Amatoxin Poisoning - Pathophysiology, Symptoms, Diagnosis, and Treatment

Introduction:

Amatoxin-containing mushrooms are rare but can have a significant impact as they are a leading cause of acute fulminant liver failure. It is important to note that not all Amanita species contain this toxin, and other mushroom species besides Amanita also contain amatoxin. Shockingly, amatoxin-containing mushrooms are responsible for approximately 95 percent of deaths caused by mushroom ingestion worldwide.

Species of Amatoxin-Containing Mushrooms:

1. Amanita Group:

• Amanita phalloides (Death Cap).

• Amanita virosa (Destroying Angel).

• Amanita verna (Fool’s Mushroom).

• Amanita ocreata.

• Amanita bisporigera.

• Amanita suballiacea.

2. Lepiota Group:

• Lepiota helveola.

• Lepiota chlorophyllum.

• Lepiota brunneolilacea.

• Lepiota josserandi.

• Lepiota fulvella.

• Lepiota subincarnata.

• Lepiota brunneoincarnata.

3. Miscellaneous:

• Galerina autumnalis (Autumn skullcap).

• Galerina venenata.

• Galerina sulciceps.

• Conocybe filaris.

It is important to be cautious when foraging for mushrooms, as certain species can easily be mistaken for edible varieties. For example, Amanita phalloides (Death Cap), which is associated with the highest number of fatalities, is often mistaken for the paddy straw mushroom.

Additionally, both Agaricus volvacea and Amanita bisporigera can be mistakenly identified as the edible and non-toxic Lepiota naucina.

What Is the Etiology of Amatoxin Poisoning?

Only a small portion of the thousands of kinds of mushrooms, about 50 to 100, are hazardous to people. The Amanita species are the main offenders in cases of mushroom toxicity among these. Amatoxins and phallotoxins are two different types of poisons found in amanita mushrooms. Amatoxins selectively prevent the body from making proteins, which damages the liver.

The fact that some Amanita species, including Amanita smithiana, create a renal toxin that harms the kidneys should be noted. On the other hand, Amanita muscaria and Amanita pantherina contain isoxazole toxins that largely cause mental alterations but do not harm the liver or kidneys.

What Is the Pathophysiology of Amatoxin Poisoning?

Due to its thermal stability, the amanitin toxin retains its toxicity whether taken raw or cooked. Amatoxin works by inhibiting RNA polymerase, which prevents mRNA from being properly transcribed. Due to the inability of hepatocytes to produce necessary protein-coding genes, centrilobular hepatic necrosis and the destruction of nucleoli occur. Over the course of 48 hours, this process results in the slow development of liver failure.

Phallotoxin, a different substance found in some mushrooms that include amatoxin, aids in developing late-onset symptoms such as vomiting, and watery diarrhea that appear more than six hours after consumption. However, as Lepiota species do not produce phallotoxins, vomiting, and diarrhea may not start for up to 12 hours after ingestion, or people may only experience liver failure symptoms for up to 24 hours after ingestion. Through OATP transporters, amatoxins are quickly absorbed from the intestines and delivered to the liver. As soon as they are inside the hepatocytes, they start to block RNA polymerase. Any symptoms or laboratory evidence of liver damage takes roughly 24 hours to start showing up.

What Are the Symptoms of Amatoxin Poisoning?

Amatoxin poisoning typically exhibits a delayed onset of symptoms and follows a triphasic pattern:

• GI Phase (Eight to 24 hours): Symptoms start to emerge within six to 24 hours (rarely 36 hours) after ingestion. These include severe abdominal pain, vomiting, and cholera-like diarrhea. On average, symptoms appear around eight to 12 hours after ingestion. The severity of poisoning tends to be greater when symptoms appear sooner.

• Honeymoon Phase (48 to 72 hours): After the initial GI symptoms, there is a temporary improvement known as the "honeymoon period," which can last up to 24 hours. During this time, patients may feel better and may even be discharged from the hospital. However, it is crucial to note that affected hepatocytes continue to deteriorate, and any remaining amatoxins that have not been eliminated by the kidneys continue to damage liver tissue as they circulate back into the liver through the bile and enterohepatic system.

• Hepatic or Cytotoxic Phase (72 to 96 hours): As liver damage progresses, transaminase levels rise, indicating liver injury. If the damage becomes extensive, complete liver necrosis can occur, requiring a liver transplant for survival. However, in cases where liver damage is partial, and kidney function remains intact, recovery and liver regeneration are possible. While severe poisonings can affect other organs such as the kidneys, brain, pancreas, and testes, these complications typically arise after liver necrosis.

Dehydration resulting from fluid loss during the GI phase can impair kidney function and hinder the elimination of amatoxins. This makes the kidneys more vulnerable to the direct effects of amatoxins, potentially leading to renal failure, which carries a poor prognosis for recovery. Proper fluid management is essential in treating amatoxin poisoning.

In mild cases, the symptoms may not progress beyond GI effects. However, in severe poisonings, over several days, GI bleeding may occur, followed by hepatic encephalopathy, hepatic coma, kidney failure, and, ultimately, death.

