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M & M!Mushrooms and Marine!

Howard A. Greller MD FACEP FACMT!

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!

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Mushroom Anatomy!and identification!

cup (volva)

(mycelial threads)

(lamella)

(annulus)

(pileus)

(stape)

Cap

Ring

Gills

Spores

Stalk Hyphae

Mushroom ID!• Books!

• Location!

• Size, color, shape!

• Spore print!

• Spore ID!

• Mycologist!

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http://namyco.org/!

Tricksy mushrooms!yeeesssss. . . precious . . .!

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Yes, horsey?!

pssst. . . Nicholas . . .!eat these. they’re yummy.!

There are old mushroom hunters, and there are bold mushroom

hunters. But there are no old, bold mushroom hunters.!

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Mushroom Taxonomy!Classification!

Cyclopeptides!Group I!

Amanita phalloides! Amanita verosa!

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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!

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Cyclopeptides!Amatoxins (cyclic octapeptides)!

- heat stabile!

- interferes with RNA polymerase II, protein translation!- sodium-taurocholate co-transporter polypeptide!- centrilobular hepatic necrosis with intact architecture!

- α-amanitin !

- poorly absorbed, enterohepatic recirculation!

Cyclopeptides!Phallotoxins (cyclic heptapeptides)!- Phalloidin!- limited absorption!- interrupts actin polymerization!- impairs cell membrane function!

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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!

Phase III!

- “quiescent” phase (no n&v)!- hepatotoxicity!

- hepatic, renal, pancreatic!- death 2-3 days after ingestion!

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Therapeutics - cyclopeptides!Early!- volume resuscitation!- ? MDAC!- ? hemodialysis / hemoperfusion!Late(r)!- thioctic (α-lipoic) acid!- penicillin G (1.6 million U/kg/day)!- silymarin (silibinin) from milk thistle!- n-acetylcysteine!- cimetidine!

Therapeutics!

• Bioartificial liver!

• Liver transplant!

• Early >> late!

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Gyrometrin!Group II!

gyromitra esculenta! morchella esculenta!

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Gyromitra species - gyromitrin!

- found in spring under conifers!- G. esculenta, G. californica, G. brunnea, G. infula!

- often confused for the edible morel!

Gyromitrin!- N-methyl-N-formyl hydrazone!

- heat sensitive (although fumes have ? toxicity)!- hydrolyzed to monomethylhydrazine !

gyromitrin! monomethylhydrazine!

➜➜➜!

Toxicity - gyromitrin!- asymptomatic for at least 6 hours!

- seizures!- initial GI symptoms!

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glutamic acid! GABA!GAD!

pyridoxine!

pyridoxal 5’ phosphate!

PPK!hydrazines!

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Therapeutics - gyromitrin!Early!- ? GI decontamination!Seizures!- benzodiazepines!- pyridoxine (vit B6)!

- 70 mg/kg up to 5 grams!- anesthetic barbiturates!

pyridoxine!

Muscarine!Group III!

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clitocybe clavipes! inocybe geophylia!

Clitocybe species - muscarine!- C. dealbata (‘the sweater’),C. illudens!

Inocybe species - muscarine!- I. Iacera, I. geophylla!

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Muscarine!Quarternary ammonium compound!

- Not nicotinic!- Does not cross BBB (no CNS) !

- Not susceptible to ACHase hydrolysis!

acetylcholine! muscarine!

Toxicity - muscarine!- Rapid onset of toxicity (within 30 minutes)!

- NO nicotinic findings (i.e. mydriasis, tachycardia, weak)!- SLUDGE!

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Therapeutics - muscarine!- Atropine (infrequently required)!

- NO oximes (i.e. 2-PAM)!

- ACLS doses to start!- titrate until relief of symptoms, dry secretions!

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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)!

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Coprine!Toxicity comes from primary metabolite!- 1-aminocyclopropanol!

coprine! 1-aminocyclopropanol!

