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Three Part Question

In [patients presenting to the ER with a suspected amatoxin-containing mushroom poisoning], is [silibinin better than conservative treatment] at [reducing the need for liver transplantation and reducing mortality]?

Clinical Scenario

A 36-year-old woman presents to the emergency department after eating some unidentified wild mushrooms 12 h previously. She is complaining of abdominal pain and diarrhoea, which started 2 h before. The toxidrome leads you to suspect that the mushroom may have been Amanita phalloides. You are aware of the dire prognosis. You discuss the case with your consultant who suggests the use of silibinin. You wonder whether this would reduce her risk of death or need for liver transplant.

Search Strategy

Medline using National Institute for Health and Care Excellence (NICE) Evidence interface 1946–date of searching 14 October 2015: (Amatoxin* ti,ab OR amanit*ti,ab OR exp AMANITA/) AND (exp SILYMARIN/OR silybin ti,ab OR silymarin ti,ab OR silibinin ti,ab) Limited to English and Humans 38 hits no new relevancies.

EMBASE using NICE Evidence interface 1974–date of searching 14 October 2015: (Amatoxin* ti,ab OR amanit*ti,ab OR exp AMANITA/) AND (exp SILYMARIN/OR silybin ti,ab OR silymarin ti,ab OR silibinin ti,ab) Limited to English and Humans 86 hits no new relevancies.

Cochrane Database of Systematic Reviews: Issue 10 of 12, October 2015: “amatoxin”:ti,ab,kw OR amanit* (word variations have been searched) 4 hits 0 relevancies.

http://www.clinicaltrials.gov was searched for ongoing trials on the subject.

Search Outcome

Thirty-eight papers were found in Medline and 86 in EMBASE. One trial was found in http://www.clinicaltrials.gov—it is currently recruiting patients (identifier: NCT00915681). Papers were excluded if they were found irrelevant to the question, of insufficient quality (consisting mostly of case reports or short case series) or because they were written neither in English nor in French. The remaining five papers were included in this review and are summarised in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Roberts, D.M., et al. 2013 Australia	12 patients with suspected A. phalloides poisoning. 9/12 (75%) patients received silibinin (combined with other treatments). Treatment protocol and other treatments differed between patients.	Retrospective case series	Mortality	33,3% (Sil) vs 33,3% (No sil)	Treatment protocol differed a lot between the patients. No statistical analysis. Few patients. Unclear if patients cared by transplant unit were transplanted or not.
			Care by liver transplant unit	66,6% (Sil) vs 0% (No sil)
Mengs, U., et al. 2012 Germany	1491 patients with amatoxin-containing mushroom poisoning (from published and unpublished data) treated with silibinin (as monotherapy or combined with other medication).	Review of the literature	Mortality	107/1491 (7,2%)	Main author is consulting for the R&D department of Madaus-Rottapharm. No control group. No statistical analysis. Study refers to unpublished data. Study protocol not published. Was it systematic? Most studies included are case reports or case series
Mitchell, T. 2011 United States	29 patients with confirmed amatoxin-containing mushroom poisoning (wild mushroom ingestion, delayed onset ≥6 hours of vomiting and diarrhea and rapidly evolving transaminitis). The patients then received a loading dose of 5 mg/kg of IV silibinin followed by a continuous IV perfusion of 20 mg/kg/day. The treatment was stopped after resolution of the coagulopathy.	Conference abstract of an uncontrolled clinical trial	Mortality (patients off protocol)	1/2 (50%)	Main author is consulting for Madaus-Rottapharm. No control group. No statistical analysis. Being a conference abstract, some information (such as results) is missing.
			Liver transplant (patients off protocol)	1/2 (50%)
			Mortality (patients on protocol)	1/27 (3,7%)
			Liver transplant (patients on protocol)	Data unclear
Zilker, T.H. 2009 Germany	604 patients with suspected amatoxin-containing mushroom poisoning. 247 patients were excluded (unclear diagnosis or lack of information on treatment). The 367 included patients all received silibinin (as monotherapy or combined with penicillin).	Conference abstract of a retrospective observational study	Combined outcome of mortality and liver transplant by treatment	5,1% (Sil) vs 8,8% (Sil + Pen) (adjusted OR: 0.58; 95% CI: 0.21–1.57; p= 0.28)	Made in collaboration with Madaus-Rottapharm. No control group. Not statistically significant. Study protocol unclear. Which database did they use? Being a conference abstract, some information (such as valuable results) is missing.
Enjalbert, F., et al. 2002 France	2108 patients hospitalized for amatoxin-containing mushroom poisoning in North America or in Europe collected from the published literature on the topic. 46 patients were excluded (lack of information on treatment). Treatments varied a lot between patients. 1632 patients received some drug therapy. Of those patients, 624/1632 (38,2%) patients received silibinin (as monotherapy or combined with other medication).	Meta-analysis	Combined outcome of mortality and liver transplant	5,4% (Sil) vs 47,3% (Support) (p≤ 0.01)	Study protocol unclear (database searched, terms used, etc.). Was it systematic? Very complex results analysis. Some results and mortality rates doesn't seem to correlate. Publication bias?
			Combined outcome of mortality and liver transplant	5,4% (Sil) vs 7,9% (Sil + Pen) (p> 0.05)
			Combined outcome of mortality and liver transplant	5,4% (Sil) vs 10,4% (Detox alone) (p> 0.05)
			Combined outcome of mortality and liver transplant	5,4% (Sil) vs 12,6% (All patients) (p> 0.05)

