacrimation, urination, defecation, vomiting, pinpoint pupils (miosis), bronchorrhea and wheezing, bradycardia
Nicotinic cholinergic symptoms: Mydriasis, tachycardia, weakness and fasciculations, sweating, abdominal pain
Of these manifestations, muscle fasciculations and weakness are typical. Respiratory findings include rhonchi, wheezing, and hypoxia, which may be severe. Most patients have bradycardia and, if poisoning is severe, hypotension. Central nervous system toxicity is common, sometimes with seizures and excitability and often with lethargy and coma. Pancreatitis is possible, and organophosphates may cause arrhythmias such as heart block and QTc interval prolongation.[11]

Students often remember the most important symptoms of muscarinic overactivation with the following mnemonic:

DUMBBELS = Defecation, Urination, Miosis, Bronchorrhea/Bronchospasm, Bradycardia, Emesis, Lacrimation, Salivation.

Treatment

To treat organophosphate poisoning, a combination of atropine and pralidoxime is used. Benzodiazepines are sometimes also given to relieve cramps and seizures.

Atropine

Atropine is an acetylcholine antagonist that is given either intravenously, or intramuscularly/intraosseously for milder cases. It competitively binds muscarinic receptors in neuronal synapses, inhibiting acetylcholine.[12] This mechanism however does not actually contribute to the breakdown of the built up acetylcholine, nor does it reverse nicotinic symptoms.

Pralidoxime

Pralidoxime is a reactivator of acetylcholinesterase that is given intravenously or intramuscularly to alleviate the nicotinic symptoms (namely respiratory and other muscle weakness and fasciculations) and clear the excess acetylcholine from synapses.[13]

Carbon Monoxide

Carbon monoxide is a colorless, odorless, tasteless gas that can lead to deadly outcomes on exposure by blocking the body's ability to transport and utilize oxygen.

Entry & Sources

Oxygen-Hemoglobin dissociation curve; CO causes the curve to shift to the left

Carbon monoxide gas enters circulation similarly to oxygen, by inhalation and gas exchange across the alveolar membrane. Exposure is usually tied to inhaling fire and smoke, or products of incomplete combustion of coal, petrol, or other gases and materials.[14]

Pathogenesis

Hemoglobin (Hb) is an oxygen-transporting molecule of the body that essentially binds oxygen where it is abundant in a tissue, and releases it in more oxygen-deprived tissues (see the image of the oxygen dissociation curve). In the alveolar capillaries where oxygen from the environment is abundant, hemoglobin binds a lot of oxygen. When it then reaches tissues with high demands in need of more oxygen, it releases the molecules it is carrying.

Different things can influence the avidity of hemoglobin to oxygen, i.e., its ability to effectively bind oxygen. Carbon monoxide binds hemoglobin with an avidity 200-300x greater than that of oxygen, forming carboxyhemoglobin (COHb). The dissociation curve of COHb is shifted to the left, with a lower maximum capacity for oxygen saturation. This is due to two mechanisms:

  1. More of hemoglobin's 4 binding sites are occupied by CO, decreasing the sites available for oxygen and lowering the possible maximum percentage of oxygen saturation, and
  2. Hemoglobin binding exhibits a phenomenon called cooperative binding, where the binding of a molecule to the first of the 4 binding sites increases the affinity of the remaining 3, meaning that once CO binds to a hemoglobin molecule, the COHb clings more eagerly to any oxygen molecule it binds to next.

Not only is there then less oxygen being carried by the hemoglobin (and subsequently to the tissues), but the COHb is now less inclined to release any of its bound oxygen to the tissues in need. This is an example of anemic hypoxia, where there is "insufficient oxygen supply to tissues relative to their metabolic needs" due to "reduced Hb or reduced transport capacity.[5]" Body metabolism shifts to anaerobic processes and lactic acid production despite the outer environmental availability of oxygen.

Symptoms

Symptom severity and progression depend on the amount of CO inhaled and the time since exposure, but classic symptoms are as follows: 

Headache 
Dizziness  
Nausea  
Changes to mental status; confusion, loss of consciousness, coma  
Tachycardia  
Hypotension  
Cherry red nail beds and mucous membranes (only seen post-mortem) 
Retinal haemorrhages  
Papilloedema[14]

N.B.: Cherry red discoloration is a clinical clue and keyword often referred to in academic case studies and tests.

