M & M Mushrooms and Marine Howard A. Greller Introduction • Mushrooms are the fruiting body of a fungus • More than 40,000 species worldwide • 5000 species in U.S., < 2% poisonous • 79% poison < 6 years old • Raw >> cooked • Allergy and anaphylaxis more common than poisoning Mushroom Anatomy and identification General properties of mushrooms. Not everyone has the “cup” (pileus) (lamella) (annulus) cup (volva) (stape) (mycelial threads) Mushroom ID • Books • Location • Size, color, shape • Spore print • Spore ID • Mycologist Melzer’s reagent (mycologist prefers) - 20 mL H2O, 1.5 g K iodide, 0.5 g iodine, 20 g chloral hydrate - Defines presence of amatoxin = dark blue Meixner reaction (reliability = doubtful) - http://namyco.org/ Several drops 10-12 N HCl on newspaper to amatoxin-containing spore - blue reaction Tricksy mushrooms yeeesssss. precious . Cortinarius speciosissimus. Nephrotoxic (non-US). Wound up with a renal transplant (from his daughter). His wife and pssst. Nicholas . the Lord he was dining eat these. they’re yummy. with are still on dialysis. Famous mushroom quote number one There are old mushroom hunters, and there are bold mushroom hunters. But there are no old, bold mushroom hunters. Mushroom Taxonomy Classification Famous mushroom quote number two Falling in love is like eating (poisonous) mushrooms. You never know if it is the real thing until it’s too late. Cyclopeptides Group I Amanita phalloides Amanita verosa Modern series have a lower case fatality rate Amanita species - cyclopeptides - A. phalloides (death cap), A. virosa (death angel) - 95% mushroom related fatalities, 50% case fatality - One mushroom enough to kill an adult Galerina autumnalis Lepiota helveola Galerina & Lepiota species - cyclopeptides - G. autumnalis, G. marginata, G. venenata - L. helveola, L. josserandi, Lbrunneoincarnata Cyclopeptides Amatoxins (cyclic octapeptides) - α-amanitin - heat stabile - poorly absorbed, enterohepatic recirculation - interferes with RNA polymerase II, protein translation - sodium-taurocholate co-transporter polypeptide - centrilobular hepatic necrosis with intact architecture Cyclopeptides Phallotoxins (cyclic heptapeptides) - Phalloidin - limited absorption - interrupts actin polymerization - impairs cell membrane function Cyclopeptides Virotoxins (cyclic heptapeptides) - Virotoxin - ? human toxicity Toxicity - cyclopeptides Phase I - not earlier than 6 hours, lasts up to 24 hours - initial cholera-like diarrhea, then nausea/vomiting Phase II - “quiescent” phase (no n&v) - hepatotoxicity Phase III - hepatic, renal, pancreatic - death 2-3 days after ingestion thioctic acid is a co-enzyme in TCA cycle, free radical scavenger Therapeutics - cyclopeptides PCN displaces amanitin from albumin, Early blocks uptake, binds circulating - volume resuscitation amatoxins, prevents amanitin from - ? MDAC - ? hemodialysis / hemoperfusion binding to RNA polymerase Late(r) Silymarin block amatnitin uptake - thioctic (α-lipoic) acid NAC is good for what ails the liver - penicillin G (1.6 million U/kg/day) Cimetidine potentially inhibits - silymarin (silibinin) from milk thistle metabolism - n-acetylcysteine - cimetidine Bioartificial Liver (“bridge” to recovery or T/P) Therapeutics Liver Transplant (EARLY > late) •Bioartificial liver •Liver transplant •Early >> late Gyrometrin Group II gyromitra esculenta morchella esculenta Gyromitra species - gyromitrin - G. esculenta, G. californica, G. brunnea, G. infula - found in spring under conifers - often confused for the edible morel Gyromitrin - N-methyl-N-formyl hydrazone - hydrolyzed to monomethylhydrazine - heat sensitive (although fumes have ? toxicity) ➜➜➜ gyromitrin monomethylhydrazine Toxicity - gyromitrin - asymptomatic for at least 6 hours - initial GI symptoms - seizures GAD - glutamic acid decarboxylase, PPK - pyridoxal phosphokinase hydrazines ! - inactivate pyridoxal 5’ phosphate ! - inhibit pyridoxal phosphokinase ! - complex with and lead to increased urinary excretion of pyridoxine GAD glutamic acid GABA pyridoxal 5’ phosphate PPK hydrazines pyridoxine Therapeutics - gyromitrin Early - ? GI decontamination Seizures - benzodiazepines - pyridoxine (vit B6) - 70 mg/kg up to 5 grams - anesthetic barbiturates pyridoxine Muscarine Group III clitocybe clavipes inocybe geophylia Clitocybe species - muscarine - C. dealbata (‘the sweater’),C. illudens Inocybe species - muscarine - I. Iacera, I. geophylla Muscarine Quarternary ammonium compound - Does not cross BBB (no CNS) - Not nicotinic - Not susceptible to ACHase hydrolysis acetylcholine muscarine When you think of rain, always bring a “sweater” Toxicity - muscarine - Rapid onset of toxicity (within 30 minutes) - SLUDGE - NO nicotinic findings (i.e. mydriasis, tachycardia, weak) Therapeutics - muscarine - Atropine (infrequently required) - ACLS doses to start - titrate until relief of symptoms, dry secretions - NO oximes (i.e. 2-PAM) Coprine Group IV Coprinus atramentarius Coprinus comatus Coprinus - coprine - C. comatus, C. atramentarius - Undergo “autodigestion” - inky caps - pleasant tasting, edible mushrooms - problematic with ethanol (disulfiram like reaction) Coprine Toxicity comes from primary metabolite - 1-aminocyclopropanol - ethanol present or ingested within 24-48 hours - usually okay if done together (delayed toxicity) ➜➜➜ coprine 1-aminocyclopropanol Toxicity - coprine - rapid onset of toxicity (within 1 hour) - inhibits aldehyde dehydrogenase - disulfiram reaction - flushing - nausea & vomiting - tachycardia - headache disulfiram Therapeutics - coprine - intravenous fluids - antiemetics - analgesics - time (for ethanol to be metabolized) + = Ibotenic acid / Muscimol Group V Amanita muscaria Amanita gemmata Modern series have a lower case fatality rate Amanita muscaria - ibotenic acid / muscimol - A. muscaria (fly agaric), A. pantherina, A. gemmata - popular children’s books and games - Babar, Super Mario Bros. NOT MUSCARINIC, NOT ANTI MUSCARINIC Ibotenic acid / muscimol Ibotenic acid - structurally similar to glutamic acid Muscimol - decarboxylated metabolite of ibotenic acid - similar to GABA ibotenic acid muscimol glutamic acid GABA Toxicity - ibotenic acid / musicmol - rapid onset (0.5 - 2 hours), resolves 6-12 hours - mild GI upset - ibotenic acid stimulates glutamic acid receptors - hallucinosis, excitation - musicmol acts as a GABA agonist - somnolence, ataxia - seizures rare (GABAB agonism) - adults manifest more GABA-ergic symptoms - pediatrics excitatory transmission predominates Therapeutics - ibotenic acid / muscimol - supportive care - benzodiazepines for seizures, excitation - no role for flumazenil for sedation Psilocybin / Psilocin Group VI Psilocybe cubensis Psilocybe cyanescens Gymnopilus spectabilis, Psathyrella foenisecii Psilocybe species - psilocybin / psilocin - P. cyanescens, P. cubensis, G. spectabilis, P. foenisecii - “magic mushrooms” - Native american religious customs, drug culture - when handled, develop blue bruises Psilocybin / psilocin Structural similarity to serotonin - interact with serotonin receptors, no adrenergic effects - rapid onset, medium duration (1 - 6 hours) - psilocybin is rapidly hydrolyzed to psilocin psilocybin serotonin psilocin illusion hallucination pallinopsia synesthesia Toxicity - psilocybin / psilocin - Early GI effects (0.5 - 1 hour) - illusions - synesthesias - “heightened perceptions” - true hallucinations are rare and dose dependent - autonomic response to altered perceptions Therapeutics - psilocybin / psilocin Primary supportive care - benzodiazepines - avoid neuroleptics - risk hallucinogen persistent perceptive disorder (HPPD) Little Brown Mushrooms Group VII russula emetica Chlorophyllum molybdites Little Brown Mushrooms (LBM) - GI toxins - Boletes, Lactarius sp., Omphalotus sp., Tricholoma sp. - Lycoperdon sp., Agaricus, Entoloma, Chlorophyllum sp. - Largest group of mushrooms - Often mistaken for edible or hallucinogenic LBM - GI toxins Heterogenous toxins - terpenes and lactones - unknown specific mechanism or toxin - direct irritant? allergic phenomenon? Toxicity - LBM - Early GI effects (0.5 - 3 hours) - rapid resolution without significant consequence - Paxillus Syndrome (rare) - P. involutus, Clitocybe claviceps, Boletus luridus - involutin? (diphenylcyclopenteneone) - immune-mediated hemolytic anemia, renal failure - repeated long term exposure Therapeutics - LBM Primary supportive care - intravenous hydration - antiemetics - antidiarrheals Prevention Orelline / Orellanine Group VIII cortinarius speciosissimus cortinarius archeri Cortinarius sp. - orelline / orellanine - C. orellanus, C. speciosissimus, C.rainierensis (NA) - Only recent recognition of toxicity Oreline / Orellanine Bipyridyl agents - similar to paraquat/diquat - heat stable - direct irritant? allergic phenomenon? orellanine paraquat Toxicity - orelline / orellanine - asymptomatic for 24 - 26 hours - headache, chills, anorexia, n/v (flu-like) - oliguric renal failure - ATN - similar prognosis to other causes of ATN Therapeutics - LBM Primary supportive care - intravenous hydration - hemodialysis - transplantation reported, but very rare Prevention Allenic norleucine Group IX amanita smithiana tricholoma magnivelare Amanita smithiana - allenic norleucine - mistaken for tricholoma magnivelare (matsutake) - Pacific N.W. US Allenic norleucine 2-amino-4,5-hexadienoic acid - limited mechanistic information - may be the compound Toxicity - allenic norleucine Phase I - early GI distress (0.5 - 12 hours) - malaise, diaphoresis, dizzy Phase II - 4-6 days after ingestion - acute renal