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MUSHROOMS-ORELLANINE/ORELLINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) The Orellanine-containing mushrooms are commonly referred to as Orellanine-and orellinine-containing mushrooms.

Specific Substances

    A) CORTINARIUS SPECIES
    1) Cortinarius limonius
    2) Cortinarius orellanoides - Cortinarius rubellus
    3) Cortinarius orellanus
    4) Cortinarius orellanosus
    5) Cortinarius rainierensis
    6) Cortinarius rubellus
    7) Cortinarius speciosissimus - Cortinarius rubellus
    8) Deadly Cort (common name for Cortinarius gentilis)
    9) Deadly webcap
    10) Orellanine
    11) Orelline mushrooms
    12) Poznan Cort (common name for Cortinarius orellanus)

Available Forms Sources

    A) SOURCES
    1) IMPLICATED MUSHROOMS
    a) Cortinarius orellanus was first implicated as being poisonous in Poland in the 1950s. By 1965, 135 cases had been reported (Grzymala, 1965). Cortinarius orellanoides (described in the literature as Cortinarius speciosissimus) was first recognized as being poisonous in 1972 in Finland and by 1974, 4 cases had been reported (Hulmi et al, 1974). By 1983, 180 cases of poisoning from these 2 species had been reported from Europe(Schumacher & Hoiland, 1983; Short et al, 1980; Marichael et al, 1977; Favre et al, 1976). Cortinarius orellanus poisoning has been reported in central Europe (Hungary) (Bozzay & Lazar, 1994).
    b) OTHERS - Cortinarius rainierensis (likely to be identical to Cortinarius orellanus), possibly C. callisteus, C. gentilis, C. splendens, and other members of the Cortinarius cinnamomeus-Cortinarius semisanguineus group have also been identified as being toxic (Watling, 1980; Tebbett & Caddy, 1984; Colon et al, 1982).
    c) A woman developed chronic renal failure after ingesting Cortinarius orellanosus mushrooms found under an oak tree in western Michigan (Judge et al, 2010).
    d) It has been observed that compounds belonging to the orellanine group of toxins have not as yet been found in either Cortinarius gentilis or Cortinarius splendens, but that other nephrotoxins could be present (Bresinsky & Besl, 1990).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Orellanine/orelline containing mushrooms are inadvertently ingested by amateur mycologists and curious children. The toxin is found in only a few Cortinarius spp mushrooms. The Cortinarius spp are dome shaped brown mushrooms with gills.
    B) TOXICOLOGY: Orellanine/orelline is a nephrotoxic alkaloid. The toxin is stable when cooked, frozen, or dried. The mechanism of toxicity is incompletely understood, though there is some evidence of oxidation in the kidney leading to a toxic metabolite that affects DNA and RNA synthesis.
    C) EPIDEMIOLOGY: Renal toxicity from ingestions of mushrooms containing orellanine/orelline is rare. Chronic renal insufficiency or failure results in approximately 50% of confirmed ingestions. There has only been 1 confirmed case of orellanine poisoning in North America. The Cortinarius spp is the largest genus of mushroom species and few contain the toxin orellanine. The range of orellanine containing mushrooms in the United States in unclear.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Patients ingesting mushrooms containing orellanine/orelline may develop nausea, vomiting, and diarrhea shortly after ingestion. These symptoms are typically mild and are often overlooked. Delayed anorexia, nausea, vomiting, chills, headache, lethargy, myalgias, arthralgias, polyuria, polydipsia, flank pain, paresthesias, and other constitutional symptoms are indications of progression to nephrotoxicity. These symptoms are delayed 2 to 14 days with a median of 8.5 days until presentation with renal insufficiency. Mild transaminitis may occur.
    2) SEVERE TOXICITY: Severe toxicity can lead to chronic renal failure and death. Urinary habit changes ranging from polyuria to anuria may occur. Patients may require lifelong hemodialysis or renal transplantation.