Bedside examinations in the case of CO poisoning are misleading, because regular pulse oximeters do not distinguish between oxygen and CO saturation, and will return normal values. The reliable alternative is arterial blood gas or CO-oximetry. Additionally, the patient will exhibit elevated serum lactate.

Treatment

The first step when someone suspects CO poisoning is to always move to an area of fresh air to limit exposure. Treatment is composed of administration of 100% oxygen, which allows for oxygen to compete with CO for hemoglobin binding. In severe cases, hyperbaric oxygen therapy is considered, as binding of hemoglobin to oxygen is higher at higher O2 partial pressures. Hyperbaric therapy therefore allows oxygen to displace CO, but at the risk of ROS production and oxidative damage to body cells and tissues.

Nitrates & Nitrites

Nitrates and nitrites are highly soluble salts which typically contaminate water in connection with agricultural fertilizers.[15] Acute exposure to these substances can cause methemoglobinemia.

Entry & Sources

Aside from fertilizers, nitrates and nitrites are also found in some pharmaceuticals used to treat heart disease and cyanide poisoning (see above), as well as in explosives. Nitrites are also the main substance in recreational inhaled drugs known colloquially as "poppers." Food manufacturers often cure processed meats with nitrates and nitrites.

Mostly, exposure is through the gastrointestinal tract. However, an important exception is volatile nitrites like "poppers" that can cause methemoglobinemia through inhalation.

Pathogenesis

Cyanosis from methemoglobinemia

Nitrates are converted by the bacteria in the human gastrointestinal and salivary gland microflora into nitrites. It is primarily nitrites that cause the toxicity, not nitrates.[16] Nitrites oxidize ferrous (Fe2+) iron in hemoglobin into its ferric (Fe3+) form, creating methemoglobin. Much like in the case of carboxyhemoglobin in the CO poisoning discussed above, the methemoglobin binds oxygen less efficiently and its oxygen dissociation curve is shifted to the left (although it does not exhibit the same cap on maximum carrying capacity). The result is another example of severe anemic hypoxia.[5]

Symptoms

The most identifiable clinical symptom of methemoglobinemia is a distinct blue-gray discoloration of the skin due to the lack of oxygenation. The greater the proportion of erythrocytes affected, the more blue the patient appears. The cyanosis also does not improve with oxygen therapy.[17] As with most cases of poisoning, the symptoms are dose-dependent: 

Those with very mild methemoglobinemia might not have any symptoms at all, or might appear a little pale and feel tired. Moderate-to-severe poisoning is associated with cyanosis (blueness of the skin), confusion, loss of consciousness, seizures, abnormal heart rhythms, and death.[16]

Treatment

Firstly, any remaining nitrites in the gastrointestinal symptoms need to be absorbed with activated charcoal before the methemoglobinemia can progress. Next, assessment of the severity is made: In patients with <30% methemoglobin and in asymptomatic patients, this supportive treatment is usually enough.[17] Otherwise, treatment protocols call for methylene blue intravenously or, when methylene blue is contraindicated (e.g., G6PD deficiency), vitamin C.

Methylene blue mechanism

Methylene Blue

In methemoglobinemia, ferrous iron is oxidized to ferric iron. The goal of treatment is to reduce ferric iron back to ferrous iron. Methylene blue is an oxidizing agent, which is of no immediate use. However, NADPH from the pentose phosphate pathway reduces methylene blue into leukomethylene blue. Leukomethylene blue can now reduce ferric iron back into ferrous iron.[18]

In patients with glucose-6-phosphate dehydrogenase deficiency, NADPH production in the pentose phosphate pathway is disrupted or absent. Therefore, methylene blue treatment may not have any therapeutic effects.

Vitamin C

Vitamin C is an antioxidant, and generally acts directly as a reducing agent. In symptomatic methemoglobinemia, is needed intravenously in large quantities to be of therapeutic benefit, but it does not need to undergo any reactions like methylene blue to be effective.

Methanol & Ethylene Glycol

high anion gap metabolic acidosis vs normal anion gap metabolic acidosis

Methanol is a single-carbon alcohol stereotypically found in improperly distilled alcoholic beverages, while ethylene glycol is a synthetic, odorless but sweet-tasting two-carbon alcohol present in antifreeze. They both pose acute risks to human life by causing anion gap metabolic acidosis.

