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Home , Amanita gemmata, Cortinarius archeri, Gyromitra esculenta, Lepiota helveola, Strychnine

M & M and Marine Howard A. Greller

Introduction

• Mushrooms are the fruiting body of a

• More than 40,000 worldwide

• 5000 species in U.S., < 2% poisonous

• 79% poison < 6 years old

• Raw >> cooked

• and anaphylaxis more common than poisoning Anatomy and identification

General properties of mushrooms. Not everyone has the “cup”

()

()

(annulus)

cup ()

(stape) (mycelial threads)

Mushroom ID

• Books

• Location

• Size, color, shape

• print

• Spore ID

• Mycologist Melzer’s reagent (mycologist prefers) - 20 mL H2O, 1.5 g K iodide, 0.5 g iodine, 20 g hydrate - Defines presence of = 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 . . . 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 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 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 helveola & Lepiota species - cyclopeptides - G. autumnalis, G. marginata, G. venenata - L. helveola, L. josserandi, Lbrunneoincarnata

Cyclopeptides (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 - cyclopeptides Phase I - not earlier than 6 hours, lasts up to 24 hours - initial cholera-like , then / Phase II - “quiescent” phase (no n&v) - 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 - ? / 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 - 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 esculenta esculenta

Gyromitra species - - G. esculenta, G. californica, G. brunnea, G. infula - found in spring under - often confused for the edible morel

Gyromitrin - N-methyl-N-formyl hydrazone - hydrolyzed to - heat sensitive (although fumes have ? toxicity)

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gyromitrin monomethylhydrazine Toxicity - gyromitrin - asymptomatic for at least 6 hours - initial GI symptoms -

GAD - decarboxylase, PPK - pyridoxal phosphokinase ! - 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 - - pyridoxine (vit B6) - 70 mg/kg up to 5 grams - anesthetic

pyridoxine Group III

clavipes 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. , , weak)

Therapeutics - muscarine - (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)

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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)

+ = / Group V

Amanita muscaria Amanita gemmata

Modern series have a lower case fatality rate

Amanita muscaria - ibotenic acid / muscimol - A. muscaria (fly ), 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,

- 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 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 - 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 - and lactones - unknown specific mechanism or - 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 failure - ALT, LDH elevated - renal tubular toxin Therapeutics - allenic norleucine Primary supportive care - no known - ? AC - consider hemodialysis given location/history, etc. Prevention

Myotoxin Group X tricholoma equestre tricholoma flavovirens

Tricholoma equestre - myotoxin - T. flavovirens - “man on horseback” (Fr), “yellow knight” (US)

Toxicity - myotoxin - unknown what the toxin is - delayed symptoms 24-72 hours after ingestion - fatigue, myalgia, weakness - nausea, diaphoresis, facial erythema - CPK elevations and - biopsy shows acute myopathy - acute myocarditis, dysrhythmias, CHF possible - mortality as high as 25% - therapy is supportive N Engl J Med 2001;345

mushroom philosophy

• Color, odor, taste, location DO NOT predict toxicity

• Symptoms NOT always from mushroom toxin

• , , other (i.e. sauce)

• Early symptoms good, late symptoms bad

• exception Group IX allenic norleucine

• not always just one type of mushroom wrap up

• Identifiable early symptoms (< 6 hours)

• Supportive care

• Delayed onset of symptoms

• MDAC

• Admission

• More aggressive therapy?

All mushrooms are edible . . . once. Goldfrank’s Far greatest proportion of foodborne illness is bacterial and viral related

Goldfrank’s OVERVIEW

CIGUATERA Amber jack, red snapper, grouper, sea bass, barracuda, sturgeon, parrot fish Ciguatera - endemic to warm waters, bottom reef dwellers - more than 500 species - large fish (more than 4 lbs) - viscera and gonads - > 50k cases in U.S./year - Hawaii & Florida > 90% of cases

Parrot fish and giant sea bass

35 degrees north to 35 degrees south

from May through August Amberjack and red snapper

Ciguatoxin - bioaccumulated & concentrated dinoflagellates - gambierdiscus toxicus - heat stable, lipid soluble - odorless, tasteless, colorless

