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Milk Thistle and Mushroom Poisoning

If you’ve been fortunate to live in the parts of the US that were soggier than usually as of late – or unfortunate enough to have had flooding from hurricanes and tropical storms – then you’ve be noticing a tremendous burst of mushrooms.

For mycologists – mushroom enthusiasts – there are two classic chestnuts: “There are old mushroom collectors and bold mushrooms collectors, but there are no old, bold mushroom collectors.”

Or, in a more concise Croatian proverb, “All mushrooms are edible, but some only once.”

As such, this is the time of year that emergency rooms and regional poison centers begin to see a burst in poisonings from mushroom ingestion, due primarily to amateur misidentification of the fruiting bodies.

Just this past week, Jason McClure at Medscape Oncology News (free reg req’d) wrote about the unusual bloom of mushrooms in the northeastern US and the concomitant bloom of mushroom poisonings this fall.

But “mushroom poisoning” is an imprecise diagnosis for the ER physician. The constellation of symptoms caused by toxic mushrooms is as diverse as the colors and shapes of these wonders of nature. From another Medscape article on emergency management of mushroom poisoning by Dr. Rania Habal from the Emergency Medicine department of NYU:

Mushrooms are best classified by the physiologic and clinical effects of their poisons. The traditional time-based classification of mushrooms into an early/low toxicity group and a delayed/high toxicity group may be inadequate. Additionally, many mushroom syndromes develop soon after ingestion. For example, most of the neurotoxic syndromes, the Coprinus syndrome (ie, concomitant ingestion of alcohol and coprine), the immunoallergic and immunohemolytic syndromes, and most of the GI intoxications occur within the first 6 hours after ingestion.

Ingestions most likely to require intensive medical care involve mushrooms that contain cytotoxic substances such as amatoxin, gyromitrin, and orellanine. Mushrooms that contain involutin may cause a life-threatening immune-mediated hemolysis with hemoglobinuria and renal failure. Inhalation of spores of Lycoperdon species may result in bronchoalveolitis and respiratory failure that requires mechanical ventilation.

Mushrooms that contain the GI irritants psilocybin, ibotenic acid, muscimol, and muscarine may cause critical illness in specific groups of people (eg, young persons, elderly persons). Hallucinogenic mushrooms may also result in major trauma and require care in an intensive care setting. Lastly, coprine-containing mushrooms cause severe illness only when combined with alcohol (ie, Coprinus syndrome).

Among the poisonous mushrooms, Amanita phalloides is perhaps the most deadly. If you’ve spent any time in a biochemical laboratory you will have learned of the primary toxin of the mushroom, α-amanitin. This potency of this toxin comes from its remarkably high affinity for RNA polymerase II, the primary RNA polymerase for making messages that are converted into proteins.

The challenge in treating α-amanitin poisoning is that it has a relatively long half-life in the body because it is conjugated with glucuronic acid in the liver and secreted in the bile. But then microbes that normally inhabit our gut cleave the glucuronide sugar molecule off the toxin, released the toxic α-amanitin.

Throughout the history of folk medicine in the Middle East and Europe, extracts of the seeds of milk thistle (Silybum marianum) were determined to have protective effects against liver toxins. I’m still not terribly pleased with understanding the history of how this came about but answering this question is one of my liberal arts pursuits. As an aside, I should make the disclosure that my laboratory and colleagues have been investigating the anticancer effects of compounds from milk thistle and still receive NIH funding to do so; however, I do not (yet) study how milk thistle compounds prevent liver toxicity.

Nevertheless, milk thistle products are quite popular in Europe and the US for the general prevention of liver toxicity from statins, acetaminophen, and alcohol. Several of my friends have joked that one could make create a successful market for an alcoholic product containing milk thistle extract.

