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M & MMushrooms 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 Anatomyand identification
cup (volva)
(mycelial threads)
(lamella)
(annulus)
(pileus)
(stape)
Mushroom ID• Books
• Location
• Size, color, shape
• Spore print
• Spore ID
• Mycologist
General properties of mushrooms. Not everyone has the “cup”
http://namyco.org/
Tricksy mushroomsyeeesssss. . . precious . . .
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 blueMeixner reaction (reliability = doubtful) - Several drops 10-12 N HCl on newspaper to amatoxin-containing spore - blue reaction
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.
Cortinarius speciosissimus. Nephrotoxic (non-US). Wound up with a renal transplant (from his daughter). His wife and the Lord he was dining with are still on dialysis. . .
Famous mushroom quote number one
Mushroom TaxonomyClassification
Falling in love is like eating (poisonous) mushrooms. You
never know if it is the real thing until it’s too late.
CyclopeptidesGroup I
Famous mushroom quote number two
Amanita phalloides Amanita verosa
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
Modern series have a lower case fatality rate
Galerina & Lepiota species - cyclopeptides- G. autumnalis, G. marginata, G. venenata- L. helveola, L. josserandi, Lbrunneoincarnata
CyclopeptidesAmatoxins (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
CyclopeptidesPhallotoxins (cyclic heptapeptides)- Phalloidin- limited absorption- interrupts actin polymerization- impairs cell membrane function
CyclopeptidesVirotoxins (cyclic heptapeptides)- Virotoxin- ? human toxicity
Toxicity - cyclopeptidesPhase I- not earlier than 6 hours, lasts up to 24 hours- initial cholera-like diarrhea, then nausea/vomitingPhase II
Phase III
- “quiescent” phase (no n&v)- hepatotoxicity
- hepatic, renal, pancreatic- death 2-3 days after ingestion
Therapeutics - cyclopeptidesEarly- volume resuscitation- ? MDAC- ? hemodialysis / hemoperfusionLate(r)- thioctic (α-lipoic) acid- penicillin G (1.6 million U/kg/day)- silymarin (silibinin) from milk thistle- n-acetylcysteine- cimetidine
thioctic acid is a co-enzyme in TCA cycle, free radical scavengerPCN displaces amanitin from albumin, blocks uptake, binds circulating amatoxins, prevents amanitin from binding to RNA polymeraseSilymarin block amatnitin uptakeNAC is good for what ails the liverCimetidine potentially inhibits metabolism
Therapeutics
•Bioartificial liver
•Liver transplant
•Early >> late
GyrometrinGroup II
Bioartificial Liver (“bridge” to recovery or T/P)Liver Transplant (EARLY > late)
gyromitra esculenta morchella esculenta
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
glutamic acid GABAGAD
pyridoxine
pyridoxal 5’ phosphate
PPKhydrazines
GAD - glutamic acid decarboxylase, PPK - pyridoxal phosphokinasehydrazines! - inactivate pyridoxal 5’ phosphate! - inhibit pyridoxal phosphokinase! - complex with and lead to increased urinary excretion of pyridoxine
Therapeutics - gyromitrinEarly- ? GI decontaminationSeizures- benzodiazepines- pyridoxine (vit B6)
- 70 mg/kg up to 5 grams- anesthetic barbiturates
pyridoxine
MuscarineGroup III
clitocybe clavipes inocybe geophylia
Clitocybe species - muscarine- C. dealbata (‘the sweater’),C. illudens
Inocybe species - muscarine- I. Iacera, I. geophylla
MuscarineQuarternary ammonium compound
- Not nicotinic- Does not cross BBB (no CNS)
- 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)
- NO nicotinic findings (i.e. mydriasis, tachycardia, weak)- SLUDGE
Therapeutics - muscarine- Atropine (infrequently required)
- NO oximes (i.e. 2-PAM)
- ACLS doses to start- titrate until relief of symptoms, dry secretions
CoprineGroup 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)
CoprineToxicity 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
Therapeutics - coprine- intravenous fluids- antiemetics- analgesics- time (for ethanol to be metabolized)
+ =
Ibotenic acid / MuscimolGroup V
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
Modern series have a lower case fatality rate
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
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
Psilocybin / PsilocinGroup VI
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 / psilocinStructural 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
Gymnopilus spectabilis, Psathyrella foenisecii
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 / psilocinPrimary supportive care- benzodiazepines- avoid neuroleptics
- risk hallucinogen persistent perceptive disorder (HPPD)
Little Brown MushroomsGroup VII
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 toxinsHeterogenous toxins
- unknown specific mechanism or toxin- terpenes and lactones
- 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 - LBMPrimary supportive care- intravenous hydration- antiemetics- antidiarrhealsPrevention
Orelline / OrellanineGroup VIII
cortinarius speciosissimus cortinarius archeri
Cortinarius sp. - orelline / orellanine- C. orellanus, C. speciosissimus, C.rainierensis (NA)- Only recent recognition of toxicity
Oreline / OrellanineBipyridyl 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 - LBMPrimary supportive care- intravenous hydration- hemodialysis- transplantation reported, but very rarePrevention
Allenic norleucineGroup IX
amanita smithiana tricholoma magnivelare
Amanita smithiana - allenic norleucine- mistaken for tricholoma magnivelare (matsutake)- Pacific N.W. US
Allenic norleucine2-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
Therapeutics - allenic norleucinePrimary supportive care- no known antidote- ? AC- consider hemodialysis given location/history, etc.Prevention
MyotoxinGroup X
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
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
wrap up• Identifiable early symptoms (< 6 hours)
• Supportive care
• Delayed onset of symptoms
• MDAC
• Admission
• More aggressive therapy?