Entry & Sources

Methanol and ethylene glycol are both components of products such as antifreeze. Additionally, methanol is present in larger amounts in homemade and/or improperly distilled alcoholic beverages, also known as "moonshine." The main risk of poisoning is through ingestion, and is somewhat commonly observed in suicide attempts.

Pathogenesis & Symptoms

Methanol

Methanol is broken down in the body by the enzyme alcohol dehydrogenase into formaldehyde, then further by aldehyde dehydrogenase (among others) into formic acid. While formaldehyde is massively toxic to the human body, it is rapidly processed into formic acid, which is the cause of the anion gap metabolic acidosis.[19]

Ethylene Glycol

Similarly, ethylene glycol is broken down by alcohol dehydrogenase into glycoaldehyde, then further by aldehyde dehydrogenase into glycolic acid. Glycolic acid is mainly but not the only cause of the anion gap metabolic acidosis. It is further broken down slowly through many mechanisms into oxalate, glyoxylic acid, and glycine. [19]

Oxalate crystals are highly toxic in an additional way, as they are now believed to deposit in tissues and cause the acute kidney injury and cerebral edema observed in ethylene glycol toxicity.[20] Thus, oxalate crystalluria is a typical for this condition.[19]

Common Pathway

The two converge at the effects of the anion gap metabolic acidosis (AGMAC). So, what does AGMAC even mean? 

Because serum is electroneutral, the sum of the positively charged particles (cations) must equal the sum of the negatively charged particles (anions). The routinely measured cations are sodium and potassium and the routinely measured anions are chloride and bicarbonate. The difference between the measured cations and the measured anions is known as the anion gap. It represents unmeasured anions, such as phosphates, sulfates, albumin and organic acids, and unmeasured cations, such as calcium and magnesium. [...] The anion gap is defined as follows: anion gap = sodium – (chloride + bicarbonate). When defined in this way the normal anion gap is 7 ± 4 mEq/L. An increase in the anion gap is usually due to unmeasured acids and is known as anion gap metabolic acidosis.[19]

Metabolic acidosis is a state where the blood pH drops below 7.35 due to either an excess of acid or a loss of bicarbonate ions. In acute cases, such as in methanol/ethylene glycol poisoning where blood pH can often drop below 7.0, the main symptoms are "decreased cardiac output, arterial dilatation with hypotension, altered oxygen delivery, decreased ATP production, predisposition to arrhythmias, and impairment of the immune response.[21]" Patients also typically exhibit Kussmaul breathing, and experience profound fatigue and nausea.

Specific Symptoms

The initial intoxicant effect of methanol is mild and overshadowed by the abdominal pain, nausea, and vomiting. After about 1-3 days, the patient experiences general weakness, as well as dyspnea and respiratory difficulties. The symptoms of acidosis continue to progress, along with increasing visual disturbances often described as "walking in a snowstorm." The visual disturbances are accompanied by loss of the pupillary reflexes, miosis, and edematous hyperemia of the optic disk. If not treated in a timely manner, the patient may experience seizures, or even coma or death from respiratory or cardiac arrest.[19]

Ethylene glycol intoxication demonstrates a 4-12 hour latency period, before it progresses through its three phases. In the first phase, CNS depression occurs more profoundly than in methanol intoxication. Patients are inebriated, with additional symptoms of vomiting, seizures, and/or hallucinations. The following phase is the cardiorespiratory phase, where the patient experiences the above-described cardiorespiratory symptoms of acidosis, possibly in addition to myositis. The final phase is the renal phase, where approximately 1-3 days after ingestion, the patient will experience the typical oxalate crystalluria with notable flank pain, oliguria, and renal failure.[19]

Treatment

Treatment of these two types of poisoning focuses on four goals:

  1. inhibiting alcohol dehydrogenase to prevent the formation of toxic acids and aldehydes,
  2. treatment of acidosis,
  3. modification of involved metabolic pathways, and
  4. hemodialysis to remove the methanol/ethylene glycol, and any already formed metabolites of them.[19]

Alcohol dehydrogenase binds much more readily with ethanol (the main intoxicant of alcoholic beverages) than with methanol or ethylene glycol. Only once it runs out of ethanol will it then begin to break down the other substances. Therefore, the first goal of treatment is accomplished by administering ethanol.

