Thursday, November 22, 2012

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.