- ethanol present or ingested within 24-48 hours!

➜➜➜!

- usually okay if done together (delayed toxicity)!

Toxicity - coprine!- rapid onset of toxicity (within 1 hour)!

- flushing!- disulfiram reaction!

- nausea & vomiting!- tachycardia!- headache!

- inhibits aldehyde dehydrogenase!

disulfiram!

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Therapeutics - coprine!- intravenous fluids!- antiemetics!- analgesics!- time (for ethanol to be metabolized)!

+! =!

Ibotenic acid / Muscimol!Group V!

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Amanita muscaria! Amanita gemmata!

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!

- structurally similar to glutamic acid!

- decarboxylated metabolite of ibotenic acid!

Ibotenic acid!

Muscimol!

- similar to GABA!

ibotenic acid! muscimol!

glutamic acid! GABA!

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Toxicity - ibotenic acid / musicmol!

- ibotenic acid stimulates glutamic acid receptors!

- rapid onset (0.5 - 2 hours), resolves 6-12 hours!

- musicmol acts as a GABA agonist!

- mild GI upset!

- somnolence, ataxia!

- hallucinosis, excitation!

- 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!

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Falling in love is like eating (poisonous) mushrooms.!

!You never know if it is the real thing

until it’s too late.!

Psilocybin / Psilocin!Group VI!

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Psilocybe cubensis! Psilocybe cyanescens!

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!

- rapid onset, medium duration (1 - 6 hours)!- interact with serotonin receptors, no adrenergic effects!

psilocybin! serotonin! psilocin!

- psilocybin is rapidly hydrolyzed to psilocin!

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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!

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Therapeutics - psilocybin / psilocin!Primary supportive care!- benzodiazepines!- avoid neuroleptics!

- risk hallucinogen persistent perceptive disorder (HPPD)!

Little Brown Mushrooms!Group VII!

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russula emetica! Chlorophyllum molybdites!

Little Brown Mushrooms (LBM) - GI toxins!- Boletes, Lactarius sp., Omphalotus sp., Tricholoma sp.!- Lycoperdon sp., Agaricus, Entoloma, Chlorophyllum sp.!

- Often mistaken for edible or hallucinogenic!- Largest group of mushrooms!

LBM - GI toxins!Heterogenous toxins!

- unknown specific mechanism or toxin!- terpenes and lactones!

- direct irritant? allergic phenomenon?!

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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!

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Orelline / Orellanine!Group VIII!

cortinarius speciosissimus! cortinarius archeri!

Cortinarius sp. - orelline / orellanine!- C. orellanus, C. speciosissimus, C.rainierensis (NA)!- Only recent recognition of toxicity!

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Oreline / Orellanine!Bipyridyl agents!

- heat stable!- similar to paraquat/diquat!

- 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 - orelline / orellanine!Primary supportive care!- intravenous hydration!- hemodialysis!- transplantation reported, but very rare!Prevention!

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Allenic norleucine!Group IX!

amanita smithiana! tricholoma magnivelare!

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Amanita smithiana - allenic norleucine!- mistaken for tricholoma magnivelare (matsutake)!- Pacific N.W. US!

Allenic norleucine!2-amino-4,5-hexadienoic acid!

- may be the compound !- limited mechanistic information!

Toxicity - allenic norleucine!

- early GI distress (0.5 - 12 hours)!- malaise, diaphoresis, dizzy!

- 4-6 days after ingestion!- acute renal failure!

- ALT, LDH elevated !

Phase I!

Phase II!

- renal tubular toxin!

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Therapeutics - allenic norleucine!Primary supportive care!- no known antidote!- ? AC!- consider hemodialysis given location/history, etc.!Prevention!

Myotoxin!Group X!

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tricholoma equestre! tricholoma flavovirens!

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

Toxicity - myotoxin!

- delayed symptoms 24-72 hours after ingestion!- fatigue, myalgia, weakness!