Grouper SYMPTOMS

• diaphoresis, chills • temperature reversal

• abdominal pain • dental pain (“loose”)

• nausea / vomiting / • paresthesias diarrhea • lingual, perioral, • dysuria extremity

• painful defecation / • arthralgia, myalgias ejaculation • , ataxia

Lipophilic sodium channel activators, bind site 5. Other toxins include brevitoxins. Binding VOLTAGE SENSITIVE SODIUM CHANNEL leads to prolonged firing, persistent activation & increased axonal volume.

CONCERNING SYMPTOMS

• t-wave abnormalities

• bradycardia

• hypotension

• pulmonary edema

• respiratory paralysis

• Toxicity - ciguatoxin - most prominent symptoms are neurologic - dysesthesias (i.e. hot/cold reversal) - “dental pain” (i.e. tooth are loose or “itch) - small percentage with bradycardia / hypotension

- Bagnis, Am J Trop Med Hyg, 1979

Barracuda

Ciguatoxin - symptoms 2-6 hours after eating - more than 75% within 12 hours - GI and diaphoresis - neurologic symptoms between 2 and 24 hours

- There is an ELISA assay Sturgeon

Reduce axonal edema, Therapeutics - ciguatoxin dissociate ciguatoxin binding, - GI decon (self) free radical scavenger, Na - consider AC - Symptomatic therapy channel blockade - antihistamines Case reports for (early - atropine for bradycardia better??), 2002 RCT = no - Mannitol - unknown mechanism, ? reverse neuro ? benefit (maybe late present??) - early >> late Other treatments: ?TCAs = - 1 g/kg of 20% solution over 30min / 2-6 hr - theories block Na channels yellofin tuna

Nonscobroid (mahi mahi, amberjack) much more often implicated than Scombroidae Scombroid (skipjack, tuna, mackerel) - temperate or tropical waters - non-scombroidae (most common) - mahi mahi, amberjack - scombroidae - skipjack, tuna, mackerel - first described cases

properly frozen and preserved tuna Elaborated by Enterobacteriaceae (Proteus, Morganella, Klebsiella, Aerobacter, Scombroid - Escherichia) and Clostridium, Lactobacillus - improper refrigeration (> 20℃ / 68℉) - bacteria on fish skin - histidine decarboxylated to histamine - heat stable - peppery tasting - “honeycomb” appearance rare

histidine decarboxylase histidine histamine

truncal and facial flushing

Symptoms - scombroid - within 5 to 90 minutes - flushing (face, neck, torso) - n/v/d, dizziness, palps, hypotension - rarely puritis, urticaria, angioedema - bronchospasm, visual loss - lasts 12-24 hours untreated mahi mahi

Differential - scombroid - Allergic reaction - MSG reaction - Disulfiram reaction - Tyramine reaction - Carcinoid - Zollinger-Ellison syndrome

Goldfrank’s Toxicologic Emergencies Therapeutics - scombroid - Supportive

- H1 / H2 blockers - Serious reactions - bronchodilators, epi, etc - Reassurance and education

diphenhydramine

TETRODOTOXIN

fugu and blue-ringed octopus

fugu hapalochlaena maculosa 50-100 species implicated Pufferfish, Blowfish - puffer fish and blue-ringed octopus - fresh and saltwater - frogs, horseshoe crabs/eggs, salamanders - puffer fish skin and gut make toxin - octopus is small (< 5”) and non-aggressive - venom expressed by beak

60x more toxic than strychnine or , 1250x than Toxicity - tetrodotoxin - highest concentrations in liver and ovary Blue ringed octopus also contains a mixture of hyaluronidases, tyramine, - female more toxic than male acetylcholine, histamine, dopamine, - blocks voltage-gated Na channels , octopine, . - blocks axonal neurotransmission - PNS, CNS, autonomic, cardiac HA, dizziness, “floating”, early miosis & later mydriasis, salivation/diaphoresis/ Symptoms - tetrodotoxin bronchospasm - GI within 3 hours - n/v/d, abd pain - Neurologic minutes to hours - progressive parasthesias - progressive weakness (bulbar), ataxia - Ascending paralysis, respiratory depression - Preserved mental status - Death reported within 17 minutes! - Survival beyond 24 hours excellent prognosis