Laboratory Monitoring

    A) A basic metabolic panel and hepatic enzymes, bilirubin and INR should be obtained in any patient with significant gastritis associated with mushroom ingestion and in patients with constitutional symptoms associated with subacute mushroom ingestion.
    B) An ECG should be obtained to screen for electrolyte abnormalities such as hypocalcemia or hyperkalemia.
    C) Renal biopsy will reveal a tubulo-interstitial nephritis in most cases with fibrosis in approximately 1/3 of the cases.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Symptomatic and supportive care should be given for gastrointestinal toxicity. After the stomach is felt to be empty of mushroom material, antiemetics should be administered liberally. Fluid administration should be given until the patient is felt to be isovolemic in order to maximize glomerular filtration rate. Electrolyte abnormalities should be treated as appropriate.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Management of severe toxicity should focus on renal replacement therapy. Renal transplantation should be considered for patients with anuric renal failure. No toxicity is expected from dermal exposure to orellanine.
    C) DECONTAMINATION
    1) PREHOSPITAL: No prehospital decontamination is indicated.
    2) HOSPITAL: In general, decontamination is impractical because of the delayed presentation of poisoned patients. Patients that present within a few hours of ingestion due to recognition of their mistake should be given activated charcoal.
    D) AIRWAY MANAGEMENT
    1) No airway compromise is anticipated from orellanine poisoning; however, co-ingestions should be considered and airway management considered as appropriate.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Orellanine may be present in the serum at the time of presentation; however, hemodialysis should only be considered for patients with evidence of renal insufficiency or failure, not for toxin removal.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Home management is not appropriate for confirmed cases of orellanine ingestion. Most patients with unknown mushroom species ingestions can be managed at home. Patients with delayed symptoms should be referred to a health care facility.
    2) OBSERVATION CRITERIA: Patients with nausea and vomiting without renal insufficiency can be observed and managed with symptomatic care.
    3) ADMISSION CRITERIA: Patients with renal insufficiency or failure should be admitted to the hospital. Patients with recalcitrant gastritis should be admitted.
    4) CONSULT CRITERIA: A mycologist should be consulted when orellanine poisoning is considered and a mushroom is available for identification. A nephrologist should be consulted for any patient with renal failure.
    H) PITFALLS
    1) Failure to identify an available mushroom in patients with renal insufficiency may result in providers attributing the toxicity to other causes. Failure to maximize GFR may lead to prolonged deposition of the toxin in the kidneys as well as concomitant damage from hypovolemia.
    I) TOXICOKINETICS
    1) Orellanine may be present in the serum for up to several weeks post-ingestion. The toxin is activated by metabolism through hepatic oxidative metabolism (P450 system). Median time to presentation is 8.5 days though renal insufficiency likely occurs within several days of ingestion and progresses over the intervening time.
    J) DIFFERENTIAL DIAGNOSIS
    1) Ingestion of mushrooms containing allenic norleucine, such as the more common species Amanita smithiana, can cause renal failure. In these patients, renal function recovery typically occurs within several months after ingestion while orellanine-induced renal failure is permanent. Dehydration secondary to gastritis from mushroom ingestion can cause renal insufficiency; however, this will improve with fluid resuscitation.

Range Of Toxicity

    A) TOXICITY: The toxic dose of mushrooms containing orellanine is unknown largely due to patient variability in susceptibility to the toxin and variability of the amount of toxin between mushrooms. Mortality is rare if renal replacement therapy is provided.