- nausea, diaphoresis, facial erythema!- CPK elevations and rhabdomyolysis!

- biopsy shows acute myopathy!- acute myocarditis, dysrhythmias, CHF possible!

- unknown what the toxin is!

- mortality as high as 25%!- therapy is supportive!

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N Engl J Med 2001;345!

mushroom philosophy!• Color, odor, taste, location DO NOT predict

toxicity!

• Symptoms NOT always from mushroom toxin!

• pesticides, allergies, other (i.e. sauce)!

• Early symptoms good, late symptoms bad!

• exception Group IX allenic norleucine!

• not always just one type of mushroom!

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wrap up!•  Identifiable early symptoms (< 6 hours)!

• Supportive care!

• Delayed onset of symptoms!

• MDAC!

• Admission!

• More aggressive therapy?!

All mushrooms are edible . . . once.!

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OVERVIEW!

CIGUATERA!

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Ciguatera!- endemic to warm waters, bottom reef dwellers!

- more than 500 species!- large fish (more than 4 lbs)!

- > 50k cases in U.S./year!- Hawaii & Florida > 90% of cases!

- viscera and gonads!

Parrot Fish! Sea Bass!

35 degrees north to 35 degrees south!

from May through August!

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Amberjack! Red Snapper!

Ciguatoxin!- bioaccumulated & concentrated dinoflagellates!

- gambierdiscus toxicus!- heat stable, lipid soluble!- odorless, tasteless, colorless!

Grouper!

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SYMPTOMS!•  diaphoresis, chills!

•  abdominal pain!

•  nausea / vomiting / diarrhea!

•  dysuria !

•  painful defecation / ejaculation!

•  temperature reversal!

•  dental pain (“loose”)!

•  paresthesias!

•  lingual, perioral, extremity!

•  arthralgia, myalgias!

•  vertigo, ataxia!

VOLTAGE SENSITIVE SODIUM CHANNEL!

CONCERNING SYMPTOMS!

•  t-wave abnormalities!

•  bradycardia!

•  hypotension!

•  pulmonary edema!

•  respiratory paralysis !

•  coma!

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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!

- GI and diaphoresis!- more than 75% within 12 hours!

- neurologic symptoms between 2 and 24 hours!

- There is an ELISA assay!

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Sturgeon!

Therapeutics - ciguatoxin!- GI decon (self)!

- Symptomatic therapy!- consider AC!

- antihistamines!- atropine for bradycardia!

- Mannitol!- unknown mechanism, ? reverse neuro ?!- early >> late!- 1 g/kg of 20% solution over 30min / 2-6 hr!- theories!

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Yellowfin Tuna!

Scombroid!- temperate or tropical waters!- non-scombroidae (most common)!

- scombroidae!- skipjack, tuna, mackerel!

- mahi mahi, amberjack!

- first described cases!

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Scombroid - histamine!

- histidine decarboxylated to histamine!

histidine! histamine!

histidine!decarboxylase!

- heat stable!

- improper refrigeration (> 20℃ / 68℉)!- bacteria on fish skin!

- peppery tasting!- “honeycomb” appearance rare!

Symptoms - scombroid!- within 5 to 90 minutes!

- n/v/d, dizziness, palps, hypotension!

- lasts 12-24 hours untreated!

- rarely puritis, urticaria, angioedema!

- flushing (face, neck, torso)!

- bronchospasm, visual loss!

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Mahi-Mahi!

Differential - scombroid!- Allergic reaction!- MSG reaction!- Disulfiram reaction!

- Carcinoid!- Zollinger-Ellison syndrome!

- Tyramine reaction!

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Therapeutics - scombroid!- Supportive!- H1 / H2 blockers!- Serious reactions!

- Reassurance and education!- bronchodilators, epi, etc!

diphenhydramine!

TETRODOTOXIN!

fugu! hapalochlaena maculosa!

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Tetrodotoxin!- puffer fish and blue-ringed octopus!