But one of the primary roadblocks in using milk thistle extracts or pure compounds for any indication is that the compounds have rather poor bioavailability. The seven major flavonolignans and one flavonoid in the typical extracts are very avidly conjugated by glucuronidation. In studies by collabortors at the University of Colorado, we now know that it takes daily doses of approximately 10-13 grams of milk thistle extract to achieve plasma concentrations consistent with known anticancer effects in vitro. It can be done, but it means taking much more than the typical 180 mg capsules you can buy at your local health food store.

However, an intravenous preparation of milk thistle extract has been available in Europe for over 20 years: Legalon SIL. This GMP-manufactured product is common to emergency rooms in Germany, France, and Belgium for the treatment of mushroom poisoning. The preparation is comprised of silybin A and silybin B – known collectively as silibinin – as a hemisuccinate that both improves the solubility and bioavailability of the compounds.

Two cases in the US – one in 2007 and another just this past month – have seen emergency IND approval of this European product. In 2007, Legalon was used to save four of five family members who had ingested Amanita phalloides while on a New Year’s Day picnic outside of Santa Cruz, California. And just last month, a team led by Dr. Jacqueline Laurin at Georgetown Medical Center successfully treated two men for accidental ingestion of Amanita. Georgetown is now an approved referral center for this IV prep of Legalon and their efforts were greatly assisted by the Santa Cruz team who handled the 2007 cases.

Less satisfying to me is the mechanism by which silybin A and silybin B protect the liver from the effects of RNA polymerase II inhibition by α-amanitin. The literature to date seems to converge on the inhibition of toxin uptake into hepatocytes by silibinin. A German group led by Herbert de Groot in Essen, Germany, published a highly-cited 1996 paper proposing that inhibition of inflammatory mediator release from Kupffer cells (the macrophage of the liver) might partly account for the hepatoprotective effects of silibinin. More recent work continues to address the modulation of inflammation.

Regardless, we are now seeing legitimate use of a medicine from a herbal tradition being used in clinical situations where emergency IRB approval and IND status have been given to such a product. Certainly, these stories may be used by marketers to promote use of their oral milk thistle products. But, as I mentioned earlier, such effects required ingestion of large doses of capsules. Instead, I present this story to SBM readers to illustrate that amidst the wooful promotion of herbal therapies, a few gems exist and are most worthy of our scientific investigation.

Posted in: Herbs & Supplements, Public Health

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13 thoughts on “Milk Thistle and Mushroom Poisoning

  1. Ed Whitney says:

    If silybin compounds work by inhibiting uptake of toxin by hepatocytes, this would suggest that timing of administration is going to be critically important. It was not clear how much time elapsed between ingestion of the mushrooms and the first dose of silibinin. If symptoms had already occurred, one would guess that most of the uptake into the hepatocytes had already taken place. Is there another credible mechanism of action that would allow for effectiveness of administration after the hepatocyte damage has been manifested by elevation of transaminases?

  2. DugganSC says:

    “There are more things in heaven and earth, Horatio, Than are dreamt of in your philosophy.” -Hamlet

    Fascinating stuff. Reminds me of all of those anecdotes you see in sociology books where the mystic rituals of the local witch doctor involving gourds and spit and multi-day rituals turn out to be very effective at breeding penicillin (no idea if this has ever actually been the case or if it’s just a romantic anecdote, but I’ve seen it more than once in chapters explaining how superstition and science meet).

  3. JPZ says:

    @David J Kroll

    Very interesting and detailed article. Is liver failure the cause of death from alpha-amanitin poisoning?

  4. nybgrus says:

    An excellent example of pharmacognosy. And a demonstration that traditional use is an excellent place to look for leads on where to start, but not sufficient for proof of efficacy or safety.

    @Ed:

    As Kroll pointed out, a big part of the problem is re-absorption after the glucoronide conjugate is cleaved off by GI bacteria. Thus, while timing is still critical, the window would plausibly be much larger making silibinin a feasible intervention.