Clinical Effects

Summary Of Exposure

    A) USES: Orellanine/orelline containing mushrooms are inadvertently ingested by amateur mycologists and curious children. The toxin is found in only a few Cortinarius spp mushrooms. The Cortinarius spp are dome shaped brown mushrooms with gills.
    B) TOXICOLOGY: Orellanine/orelline is a nephrotoxic alkaloid. The toxin is stable when cooked, frozen, or dried. The mechanism of toxicity is incompletely understood, though there is some evidence of oxidation in the kidney leading to a toxic metabolite that affects DNA and RNA synthesis.
    C) EPIDEMIOLOGY: Renal toxicity from ingestions of mushrooms containing orellanine/orelline is rare. Chronic renal insufficiency or failure results in approximately 50% of confirmed ingestions. There has only been 1 confirmed case of orellanine poisoning in North America. The Cortinarius spp is the largest genus of mushroom species and few contain the toxin orellanine. The range of orellanine containing mushrooms in the United States in unclear.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Patients ingesting mushrooms containing orellanine/orelline may develop nausea, vomiting, and diarrhea shortly after ingestion. These symptoms are typically mild and are often overlooked. Delayed anorexia, nausea, vomiting, chills, headache, lethargy, myalgias, arthralgias, polyuria, polydipsia, flank pain, paresthesias, and other constitutional symptoms are indications of progression to nephrotoxicity. These symptoms are delayed 2 to 14 days with a median of 8.5 days until presentation with renal insufficiency. Mild transaminitis may occur.
    2) SEVERE TOXICITY: Severe toxicity can lead to chronic renal failure and death. Urinary habit changes ranging from polyuria to anuria may occur. Patients may require lifelong hemodialysis or renal transplantation.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) Headache was reported by Short et al (1980) and Grzymala (1959) in patients poisoned by Cortinarius orellanoides (reported as C. speciosissimus).
    2) INCIDENCE: Of 132 patients with orellanine poisoning, 66% experienced headaches (Benjamin, 1995).
    B) CHILL
    1) A constant sensation of coldness has been reported by some patients (Grzymala, 1957).
    2) INCIDENCE: Of 132 patients with orellanine poisoning, 58% experienced chills (Benjamin, 1995).
    C) PARESTHESIA
    1) Paresthesias of the extremities were reported in one group studied (Bouget et al, 1990).
    D) TINNITUS
    1) Tinnitus was noted in 49 of 132 patients (37%) (Grzymala, 1959).
    E) DROWSY
    1) INCIDENCE: Somnolence was seen in 41 of 132 (31%) patients in one study (Grzymala, 1959); loss of consciousness is also possible (Michelot & Tebbett, 1990).
    F) SEIZURE
    1) Seizures and muscle tremors of the face have been reported (Michelot & Tebbett, 1990).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) Nausea and vomiting may occur within 36 hours (Judge et al, 2010; Frank et al, 2009; Short et al, 1980) but is often NOT considered severe enough to warrant treatment and may diminish after a few hours to nothing more than nausea and anorexia.
    2) Persistent complaints of gastrointestinal symptoms (lasting months) have been reported infrequently in some patients (Horn et al, 1997).
    3) INCIDENCE: Of 132 patients with orellanine poisoning, 81% experienced nausea and 70% reported vomiting (Benjamin, 1995).
    B) LOSS OF APPETITE
    1) Anorexia may be reported after these poisonings and may be prolonged in duration (Short et al, 1980).
    C) THIRST FINDING
    1) A severe, burning thirst has been reported as a symptom of orellanine poisoning (Short et al, 1980). Patients often have a dry mouth (Lampe & Ammirati, 1990).
    2) INCIDENCE: Of 132 patients with orellanine poisoning, 98% described thirst after intoxication (Benjamin, 1995).
    D) DIARRHEA
    1) Diarrhea and constipation have occurred in 132 cases, 34 (26%) had constipation, 28 (21%) diarrhea (Grzymala, 1959).
    2) CASE REPORT: Vomiting and diarrhea developed in a 53-year-old woman 3 days after ingesting Cortinarius orellanosus mushrooms (Judge et al, 2010).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) A mild cytolytic hepatitis may occur (Michelot & Tebbett, 1990).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) SUMMARY
    a) Within 3 to 20 days symptoms of renal failure occur with lumbar and flank pain, chills and night sweats (usually without fever), oliguria, occasionally followed by diuresis (Judge et al, 2010; Calvino et al, 1998) and slow recovery or followed by chronic renal failure requiring prolonged intermittent dialysis or renal transplant (Frank et al, 2009; Eivindson et al, 2000; Holzl et al, 1997; Bouget et al, 1990; Hall et al, 1987; Grzymala, 1957).
    1) Numerous species may contain the bipyridine derivate orellanine; the species Cortinarius orellanoides (= C. speciosissimus) contains orellanine, and has produced acute renal failure (Holzl et al, 1997).
    b) INCIDENCE: Renal failure occurs in about 30% to 46% of cases (Bouget et al, 1990; Grzymala, 1965) (Grault, 1981).
    c) INCUBATION: Typically a long incubation period (10 to 14 days; average onset 1 week) with frequent renal involvement (Holzl et al, 1997; Horn et al, 1997; Kilner et al, 1999).
    d) OUTCOME: In about 30% to 75% of exposures, acute renal failure develops. Effects are irreversible in approximately half of the cases (Judge et al, 2010; Horn et al, 1997).