Comment(s)

Silibinin (INN), also known as silybin (both from Silybum, the generic name of the plant from which it is extracted), is the major active constituent of silymarin, a standardised extract of the milk thistle seeds, containing a mixture of flavonolignans consisting of silibinin, isosilibinin, silicristin, silidianin and others. For the purpose of this review, the terms silybin, silibinin and silymarin were used interchangeably. Although many species of mushrooms can produce amatoxins (such as Lepiota spp. and Galerina spp.), most North American cases are due to Amanita spp. poisonings. For the purpose of this review, it was decided not to search for the terms ‘Galerina’ or ‘Lepiota’. After reviewing the studies, it became clear that the evidence supporting the use of silibinin in amatoxin-containing mushroom poisoning is weak. Many studies were sponsored by the pharmaceutical industry producing silibinin. Some studies referred to unpublished data and study protocol were rarely adequately reported. Reviews referred mostly to case series and case reports involving important heterogeneity of cointerventions. There is a high risk of publication bias. Finally, no controlled clinical trials on the subject were found during this review.

Clinical Bottom Line

Although the use of silibinin might be beneficial in patients exposed to a toxic dose of amatoxin, these results are based on a weak level of evidence. Given the lack of alternative treatments in patients with suspected amatoxin-containing mushroom poisoning and the relatively few adverse effects documented with the use of silibinin, its use could still be considered in some patients.

References

1. Roberts DM, Hall MJ, Falkland MM, et al. Amanita phalloides poisoning and treatment with silibinin in the Australian Capital Territory and New South Wales. Med J Austr 2013;198:43–7.
2. Mengs U, Pohl RT, Mitchell T. Legalon® SIL: The antidote of choice in patients with acute hepatotoxicity from amatoxin poisoning. Curr Pharm Biotechnol 2012;13:1964–70.
3. Mitchell, T. The American experience with intravenous silibinin (IS) for amatoxin mushroom poisoning (AMP): An interim report. Hepatology 2011;54:510A–11A.
4. Zilker, T.H. Prognosis and treatment of amatoxin poisoning. Clin Toxicol 2009;47:467.
5. Enjalbert F, Rapior S, Nouguier-Soulé J, et al. Treatment of amatoxin poisoning: 20-Year retrospective analysis. J Toxicol Clin Toxicol 2002;40:715–57.