1. Mushroom intoxication

2. Introduction Epidemiology Mushroom Poisoning Syndrome
In the United States, approximately 6000 mushroom exposures occur annually
95% cases, poisoning occurs as misidentification of mushroom by amateur mushroom hunter
10,000 species of mushrooms worldwide, but of these, only 50 to 100 are potentially toxic
Most no toxic effect or mild symptoms but sometimes severe toxicity and mortality
the species of mushroom ingested is not identified
Mushroom Poisoning Syndrome
There are 12 groups of identified mushroom toxins with 14 described clinical syndromes
Step of Treatment
Defining which clinical syndrome predominant
Initiating general supportive care
Administering specific treatment for each syndrome

3. Mushroom Poisoning Syndrome

9. Amanita smithiana

10. Pathogenesis Toxin Renal toxicity Human pathologic finding
Allenic norleucine
Heat-stable toxin
Renal toxicity
Causes renal toxicity in cell culture and animal models
Renal tubular epithelial cell necrosis within 12 hours
Human pathologic finding
Light microscopy : diffuse interstitial fibrosis without inflammatory changes
Renal tubules were dilated and contained cellular debris
Electron microscopy : involvement of both the proximal and distal tubules
many large vesicles present, mitochondrial membrane disruption

11. Clinical manifestations
Early GI symptom
1-6 hr post-digestion
Nausea, Vomiting, Diarrhea, Abdominal cramping
Increased urine output, Diaphoresis, Dizziness (less common)
Late renal toxicity
After days
Begin to have symptoms of renal failure, most notably oliguria and anuria
LFT abnormality
Small initial elevation in AST and ALT up to 300 to 400 units/L (six times the normal upper limit)
> Resolve by 4 day post-ingestion
Lactate dehydrogenase (LDH) has also been noted to be elevated

12. Differential diagnosis
No diagnostic lab test
Hepatotoxicity and kidney disease that overlap with the poisoning syndromes caused by amatoxin-and orellanine-containing mushrooms
DDx Amatoxin-containing mushroom poisoning  
ALT/AST up to 300 to 400 Units/L but will usually not have values over 1000 Units/L
> resolve by four days post-ingestion
DDx Orellanine-containing mushroom poisoning
More delayed onset of symptoms

13. Management Possible amatoxin-containing mushroom GI decontamination
Prevention of toxin absorption and supportive care, No specific antidote
Possible amatoxin-containing mushroom 
Initiate specific therapy for amatoxin-containing mushroom toxicity
GI decontamination 
Within one hour of ingestion, activated chalcoal administration (1 g/kg, maximum dose: 50g)
Not undergo gastric emptying by gastric lavage or syrup of ipecac
Vomiting and diarrhea 
Conservative Tx ( Fluid repletion but not overhydration )
Acute kidney injury 
The effect of dialysis on toxin elimination has not been evaluated
Dialysis typically begins four to seven days after mushroom ingestion
All cases of A. smithiana-induced renal failure have been self-limited
Supportive dialysis between two to five weeks, though in one case for six months

14. Amatoxin-containing mushroom poisoning

15. Pathogenesis Cyclopeptide toxin Hepatic toxicity Amatoxin detection
Amatoxins, alpha-amanitin : most responsible for human toxicity
Phallotoxins : subacute GI toxicity by reducing mucosal cell membrane integrity
Verotoxins : lesser role in human toxicity
Insoluble in water
Lethal dose of amatoxin: as low as 0.1 mg/kg or approximately two mushroom caps
Hepatic toxicity
Active transport by the hepatocyte membrane protein concentrates the toxin within liver cell
Organic anion transporting polypeptide(OATP), sodium taurocholate co-transporter (NTCP)
Bind to DNA-dependent RNA polymerase type II and stop intracellular protein synthesis
> ultimately resulting apoptosis
Other organ damage by rapid cellular turnover ; GI tract, proximal convoluted renal tubule
Amatoxin detection  
Laboratory confirmation of amatoxin poisoning
Urine(DOC), Blood, Gastric aspirates

16. Clinical manifestations
Gastroenteritis
Abdominal pain, vomiting, and severe, cholera-like diarrhea between 6 and 24 hours
Profound GI fluid loss lead to dehydration, acute renal failure, and circulatory shock
Apparent recovery
Improve between approximately 24 to 36 hours post-ingestion
Elevation AST/ALT between 24 and 36 hours
Fulminant hepatic and multiple organ failure
2-4 days post-ingestion, severe patients develop hepatic failure with acute renal failure,
severe gastroenteritis, acute pancreatitis.
Mortality rate : up to 30%