Severe acidosis is corrected is corrected by the administration of bicarbonate, bringing the blood pH up to near normal levels. Bicarbonate is also thought to remove formic acid from the central nervous system.[19]

In the case of ethylene glycol, part of the treatment goals is to shift body metabolism of the substance away from the formation of oxalate crystals and towards the less toxic glycine for example. This may be encouraged by administering thiamine and pyridoxine. In methanol poisoning however, the breakdown of formic into CO2 is the final step of metabolism, and is folate-dependent. This step is therefore further supported clinically by the administration of folate.[19]

Paracetamol

Paracetamol, also known as acetaminophen in the U.S., is the analgesic, antipyretic, often over-the-counter drug found in products such as Paralen, Panadol, and Tylenol. It can be taken orally, intravenously, or as a suppository. Paracetamol poisoning is often the result of ingestion of large amounts in connection to suicidal or self-injurious behavior. While it rapidly causes gastroenteritis, it is lethal due to its acute hepatotoxicity.

Pathogenesis

It is not paracetamol itself that is directly toxic, but rather its highly reactive metabolite NAPQI. Thus, it is a "pro-poison." Paracetamol is detoxified in the liver by the action of two enzymes of the cytochrome P450 system, producing NAPQI. At normal therapeutic doses, NAPQI is then conjugated with glutathione and harmlessly processed and excreted. In larger doses, glutathione is rapidly depleted, and NAPQI then binds other cellular proteins at their cysteine residues to form protein adducts. As NAPQI binds mitochondrial proteins, electrons leak out and reactive oxygen species like the superoxide anion are formed. Through a series of chain reactions, this ROS formation catalyzes further ROS formation in a vicious cycle, ultimately leading to hepatocellular necrosis. The result is a deficit in the liver's synthetic function, and therefore leads to coagulopathy (due to lack of clotting factors) and hypoglycemia. Additionally, the deficit of hepatic metabolism leads to a disruption of the urea cycle, leading to hyperammonemia that in the CNS causes hepatic encephalopathy. Patients can experience lactic acidosis, acute kidney injury, and hepatorenal syndrome. Finally, paracetamol is a CNS depressant in large concentrations, and can therefore lead to coma.[22]

Symptoms

Symptoms of acute paracetamol toxicity occur in 4 stages:[23]

Stages of Paracetamol Poisoning Symptoms, Via Omalley, 2019a
Stage Time Postingestion Description
I 0-24 hours Anorexia, nausea, vomiting
II 24-72 hours Right upper quadrant abdominal pain (common)

AST, ALT, and, if poisoning is severe, bilirubin and PT (usually reported as the INR) sometimes elevated

III 72-96 hours Vomiting and symptoms of liver failure

Peaking of AST, ALT, bilirubin, and INR

Sometimes renal failure and pancreatitis

IV > 5 days Resolution of hepatotoxicity or progression to multiple organ failure (sometimes fatal)

Treatment

Glutathione (GSH) synthesis: Production of cysteine is the rate-limiting step

The main current treatment for paracetamol overdose is N-acetylcysteine (NAC). However, in some cases, this is preceded by activated charcoal decontamination (which is more effective than gastric lavage): 

Decontamination with activated charcoal is only indicated if all of the following criteria is met:
- Paracetamol capsule or tablet is the ingestant AND
- Presents within 2 hours of ingestion and (>10 g or 200 mg/kg, whichever is lower) of immediate release paracetamol OR
- Within 4 hours of 30 g or greater of immediate release paracetamol OR
- Within 4 hours of a toxic ingestion (>10 g or 200 mg/kg, whichever is lower) of sustained release paracetamol
AND
- There is no co-ingestant that may lead to decreasing GCS or seizures[24]

N-acetylcysteine can be given orally or intravenously. Once in the body, it loses its acetyl group to become cysteine. In the production of glutathione, the formation of cysteine is the rate-limiting factor. Thus, supplementing with a cysteine precursor allows the body to rapidly replenish glutathione stores to bind the NAPQI before it can wreak havoc on the hepatocytes.[25] In treating paracetamol poisoning, time is of the essence to save as much hepatic function as possible. It is ideal to treat within a few hours at most.

Amanita Phalloides (Death Cap)

Amanita Phalloides, the Death Cap mushroom

The death cap mushroom is responsible for the vast majority of mushroom-related fatalities, and is considered the most poisonous mushroom on earth.