    1) Improvement is generally seen in a few weeks. The remaining cases may require hemodialysis for months or years (Bouget et al, 1990; Kilner et al, 1999) and renal transplantation is possible (Svendsen et al, 2002).
    2) CASE SERIES
    a) Between 1979 and 1991, 26 patients in Sweden were intoxicated with C. orellanoides (= C. speciosissimus):
    1) 35% developed end stage renal failure;
    2) 27% had initial acute renal failure but regained normal function in 5 to 12 years;
    3) 38% never had renal impairment.
    4) Ref: Holmdahl & Blohme, 1992
    3) CASE REPORTS
    a) A 53-year-old woman developed vomiting and diarrhea 3 days after ingesting Cortinarius orellanosus mushrooms found under an oak tree in western Michigan. She presented to the ED nine days after ingestion with oliguria and acute renal failure, necessitating urgent hemodialysis. Renal biopsy revealed severe interstitial edema, moderate interstitial nephritis, and acute tubular necrosis. Despite supportive care, she remained anuric, requiring peritoneal dialysis 5 times a week (Judge et al, 2010).
    b) A 66-year-old health female developed acute renal failure (urea 32.8 mmol/L, creatinine 1032 mcmol/L), along with hyponatremia (121 mmol/L), 4+ proteinuria and microscopic hematuria, 10 days after ingesting Cortinarius orellanus. The patient was treated with hemodialysis and started on prednisolone 60 mg once daily along with N-acetylcysteine (using the standard administration schedule for acetaminophen poisoning {150 mg/kg over 15 minutes, then 50 mg/kg over 4 hours followed by 100 mg/kg over 16 hours}).
    1) Renal function improved over the next 7 days and hemodialysis was discontinued after 17 days after ingestion. Prednisolone was gradually weaned over 6 weeks and 2 months after exposure serum urea was 9.5 mmol/L and creatinine 168 mcmol/L (Kilner et al, 1999).
    c) Four patients developed varying symptoms of intoxication following a shared meal which contained Cortinarius orellanus. Three (ages 37, 78 and 70) of the 4 patients developed acute renal failure which required hemodialysis; the two elderly patients required chronic hemodialysis. The fourth patient, a 56-year-old female developed symptoms of nausea, vomiting and malaise, and recovered completely without therapy (Horn et al, 1997).
    d) Four patients (18 to 26 years of age) developed acute tubular injury and interstitial nephritis resulting in renal failure after ingesting unknown amounts of Cortinarius orellanus mushrooms. Three patients required intermittent dialysis; one of them required chronic hemodialysis (Frank et al, 2009).
    e) Eight patients (4 women and 4 men; mean age: 51 +/- 9 years) presented with a 4-day history of persistent upper gastrointestinal tract symptoms (eg, nausea, vomiting, and abdominal pain) about 6 days after ingesting a meal containing cortinarius orellanus mushrooms (4 patients ingested large amounts; 3 ingested moderate amounts; 1 ingested medium amounts). Two patients were diabetic and 3 patients were being treated for hypertension. All patients developed acute renal injury, with 6 patients in the most severe stage. Four patients were treated with renal replacement therapy (RRT). Six patients received N-acetylcystine and corticosteroid treatment, but a beneficial effect of this combination was not demonstrated in patients with either acute renal injury or chronic renal disease. Overall, the ingested amount of C. orellanus correlated with the severity of both acute renal injury or chronic renal disease. Although all patients survived, 7 patients had chronic renal disease 12 months postingestion of whom 3 required chronic RRT and 2 other patients had advanced chronic renal disease (Grebe et al, 2013).
    B) CRUSH SYNDROME
    1) Postmortem examination of fatal cases has revealed tubular necrosis and interstitial nephritis (Grzymala, 1957; Short et al, 1980).
    2) Tubulointerstitial lesions characterized by inflammatory edema and infiltrates of polynuclear cells have also been reported (Bouget et al, 1990; Calvino et al, 1998).
    3) ANIMAL DATA: This has also been reported in animal experiments using Cortinarius orellanoides (= C. speciosissimus (Holmdahl et al, 1987).
    4) CASE REPORTS
    a) Symptoms of renal failure did not occur in a 32-year-old ex-drug addict until 10 days after ingesting Cortinarius orellanus (Calvino et al, 1998). The patient later admitted eating the mushroom believing it had hallucinogenic properties. Although recovery of diuresis occurred 9 days after admission following hydration and hemodialysis, the patient had a serum creatinine of 5 mg/dL five months after exposure.
    b) In a similar case, a 32-year-old, previously healthy male ingested part of a C. orellanus mushroom and developed signs/symptoms of renal failure within 4 days of exposure. Renal biopsy indicated that tubulointerstitial damage and inflammation were present. The patient remained on hemodialysis and was awaiting a kidney transplant from a sibling (Eivindson et al, 2000).
    C) ALBUMINURIA
    1) Albuminuria may be seen during the renal phase of the illness (Michelot & Tebbett, 1990; Kilner et al, 1999).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RENAL NECROSIS
    a) MICE injected IP with orellanine developed kidney necrosis.

