1. 1 Mushrooms, Mycology and Toxicology Tracy A. Cushing, MD MPH University of Colorado School of Medicine

2. 2 Epidemiology  <0.5% of all toxic exposures over 19 years (AAPCC)  Estimated 5 exposures per 100,000 pop.  95% of exposures are unidentified  22 deaths in 19 years of AAPCC data

3. 3 Mushroom Life Cycle Spore Spore Germination Mycelium Mushroom Primordia Mature Mushroom

4. Mushroom Anatomy  Cap (pleus)  Scales  Ring (annulus)  Cup (volva)  Gills (Lamellae)  Stem (stape)  Mycelial threads 4

5. 5 Classification  10 main toxins: 1. General GI irritants 2. Cyclopeptides 3. Gyromitrin 4. Muscarine 5. Coprine 6. Ibotenic acid & muscimol 7. Psilocybin 8. Orellanine 9. Allenic norleucine 10. Myotoxins

6. 6 Classification  Onset of symptoms……. Early (0-4) Late (>6 hrs) GI toxins Ibotenic acid/muscimol Psilocybin Muscarine Coprine Cyclopeptides Gyromitrin Orelline/orellanine Allenic norleucine Myotoxin

7. 7 ….and target organ system  CNS  Hepatic  Renal  Muscle  PNS Ibotenic acid/muscimol Psilocybin Gyromitrin Amatoxins -Amanita -Galerina -Lepiota Orellanine Allenic norleucine “Myotoxin” (Tricholoma) Muscarine

8. 8 I. Gastrointestinal Toxins  Nausea, vomiting, abdominal cramping, diarrhea  Onset within 1-2 hours of ingestion**  Watery/loose stools  Symptom remission in 8-12 hours  Supportive care (IVF, antiemetics, loperamide as needed).

9. 9 GI-toxic Species  Chlorophyllum molybdites  -summer, white, large, free gills  Omphalotus illudens  -bright orange/yellow, grows in clusters along stumps/roots  -sharp-edged gills  Amanaita flavorubescens/ Amanita brunnesce  -broad yellow-brown caps  -stalks enlarge towards base

10. 10 II. Isoxazole-derived Toxins  Ibotenic acid ------------> glutamic acid  Muscimol------------> GABA  Onset 30-120 minutes  Ataxia, somnolence, delirium, hallucinations  Children: hyperactivity, hyperreflexia, seizures

11. 11 Amanita muscaria Amanita pantherina

12. 12 III. Coprine Toxins  Glutamine-derived toxin  Inhibits acetaldehyde dehydrogenase  Symptom onset within 15-30 min of alcohol ingestion  Severe headache, flushing, tachycardia, hyperventilation, palpitations  EtOH sensitivity lasts 2-72 hours  Supportive treatment, no role for AC

13. 13  Coprinus atramentarius

14. 14 IV. Muscarine  Onset 30-60 min  Salivation, urination, lacrimation, diarrhea, diaphoresis, abdominal pain, vomiting (SLUDGE)  Bradycardia, bronchospasm  Miosis Treatment:  Supportive care  Atropine for bradycardia, excessive secretions (1 mg IV adults/0.01 mg/kg IM or IV kids)

15. 15 Clitocybe, Inocybe

16. 16 V. Psilocybin & psilocin  “Magic Mushrooms”  Plentiful in North America  Structurally similar to serotonin  5HT(2)  30-60 min: ataxia, hyperkinesis, visual hallucinations.  may develop anxiety, agitation, tremors, seizures.  Resolution in 6-12 hours.

17. 17 Psilocybe cubensis

18. 18 Late-onset Toxins  Usually more severe / serious  May be hours – days after ingestion  Liver, Kidneys, Muscle  History Cyclopeptide Orellanine/orelline Gyromitrin

19. 19 A. Cylopeptide Toxins  Most toxic: “amatoxin” found in Amanita phalloides; A. tenuifoilia; A. virosa.  -Galeria autumnalis; G.marginata, G. venenata  Lepiota josserandi; L. helveola  Limited protein binding, low plasma concentration  ++ Enterohepatic circulation  LD 50 = 0.1 mg /kg  1.5-2.5 mg amanitin in 1 gm A.phalloides