All mushrooms are edible . . . once.
OVERVIEW
CIGUATERA
Goldfrank’sFar greatest proportion of foodborne illness is bacterial and viral related
Goldfrank’s
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
35 degrees north to 35 degrees south
from May through August
Amber jack, red snapper, grouper, sea bass, barracuda, sturgeon, parrot fish
Parrot fish and giant sea bass
Ciguatoxin- bioaccumulated & concentrated dinoflagellates
- gambierdiscus toxicus- heat stable, lipid soluble- odorless, tasteless, colorless
Amberjack and red snapper
Grouper
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
Lipophilic sodium channel activators, bind site 5. Other toxins include brevitoxins. Binding leads to prolonged firing, persistent activation & increased axonal volume.
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
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
Barracuda
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
Sturgeon
Reduce axonal edema, dissociate ciguatoxin binding, free radical scavenger, Na channel blockadeCase reports for (early better??), 2002 RCT = no benefit (maybe late present??)Other treatments: ?TCAs = block Na channels
Scombroid- temperate or tropical waters- non-scombroidae (most common)
- scombroidae- skipjack, tuna, mackerel
- mahi mahi, amberjack
- first described cases
yellofin tuna
Nonscobroid (mahi mahi, amberjack) much more often implicated than Scombroidae (skipjack, tuna, mackerel)
properly frozen and preserved tuna
Scombroid - histamine
- histidine decarboxylated to histamine
histidine histamine
histidinedecarboxylase
- 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
Elaborated by Enterobacteriaceae (Proteus, Morganella, Klebsiella, Aerobacter, Escherichia) and Clostridium, Lactobacillus
truncal and facial flushing
Differential - scombroid- Allergic reaction- MSG reaction- Disulfiram reaction
- Carcinoid- Zollinger-Ellison syndrome
- Tyramine reaction
mahi mahi
Goldfrank’s Toxicologic Emergencies
Therapeutics - scombroid- Supportive- H1 / H2 blockers- Serious reactions
- Reassurance and education- bronchodilators, epi, etc
diphenhydramine
TETRODOTOXIN
fugu hapalochlaena maculosa
fugu and blue-ringed octopus
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
50-100 species implicatedPufferfish, Blowfish
60x more toxic than strychnine or curare, 1250x than cyanide
Blue ringed octopus venom also contains a mixture of hyaluronidases, tyramine, acetylcholine, histamine, dopamine, tryptamine, octopine, taurine.
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
HA, dizziness, “floating”, early miosis & later mydriasis, salivation/diaphoresis/bronchospasm
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
HA, dizziness, “floating”, early miosis & later mydriasis, salivation/diaphoresis/bronchospasm
“I want to eat fugu, but I don’t want to die”
> 1,500 restaurants in TokyoAvg. 150 people/year with s&s. (61% death rate)
HA, dizziness, “floating”, early miosis & later mydriasis, salivation/diaphoresis/bronchospasm
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
Toxicity - saxitoxin- blocks voltage-sensitive Na channel
- similar to tetrodotoxin
saxitoxin s.aks-itoxin
Paralytic shellfish poisoninghttp://www.whoi.edu/
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
- GI symptoms less common
- ataxia, muscular weakness- dysphagia, dysarthria, dysphonia, blindness- paralysis
- weakness can last weeks
- supportiveTherapeutics - saxitoxin
Neurotoxic shellfish poisoninghttp://www.whoi.edu/
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)
Clams
Toxicity - domoic acid- glutamate agonist
- analog of glutamic and kainic acids
domoic acid kainic acid
- AMPA & kainate receptor damage ➜ Ca influx
Amnestic shellfish poisoning
Amnestic shellfish poisoninghttp://www.whoi.edu/
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)
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
Diarrhetic shellfish poisoninghttp://www.whoi.edu/
Phosphorylation of proteins controlling Na secretion of intestinal cells or influencing permeability of cell membranesS. intestine: degeneration of absorp epith
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)
- supportiveTherapeutics - okadoic acid