Silibinin for Amatoxin Poisoning: Preventing the Last [Thanksgiving] Supper?

Ingestion of cyclopeptide mushrooms can lead to irreversible hepatotoxicity that may potentially be life-threatening. The mechanism by which hepatotoxicity occurs is through the activity of α-amanitin, which is taken up by hepatocytes and inhibits DNA-dependent RNA polymerase II, preventing DNA transcription into mRNA, which consequently halts the process of protein production. This causes injury of organ systems that are highly dependent on protein synthesis, such as the gastrointestinal mucosa, kidneys, and liver, which eventually leads to tissue necrosis. In addition, it is hypothesized that the activity of this toxin can lead to the production of free oxygen radicals that further exacerbate hepatocellular necrosis. It is reported that the lethal dose of α-amanitin in humans is 0.1 mg/kg body weight, which is equivalent to as little as one fresh mushroom (30 to 50 grams).

The most difficult part in terms of the management of cyclopeptide mushroom poisoning is the fact that there is no standard antidote that has been proven to be effective, and in many instances, their use is somewhat controversial. Those that have been tried include activated charcoal, high doses of intravenous penicillin G, intravenous N-acetylcysteine, intravenous cimetidine, and hemoperfusion. Aggressive hydration is indicated to prevent injury to the kidneys. In cases of severe cyclopeptide mushroom poisoning, liver transplantation may be warranted.

Quite recently, however, there has been some talk regarding silibinin, a water-soluble derivative of silymarin (milk thistle), as an antidote for the treatment of cyclopeptide mushroom poisoning. It has been used in Europe for decades for the treatment of acute amatoxin poisoning, and is currently being investigated as a study drug in the United States for the same indication. It is thought to act through competitive inhibition of the transporter system that is necessary for uptake of amatoxin into hepatocytes. Not only does this interrupt primary circulation of amatoxin, but it also disrupts enterohepatic recirculation of the toxin as well, the latter process being relevant to toxicity since many patients present long after complete absorption of the cyclopeptide. Silibinin seems to also possess anti-inflammatory and antioxidant properties, preventing injury and oxidative stress to the liver in the setting of amatoxin poisoning; it may also stimulate protein synthesis, thereby preventing further damage to the liver, allowing for regeneration of injured tissue within the liver and restoration of hepatic function.

The dosing schedule for silibinin as an investigational antidote for highly suspected or confirmed amatoxin ingestion in patients at least two years of age is as follows:

  • Loading dose of 5 mg/kg IV infused over one hour followed by a maintenance infusion of 20 mg/kg/day 
  • Infusion is to be continued until coagulopathy has resolved and liver function tests normalize

At this point, you may be asking where the evidence is to show that silibinin improves long-term clinical outcomes in patients with amatoxin poisoning. The short answer is that there is not a whole lot of evidence to support this hypothesis. Although there are plenty of published case reports that show its potential benefit in acute toxicity, a retrospective study conducted by Zilker and colleagues (Clin Toxicol 2005; 43:438) demonstrated that there are simply not enough cases of amatoxin poisoning to draw a meaningful conclusion regarding the effectiveness of silibinin when compared to other therapies.

Some logistical issues regarding drug procurement include the following:

  • Because this is a study drug, in the setting where ingestion of amatoxin is highly suspicious, consultation with the toxicology service and/or local poison control center is necessary.
  • Contact would need to be made with the principal investigator of the open-label multicenter study in order to enroll the patient(s) into the study and retrieve the drug.
  • Arrangements would have to be made to have the drug flown in and couriered to the institution.
  • An emergency investigational new drug application with the study protocol would need to be completed and approved by an institutional review board prior to administration of the agent.

These factors are important to consider because a delay in treatment with silbinin for amatoxin poisoning by more than 48 hours has been shown to be associated with a more severe course of coagulopathy and hepatic injury.

Since a trial is ongoing in the United States and the adverse events associated with treatment are relatively benign (facial flushing and rash), the potential benefits of silibinin do seem to outweigh the risks associated with treatment. Perhaps the results of the trial may shed some light regarding its place in therapy for amatoxin poisoning.

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One thought on “Silibinin for Amatoxin Poisoning: Preventing the Last [Thanksgiving] Supper?

  1. Prevention and Treatment of Amatoxin Induced Hepatic Failure With Intravenous Silibinin (Legalon® SIL): An Open Multicenter Clinical Trial has been enrolling patients since mid 2009. Over 60 patients in the USA have been treated with intravenous SIL. It is the first and only prospective clinical trial ever carried out with regards to amatoxin poisoning.As long as renal function has been preserved and urine output maintained by the use of aggressive intravenous hydration, SIL has been reliably effective when started within 96 hours of ingestion. A drop in the INR by the 48th hour of infusion is sustained and predictive of complete recovery. Most patients require < 96 hours of SIL therapy and are discharged in well under seven days.A few clarifications with regards to the logistical considerations: 1) Further PCC/TOX consultation discussed above is not a necessity for treatment with SIL. The diagnosis of amatoxin poisoning is pathognomonic in the setting of rapidly rising transaminases within 24 hours of a six or greater hour delayed onset of post-ingestion vomiting and diarrhea following the ingestion of foraged mushrooms.2) The PI and co-I are readily available for consultation 24/7 via an 800 hotline. 3) SIL is provided free of charge and delivery arrangements are made by the sponsor. Delivery to a treating hospital anywhere in the country occurs within 24 hours or less following contact with the PI.4) Patients are enrolled in our Open IND, so no new arrangements are necessary. Emergency approval from the hospital IRB chair is usually obtained by a quick phone call.S Todd Mitchell MD,MPHPrincipal Investigator(831)-227-6048 Cell/Mobilehttp://www.clinicaltrials.gov/ct2/show/study/NCT00915681https://sites.google.com/site/legalonsil/

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