Pathogenesis

Death cap mushrooms contain an amatoxin called α-amanitin. This toxin is heat-stable, i.e. it is not degraded by cooking. Once one of these mushrooms is eaten, the amatoxin absorbed from the GI tract is taken up by the liver through portal circulation. In the hepatocytes, it non-covalently binds DNA-dependent RNA polymerase II. Without RNA polymerase II, no mRNA is produced, and subsequently, no proteins are produced. The liver cell eventually undergoes apoptosis or necrosis.[26]

Symptoms

The symptom progression of A. phalloides poisoning is peculiar: After a few hours and up to a day, the mushroom acts on the stomach lining, causing what appears to be severe gastroenteritis. This leads to massive fluid loss. A day or so later, GI symptoms subside in what the patient assumes is a complete recovery from potential food poisoning. Finally, fulminant liver failure develops, with all the classic symptoms:

dramatic rise in transaminases and bilirubin associated with coagulopathy, hypoglycemia, acidosis, renal failure (potentially hepatorenal syndrome), and hepatic encephalopathy. Multi-organ failure, disseminated intravascular coagulation, rapid central nervous system deterioration, severe hemorrhagic manifestations, and death may occur within 1–3 weeks after ingestion.[26]

Treatment

Upon suspicion of A. phalloides consumption, gastric lavage +/- activated charcoal should be provided. Silibinin is given as a hepatoprotective agent, along with N-acetylcysteine for its experimentally demonstrated protective/supportive effects. There is no real antidote to amatoxins, only supportive measures to give the patient better odds. In case the liver progresses to fulminant hepatic failure, liver transplantation may be the only remaining option.[5]

