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