17. Management
Treatment should not wait for laboratory confirmation
Perform gastrointestinal decontamination : activated charcoal (AC)
Not undergo gastric emptying by gastric lavage or syrup of ipecac
Prevent enterohepatic circulation of amatoxins : multiple dose AC (MDAC)
Amatoxin circulates in the serum of poisoned patients for up to 30 hours after ingestion
0.5 grams/kg (maximum dose 50 g) every four hours and continue until four days
Aggressively manage fluid losses caused by vomiting and diarrhea
Disrupt hepatocellular uptake of amatoxins
: silibinin or high-dose intravenous penicillin-G
Provide antioxidant therapy : intravenous N-acetylcysteine
Supportive care of fulminant hepatic failure & liver transplantation
Optimal timing for the administration is within 24 hours post-ingestion

18. Amatoxin uptake inhibitors
Silibinin dihemisuccinate 
Extract of the Mediterranean milk thistle (Silybum marianum)
Inhibit OATP 1B3 and NTCP in hepatocyte membranes
Intracellular effects by stimulation of RNA polymerase type I
Initial IV loading dose of 5 mg/kg > continuous IV infusion at dose of 20 mg/kg per day
for six days or until the patient shows clinical signs of recovery
** Silymarin : contains several flavonolignans, including silybin, 10 grams daily
Legalon140mg/cap : 140mg silymarin ( 60mg silybin ) > 70 capsules
Penicillin G
Inhibit OATP 1B3 in hepatocyte membranes, weaker than silibinin in vitro
300,000 to 1,000,000 units/kg per day (maximum dose: 40 million units) continuous infusion
> 500,000 units/kg for two days
Penicillin allergy : IV ceftazidime 4.5 grams every two hours
Antioxidant effects
Enhanced amatoxin excretion into the bile
Improves cellular survival in human hepatocytes exposed to alpha-amanitin

19. Antioxidant therapy N-acetylcysteine Others
Amatoxins enhance lipid peroxidation that contributes to membrane instability and cell death
N-acetylcysteine 
Initial loading dose of 150 mg/kg IV over 15 to 60 minutes (recommend 60 minutes).
4 hour infusion at 12.5 mg/kg per hour > 16 hour infusion at 6.25 mg/kg per hour
Duration ?
AAP intoxication : check AAP concentration, INR, AST/ALT q 12 hours
Others
Cimetidine : 300 mg IV every 8 hours until clinical improvement
Vitamin C : 3 grams IV daily until clinical improvement  

20. Delayed renal failure Toxin Renal toxicity Symptom Treatment
orellanine, orellinine, cortinarin A, and cortinarin B
Renal toxicity
Orellanine : chemical similarity with herbicides paraquat and diquat
concentration in kidney, producetion interstitial nephritis and tubulointerstitial fibrosis
detected in renal tissue obtained by biopsy up to six months after exposure
Symptom 
Non-specific symptom : headache, GI trouble, myalgias, dizziness ; hr post-ingestion
Renal failure : 3 to 20 days post-ingestion ( median 8day )
Treatment
Conservative Tx & Dialysis

21. Delayed renal failure
Outcome

22. CASE

23. 58 / F
9/1 5pm 산에서 채취한 버섯 복용 후 9pm vomiting 지속되어 9/2 대구 파티마 병원 내원하여 Conservative Tx 중 Anuria 증상 있으며 BUN/Cr 상승되어 CRRT 위해 9/3 전원
Lab finding
CBC / k INR 1.28
BUN/Cr 50.3/5.89 OT/PT 167/276 LDH 2234
65 / M
9/1 5pm 산에서 채취한 버섯 복용 후 9pm vomiting, diarrhea 지속되어 9/2 대구 파티마 병원
내원하여 Conservative Tx 중 Anuria 증상 있으며 BUN/Cr 상승되어 CRRT 위해 9/3 전원
CBC / k INR 1.03
BUN/Cr 502.7/7.42 OT/PT 75/269 LDH 2266

24. HAD #1 r/o Amatoxin intoxication r/o Amanita smithiana intoxication
- Admission ICU
Penicillin G infusion
N-acetylcysteine infusion
Legalon 140mg 3T #3 PO
CRRT

25. HAD #2 r/o Amatoxin intoxication r/o Amanita smithiana - Lab finding
F : B/Cr 20.5/3.11 OT/PT 79/187 LDH 1978
M: B/Cr 41.3/6.59 OT/PT 10/154 LDH 1953
- GW transfer, 화,목,토 HD start

26. Hospital corse Amanita smithiana
- HAD #10 USG : Diffusely increased parenchymal echogenicity of both kidneys
- HAD #12 Kidney GFR : Lt Kidney : ml/min, Rt Kidney : ml/min
- Renal biopsy