To assess the severity and predict clinical outcomes of amatoxin poisonings, a classification system proposed by Heinz Faulstich and Thomas R. Zilker in the 1994 "Handbook of Mushroom Poisoning, Diagnosis, and Treatment" can be used. This classification is based on observed symptoms rather than the concentrations of amatoxin in blood or urine:

• Grade 1: Typical latency period with GI symptoms but no subsequent liver or kidney damage.

• Grade 2: Patients display all symptoms of amatoxin poisoning, with no coagulation malfunction and a mild to moderate increase in transaminases (>500 U/L).

• Grade 3: Patients experience severe hepatic damage, with a significant increase in transaminases, as well as impaired clotting function.

• Grade 4: Transaminases show a steep rise, clotting factors decline sharply, bilirubin levels increase, and kidney dysfunction becomes apparent.

Grade 1 and 2 cases usually require symptomatic treatment only. Grade 3 cases warrant transfer to a liver transplant center. Unfortunately, Grade 4 cases have a poor prognosis despite therapeutic interventions. It is important to note that a substantial increase in transaminase levels does not always indicate a fatal outcome, whereas a mild increase suggests a higher chance of survival.

How Is Amatoxin Poisoning Diagnosed?

Diagnosing amatoxin poisoning poses challenges due to the delayed appearance of symptoms and the deceptive period of false recovery or pseudo-remission following gastrointestinal toxicity. Therefore, it is crucial to conduct a comprehensive chemistry panel, including liver function tests and a baseline INR, for all cases involving the ingestion of mushrooms suspected to be hepatotoxic. These diagnostic measures are essential for the timely detection and monitoring of liver damage associated with amatoxin poisoning.

How Is Amatoxin Poisoning Treated?

The primary approach to treating amatoxin mushroom toxicity is supportive care, as there is no specific antidote available. The initial focus should be on establishing two large bore intravenous lines to address fluid loss, correct electrolyte imbalances, and normalize glucose levels. If the patient presents within two to four hours of ingestion, decontamination with oral-activated charcoal may be considered. Once the stomach is emptied, antiemetics can be administered if necessary. Various agents have been used in the treatment of amatoxin poisoning, although their efficacy is supported by anecdotal evidence:

• N-acetyl-cysteine (IV): Administered similarly to Acetaminophen poisoning, this treatment aims to mitigate potential liver injury and replenish glutathione levels.

• Penicillin (IV): High-dose Penicillin (four million units every four hours) is believed to compete with the liver's uptake of amatoxin.

• Silymarin: Both pharmaceutical formulations available in Europe as intravenous preparations and over-the-counter raw milk thistle extract used in North America have been utilized in the majority of documented cases. Silymarin is thought to inhibit the OAT-P transporter, slowing the entry of amatoxin into the liver. Recommended doses are 1 gram orally four times daily or intravenous Silibinin (a purified alkaloid of Silymarin) administered at 5 mg/kg over one hour, followed by 20 mg/kg per day as a continuous infusion.

• Activated Charcoal: If administered early after ingestion, activated charcoal may reduce the absorption of amatoxins and prevent toxin reabsorption during enterohepatic recirculation. A dose of 1 gram per kilogram may be given every two to four hours.

• Cyclosporine: In vitro studies suggest that Cyclosporine, an OAT-P transporter inhibitor, may be effective, but its use for amatoxin mushroom toxicity is currently limited to case reports. Although Cyclosporine is well-studied for other indications, its application in this context requires further investigation.

• Other therapies, such as intravenous Cimetidine or Thioctic acid, have been attempted, but their efficacy is supported only by animal models.

In severe cases of liver injury despite aggressive fluid resuscitation and supportive care, a liver transplant may be the only life-saving option. Rapid progression to hepatic encephalopathy (loss of brain function due to liver damage), hepatorenal syndrome, or coagulopathy (a multiorgan condition affecting the liver and kidney) are indications for liver transplantation. Early consideration for transfer to a specialized liver transplant setting and intensive care unit is crucial in managing mushroom ingestions.

In the presence of renal failure, dialysis may be employed, although it should be noted that dialysis does not effectively remove amatoxin from the bloodstream, even when initiated shortly after ingestion.

Conclusion:

Mushroom poisoning is relatively uncommon in the US, but its toxicity can have severe consequences. Due to the toxin's ability to impact multiple organs, a collaborative approach involving an interprofessional team is crucial for accurate diagnosis and effective management of poisoning cases. The amount of mushrooms consumed plays a pivotal role in determining the outcome, with data suggesting that absorption rates may vary among individuals. Notably, children have been found to absorb higher doses of the toxin compared to adults, leading to increased morbidity and mortality in this population. While mortality rates associated with mushroom poisoning have significantly decreased in the US, liver failure remains a frequent and concerning complication. Instances have been reported where individuals require immediate liver transplants as a life-saving intervention. Educating the public is key to preventing mushroom poisoning. Some mushrooms may appear safe but have been sprayed with toxic pesticides, emphasizing the importance of thorough food washing. It is important to note that there is no single definitive test to identify toxic mushrooms. Consequently, the best advice is to refrain from consuming wild mushrooms and instead purchase them from a reputable grocery store.