Mushroom intoxication

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

Mushroom Poisoning Syndrome

Amanita smithiana

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

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 1 - 4 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

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

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

Amatoxin-containing mushroom poisoning

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

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%

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

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

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  

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 ; 24-36 hr post-ingestion Renal failure : 3 to 20 days post-ingestion ( median 8day ) Treatment Conservative Tx & Dialysis

Delayed renal failure Outcome

CASE

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 15000-10.8/31.7-217k 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 7100-11.4/33.5-127k INR 1.03 BUN/Cr 502.7/7.42 OT/PT 75/269 LDH 2266

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

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

Hospital corse Amanita smithiana - HAD #10 USG : Diffusely increased parenchymal echogenicity of both kidneys - HAD #12 Kidney GFR : Lt Kidney : 16.72 ml/min, Rt Kidney : 19.61 ml/min - Renal biopsy