    @JPZ:

    We covered amanitin briefly at some point this year and IIRC it is indeed fulminant liver failure that is the ultimate cause of death. Though in doing a quick search it seems kidney failure is also a large component.

  5. JPZ says:

    @nybgrus

    Thanks! I was just curious (thanks to this interesting article).

  6. rork says:

    Thanks for article.

    It was indeed a great shroom year here in MI starting in August. I saw species I had never collected before, and at times you could see over 20 different types of just boletes in a day, including some outstanding ones in stirp edulus (“porcini”, “steinpilz”). We had great chanterelles and hedgehog shrooms (Hydnum repandum) too, and many others. If you want to pick for the table, you must study and know genus Amanita – it is part of your defense system. I just avoid the entire genus, like most others, even though it contains some edible species. Learn Galerina autumnalis too.

  7. nybgrus says:

    @rork:

    A friend of mine back home last year had some shrooms growing in his newly landscaped garden. He was going to remove them but thought they looked interesting. He asked me to take a look and to me they looked exactly like morels. However, I did some research and found there is a “false” morel that is not good to eat. I think he still has them growing though I am not sure. Any tips on how to differentiate the two? Because I love me some morels with a beautiful beef roast, gravy, and glass of good red wine :-)

  8. Calli Arcale says:

    There are several key features to look for in identifying the false morel.

    1) It’s ugly. Yeah, I know the regular morel is no pageant winner, but the false morel is much uglier.

    2) It is porous inside, like a sponge. The true morel will actually be hollow inside, like a very weird finger puppet. This is a very good indicator, but involves cutting the mushroom in half lengthwise. (Which is useful for cooking anyway, so you might as well do it.)

    3) Exterior is covered with wrinkles, sort of like a brain. A real morel will have pits instead, a bit like Saturn’s moon Hyperion, or a honeycomb.

    4) Cap of a true morel is fused to the stem by the base of the cap; false morels often have a cap that is attached deep inside the cap rather than at its base. Basically, if the cap makes you think of a shiitake mushroom or a straw mushroom or the old supermarket staple the button mushroom, it’s NOT a morel.

    5) Most true morels have a cap longer than the stem. There are some exceptions, but false morels generally have a stem much longer than the cap.

    Some online resources with pics:
    http://thegreatmorel.com/falsemorel.html
    http://www.michiganmorels.com/morels2.shtml
    http://www.fungaljungal.org/morels/falsemo.htm

    And, of course, the most important rule — when in doubt, leave it be. Morels are delicious, but it’s not worth your life.

  9. nybgrus says:

    @Calli:

    Thanks!

    I think they are definitely real morels then! Sounds spot on – especially the hollow part and the short stems. I’ll be back home in 10 days so I’ll check and see if they are still growing.

  10. Chris says:

    Morels are more of a spring time shroom. Right now it is chanterelle season.

  11. Calli Arcale says:

    That’s a good point about the season, Chris. I’ve only ever found morels (true morels) in spring. I don’t know if there are any which bloom this time of year.

    Chanterelles are fantastic. I remember one year I was camping with my family (I was a teenager at the time) up north. Chanterelle season is earlier the further north you go, and they were all over the place. We picked some and cooked them with the fish we’d caught. Now that I’m an adult, I’m actually less inclined to do that; I’m nervous about mushroom mimics.

    I’ll never forget the small cluster of morels we found growing in the actual city one day, just on the little strip of grass between the street and the sidewalk on public property. Plain as day. Luckily, they obviously hadn’t mowed since the ‘shrooms emerged. Some of them were huge. We looked around, didn’t see anyone, and picked the lot of them.

  12. Chris says:

    In the late 1960s my parents rented a little house in Missouri across the river from Ft. Leavenworth where he was stationed. That spring they found morels growing next to the house near the dryer vent.

    I usually just get my fresh mushrooms at the local farmer’s market, and I just had some chanterelles last week. Oh, yummy!

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