Further Reading

References

  1. ↑ a b Information on Cyanide Compounds. (n.d.). Stanford Environmental Health & Safety; Stanford University. Retrieved April 13, 2026, from https://ehs.stanford.edu/reference/information-cyanide-compounds
  2. ↑ a b c d e Bledsoe, A. (2025, October 27). Cyanide Poisoning: Unveiling the Most Common Sources and Understanding the Risks. PanFlavor. https://panflavor.com/what-is-the-most-common-source-of-cyanide-poisoning/
  3. ↑ Implementing decision - EU - 2024/816 - EN. (2024). EUR-Lex; Europa.eu. https://eur-lex.europa.eu/eli/dec_impl/2024/816/oj/eng
  4. ↑ a b c Piršelová, B., & Jakubčinová, J. (2025). Plant cyanogenic glycosides: from structure to properties and potential applications. Frontiers in plant science, 16, 1612132. https://doi.org/10.3389/fpls.2025.1612132
  5. ↑ a b c d e Department of Pathophysiology. (2025). Repetitorium: General pathophysiology. Moodle UK; Second Faculty of Medicine, Charles University. Retrieved April 18, 2026, from https://dl1.cuni.cz/pluginfile.php/2051459/mod_resource/content/1/Repetitorium%20General%20pathophysiology%20%28updated%202025%29.pdf
  6. ↑ a b c d e CLRN team. (2025, July 2). how does cyanide kill you biology. California Learning Resource Network. https://www.clrn.org/how-does-cyanide-kill-you-biology/
  7. ↑ Cyanide. (2024, September 6). Chemical Emergencies; U.S. Centers for Disease Control and Prevention. https://www.cdc.gov/chemical-emergencies/chemical-fact-sheets/cyanide.html
  8. ↑ BenchChem Technical Support Team. (2026). The Multifaceted Mechanism of Action of Thiosulfate in Biological Systems: An In-depth Technical Guide. In Bench Chem. https://pdf.benchchem.com/1220/The_Multifaceted_Mechanism_of_Action_of_Thiosulfate_in_Biological_Systems_An_In_depth_Technical_Guide.pdf
  9. ↑ Sodium nitrite. (2026, March 23). Chemical Hazards Emergency Medical Management; U.S. Department of Health & Human Services. https://chemm.hhs.gov/countermeasure_sodium-nitrite.htm
  10. ↑ Madsen, J. M. (2024, October 8). Nerve chemical-warfare agents. MSD Manual Professional Version. https://www.msdmanuals.com/professional/injuries-poisoning/mass-casualty-weapons/nerve-chemical-warfare-agents
  11. ↑ a b c Omalley, G. (2019b). Organophosphate poisoning and carbamate poisoning. MSD Manual Professional Version. https://www.msdmanuals.com/professional/injuries-poisoning/poisoning/organophosphate-poisoning-and-carbamate-poisoning
  12. ↑ Atropine sulfate - Medical countermeasures database. (2013). Chemical Hazards Emergency Medical Management; U.S. Department of Health & Human Services. https://chemm.hhs.gov/countermeasure_atropine-sulfate.htm
  13. ↑ U.S. Food and Drug Administration. (2010). PROTOPAM chloride (pralidoxime chloride) for injection (p. 2). https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/014134s022lbl.pdf
  14. ↑ a b Hewitt, J. (2022). Case of the month #34 carbon monoxide poisoning. The Faculty of Intensive Care Medicine. https://www.ficm.ac.uk/documents/case-of-the-month-34-carbon-monoxide-poisoning/overview
  15. ↑ Nečas, E., Kofránek, J., Krijt, J., Maršálek, P., Maruna, P., Mělková, Z., Prokešová, L., Šimák, J., Šulc, K., & Vokurka, M. (2000). Obecná patologická fyziologie (P. Klener, Ed.; p. 80). Charles University in Prague, Karolinum Press.
  16. ↑ a b Mekonnen, S. (2017, December 5). Nitrate and nitrite poisoning. Poison Control; National Capital Poison Center. https://www.poison.org/articles/causes-and-symptoms-of-nitrate-nitrite-poisoning-174
  17. ↑ a b Chui, J. S. W., Poon, W. T., Chan, K. C., Chan, A. Y. W., & Buckley, T. A. (2005). Nitrite-induced methaemoglobinaemia - aetiology, diagnosis and treatment. Anaesthesia, 60(5), 496–500. https://doi.org/10.1111/j.1365-2044.2004.04076.x
  18. ↑ Mak, R. S. P., & Liebelt, E. L. (2021). Methylene blue an antidote for methemoglobinemia and beyond. In Lippincott Williams & Wilkins. Wolters Kluwer Health. https://cme.lww.com/ovidfiles/00006565-202109000-00009.pdf
  19. ↑ a b c d e f g h i Henderson, W. R., & Brubacher, J. (2002). Methanol and ethylene glycol poisoning: A case study and review of current literature. CJEM, 4(01), 34–40. https://doi.org/10.1017/s1481803500006035
  20. ↑ Ethylene glycol/methanol. (2026). Gloucestershire Hospitals ; NHS Foundation Trust. https://www.gloshospitals.nhs.uk/our-services/services-we-offer/pathology/tests-and-investigations/ethylene-glycolmethanol/
  21. ↑ Kraut, J. A., & Madias, N. E. (2010). Metabolic acidosis: Pathophysiology, diagnosis and management. Nature Reviews. Nephrology, 6(5), 274–285. https://doi.org/10.1038/nrneph.2010.33
  22. ↑ Chidiac, A. S., Buckley, N. A., Noghrehchi, F., & Cairns, R. (2023). Paracetamol (acetaminophen) overdose and hepatotoxicity: Mechanism, treatment, prevention measures, and estimates of burden of disease. Expert Opinion on Drug Metabolism and Toxicology, 19(5), 297–317. https://doi.org/10.1080/17425255.2023.2223959
  23. ↑ Omalley, G. (2019a). Acetaminophen poisoning. MSD Manual Professional Version. https://www.msdmanuals.com/professional/injuries-poisoning/poisoning/acetaminophen-poisoning
  24. ↑ Quay, K. (2020, January 15). Paracetamol poisoning. Starship Child Health. https://www.starship.org.nz/guidelines/paracetamol-poisoning/
  25. ↑ Atkuri, K. R., Mantovani, J. J., Herzenberg, L. A., & Herzenberg, L. A. (2007). N-Acetylcysteine—a safe antidote for cysteine/glutathione deficiency. Current Opinion in Pharmacology, 7(4), 355–359. https://doi.org/10.1016/j.coph.2007.04.005
  26. ↑ a b Kayes, T., & Ho, V. (2024). Amanita Phalloides-associated liver failure: Molecular mechanisms and management. International Journal of Molecular Sciences, 25(23), 13028. https://doi.org/10.3390/ijms252313028