20. 20 Amanita Phalloides “Death Angel”

21. 21 Galeria autumnalis Lepiota josserandi

22. 22 Clinical Presentation  Stage I – gastroenteritis, diarrhea (5-24 hrs)  Stage II – transient improvement (12-36 hrs)  Stage III – hepatic failure; renal failure; death (2-6 DAYS)  Amatoxin inhibits RNA polymerase II - no transcription

23. 23 Treatment  Supportive, ABC’s  Fluids / electrolytes / glucose  Thiocytic Acid (?)  Penicillin G (1 gm/kg/d) (?)  Silibinin (milk thistle) (?)  Cimetidine  NAC - encephalopathy  Liver Transplantation (1983)   10-20% mortality (higher in kids)

24. 24 B. Gyromitrin  Gyromitra species  Inhibits GABA by interfering with pyridoxine  Europe > North America  Onset 5-10 hours  Headache, weakness, nausea, vomiting, cramping, delirium, seizures  Rarely progresses to coma, hepatorenal failure, or death

25. 25 Treatment  Supportive  Activated charcoal  Benzodiazepines  Pyridoxine 70 mg/kg IV for intractable seizures

26. 26 Gyromitra sp. (false morel)

27. 27 C. Orellanine & orelline  Onset 24-36 hrs (delayed GI toxicity)  HA, chills, myalgias, nausea, vomiting, abdominal/flank pain  Oliguric renal failure (days-weeks)  Hematuria, leukocyturia, proteinuria

28. 28 Cortinarius speciosissimus  US: cortinarius rainierensis

29. 29 Treatment ã Supportive ã Dialysis ã Kidney Transplant ã Permanent kidney failure 8-50% ã No role for prophylactic dialysis

30. 30 Newcomers to the Tox Scene  Amanita smithiana - allenic norleucine; renal failure  Tricholoma equestre  -unknown toxin; severe rhabdomyolysis

31. 31 Amanita smithiana  All 13 cases in Pacific NW  Onset 30 min - 12 hrs (early GI toxicity)  Nausea, vomiting, anorexia, malaise, dizziness, diaphoresis  Acute renal failure 4-6 days later  Elevated BUN, Creatinine, ALT

32. 32  No deaths  Prolonged dialysis  Toxin: allenic norleucine (amino acid)  Early onset GI symptoms vs. late (A. smithiana vs. C. rainierensis)  Treatment: - Supportive - Activated charcoal - Dialysis

33. 33 Tricholoma equestre  12 patients-all had eaten 3 meals of mushrooms  Southwestern France  Onset 24-36 hours  Fatigue, myalgias, proximal muscle weakness  Mean CPK 22,000 women; 34,000 men  AST 1200/ALT 600  3 deaths

34. 34 Tricholoma equestre  Toxin unknown-acute myopathy on biopsy  CK elevation reproduced in mice  No US cases

35. 35References  Auerbach, P. & Schneider, S. “Mushroom Toxicity” Wilderness Medicine 4th Ed. Mosby 2001; 1141-1160  Bedry, R. et al “Wild mushroom intoxication as a cause of rhabdomyolysis” NEJM 345; Sept 13, 2001; 798-802  Bickel, M. et al “Severe rhabdomyolysis, acute renal failure, and posterior encephalopathy after ‘magic mushroom’ abuse” Euro J Em Med 2005; 12; 306-308  Burton, J. et al “Liver Transplantation in Mushroom Poisoning” J Clin Gastroenterology 2002; 35(3); 276-280  Diaz, J. “Evolving global epidemiology, syndromic classification, general management, and prevention of unknown mushroom poisoning” Crit Care Med 2005 Vol. 33, No. 2; 419-426  Goldfrank, L.R: Mushrooms in Goldfrank’s Toxicologic Emergencies 8th Ed. Goldfrank, L., Flomenbaum, N. et al. Appleton and Lange. 2006 1564-1576  Marx, J., Hochberger, R., Walls, R. Rosen’s Emergency Medicine 5th Ed Ch. 158 “Plants, Mushrooms, and Herbal Medicines” Mosby 2002; 2203-2205  Vicellio, P. & Shih, R. “Mushroom Poisoning” Emergency Toxicology 2nd Ed. Lippincott-Raven 1998; 1081-1086