JAPANESE 4 STAGES

• Oral paresthesias, ? GI

• Advanced paresthesias, ext paralysis, + DTR

• Gross incoordination, aphonia, dysphagia, resp distress, hypotension, fully conscious

• Mental impairment, resp paralysis, ↓BP HA, dizziness, “floating”, early miosis & later mydriasis, salivation/diaphoresis/ Differential Dx - tetrodotoxin bronchospasm - Botulism - Guillan-Barré - Progressive supranuclear palsy (PSP) - Ciguatera

“I want to eat fugu, but I don’t want to die”

> 1,500 restaurants in Tokyo Avg. 150 people/year with s&s. (61% death rate)

FUGU WA KUITASHII, INOCHI WA OSHISHII

HA, dizziness, “floating”, early miosis & later mydriasis, salivation/diaphoresis/ Therapeutics - tetrodotoxin bronchospasm - aggressive supportive care - diagnostic testing to exclude other causes - no specific laboratory study - admission, observation SHELLFISH POISONING

Shellfish poisoning - dinoflagellate or algae contamination - paralytic shellfish poisoning - protogonyaulax catanella & tamarensis - neurotoxic shellfish poisoning - ptychodiscus brevis (gymnodinium breve) - amnestic shellfish poisoning - nitzschia pungens - “diarrhetic” shellfish poisoning - dinophysis or prorocentrum Paralytic shellfish poisoning http://www.whoi.edu/

Toxicity - - blocks voltage-sensitive Na channel - similar to tetrodotoxin

saxitoxin s.aks-itoxin

Algae “bloom” at certain times and under certain conditions. Red Tide associated with PSP, but can be other colors. Symptoms - saxitoxin - neurologic (within 30 min) - paresthesias, numbness, “floating”, HA, vertigo - ataxia, muscular weakness - dysphagia, dysarthria, dysphonia, blindness - paralysis - weakness can last weeks - GI symptoms less common Therapeutics - saxitoxin - supportive

Neurotoxic shellfish poisoning http://www.whoi.edu/ Toxicity - brevetoxin - stimulates voltage-sensitive Na channel - similar to ciguatera

brevetoxin

ciguatera

Clams

Symptoms - brevetoxin - GI symptoms - n/v/d, abd pain, rectal burning - neurologic - paresthesias, “hot/cold reversal”, myalgias, HA - vertigo, ataxia, - dysphagia, bradycardia, ⬇ DTRs, mydriasis - NO paralysis - GI with neuro symptoms simultaneously - incubation ≈ 3 hr (15 min - 18 hr) - duration ≈ 17 hr (1 - 72 hr) Amnestic shellfish poisoning

Amnestic shellfish poisoning http://www.whoi.edu/

Toxicity - - glutamate agonist - analog of glutamic and kainic acids - AMPA & kainate damage ➜ Ca influx

domoic acid Symptoms - domoic acid - onset within 5 hr (15 min - 36 hr) - neurologic - memory loss (10% long term anterograde) - chewing/grimacing - ophthalmoplegia - seizures, hemiparesis - GI symptoms less common - carries mortality of ~ 2% (older)

diarrhetic shellfish poisoning Diarrhetic shellfish poisoning http://www.whoi.edu/

Phosphorylation of proteins controlling Na secretion of intestinal cells or influencing Toxicity - okadoic acid permeability of cell membranes - phosphatase a1 & a2 inhibitor S. intestine: degeneration of absorp epith - phosphorylates proteins control Na secretion - permeability of intestinal cell membranes - degeneration of absorptive epithelium

okadoic acid

may through august most prominent times Symptoms - okadoic acid - GI symptoms (30 min - 2 hours) - n/v/d, abd pain - self limited (2 - 3 days) Therapeutics - okadoic acid - supportive