- fresh and saltwater!

- octopus is small (< 5”) and non-aggressive!- venom expressed by beak!

- puffer fish skin and gut make toxin!- frogs, horseshoe crabs/eggs, salamanders!

Toxicity - tetrodotoxin!- highest concentrations in liver and ovary!

- female more toxic than male!- blocks voltage-gated Na channels!

- blocks axonal neurotransmission!- PNS, CNS, autonomic, cardiac!

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Symptoms - tetrodotoxin!- GI within 3 hours!

- n/v/d, abd pain!- Neurologic minutes to hours!

- Ascending paralysis, respiratory depression!

- Death reported within 17 minutes!!

- progressive parasthesias!- progressive weakness (bulbar), ataxia!

- Survival beyond 24 hours excellent prognosis!

- Preserved mental status!

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!

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Differential Dx - tetrodotoxin!- Botulism!

- Progressive supranuclear palsy (PSP)!- Guillan-Barré!

- Ciguatera!

FUGU WA KUITASHII, INOCHI WA OSHISHII!

Therapeutics - tetrodotoxin!- aggressive supportive care!

- no specific laboratory study!- diagnostic testing to exclude other causes!

- admission, observation!

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SHELLFISH POISONING!

Shellfish poisoning!

- paralytic shellfish poisoning!

- amnestic shellfish poisoning!

- dinophysis or prorocentrum!

- neurotoxic shellfish poisoning!

- “diarrhetic” shellfish poisoning!

- dinoflagellate or algae contamination!

- protogonyaulax catanella & tamarensis!

- ptychodiscus brevis (gymnodinium breve)!

- nitzschia pungens!

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Paralytic Shellfish Poisoning!

Toxicity - saxitoxin!- blocks voltage-sensitive Na channel!

- similar to tetrodotoxin!

saxitoxin! s.aks-itoxin!

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Symptoms - saxitoxin!- neurologic (within 30 min)!

- paresthesias, numbness, “floating”, HA, vertigo!

- GI symptoms less common!

- ataxia, muscular weakness!- dysphagia, dysarthria, dysphonia, blindness!- paralysis!

- weakness can last weeks!

- supportive!Therapeutics - saxitoxin!

Neurotoxic Shellfish Poisoning!

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Toxicity - brevetoxin!- stimulates voltage-sensitive Na channel!

- similar to ciguatera!

brevetoxin!

ciguatera!

Symptoms - brevetoxin!

- neurologic!

- vertigo, ataxia, tremor!

- GI symptoms!

- dysphagia, bradycardia, ⬇ DTRs, mydriasis!- NO paralysis!

- n/v/d, abd pain, rectal burning!

- paresthesias, “hot/cold reversal”, myalgias, HA!

- GI with neuro symptoms simultaneously!- incubation ≈ 3 hr (15 min - 18 hr)!- duration ≈ 17 hr (1 - 72 hr)!

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Amnestic Shellfish Poisoning!

Toxicity - domoic acid!- glutamate agonist!

- analog of glutamic and kainic acids!

domoic acid! kainic acid!

- AMPA & kainate receptor damage ➜ Ca influx!

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Symptoms - domoic acid!

- neurologic!- memory loss (10% long term anterograde)!

- GI symptoms less common!- seizures, hemiparesis!- ophthalmoplegia!- chewing/grimacing!

- onset within 5 hr (15 min - 36 hr)!

- carries mortality of ~ 2% (older)!

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Diarrhetic Shellfish Poisoning!

Toxicity - okadoic acid!- phosphatase a1 & a2 inhibitor!

- phosphorylates proteins control Na secretion!

okadoic acid!

- permeability of intestinal cell membranes!- degeneration of absorptive epithelium!

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Symptoms - okadoic acid!- GI symptoms (30 min - 2 hours)!

- n/v/d, abd pain!- self limited (2 - 3 days)!

- supportive!Therapeutics - okadoic acid!

Questions?!