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLOOD IN URINE
    1) CASE SERIES: Microscopic hematuria and leukocyturia were seen in 7 of 26 patients exposed to C. orellanus (Bouget et al, 1990).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) CASE SERIES: A skin rash was noted in 3 of 26 patients after ingesting a soup of C. orellanus (Bouget et al, 1990).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) Myalgias have been reported in poisoned patients as have lumbar and loin pain (Short et al, 1980).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) A basic metabolic panel and hepatic enzymes, bilirubin and INR should be obtained in any patient with significant gastritis associated with mushroom ingestion and in patients with constitutional symptoms associated with subacute mushroom ingestion.
    B) An ECG should be obtained to screen for electrolyte abnormalities such as hypocalcemia or hyperkalemia.
    C) Renal biopsy will reveal a tubulo-interstitial nephritis in most cases with fibrosis in approximately 1/3 of the cases.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Depending upon the stage when patient is first seen the following are found: elevated BUN and creatinine levels vary with the degree and duration of renal damage (Michelot & Tebbett, 1990).
    4.1.3) URINE
    A) URINALYSIS
    1) Microscopic (and rarely gross) hematuria, massive albuminuria with RBC casts and leukocytes may be present in a concentrated urine early. Urine with low specific gravity still containing albumin and a few casts is frequently found as renal failure progresses (Michelot & Tebbett, 1990; Benjamin, 1995).

Methods

    A) OTHER
    1) A rapid qualitative test to detect the presence of orellanine in a cortinariod fruiting body has been proposed by Schumacher & Holland (1983):
    1) Either a fresh or dried mushroom (fruity body) is crushed in water, allowed to stand for 10 minutes, then filtered.
    2) The filtrate is mixed with an equal amount of 3% ferric chloride hexahydrate dissolved in 0.5 normal hydrochloric acid.
    3) A dark, grey-blue color, somewhat like ink, presumes the presence of orellanine.
    B) CHROMATOGRAPHY
    1) RENAL BIOPSY - Orellanine may be detected by thin-layer chromatography in renal biopsy tissue up to 6 months after intoxication (Frank et al, 2009).
    2) Orellanine has been detected in plasma using fluorometry on cellulose chromatograms after thin layer chromatography and photodecomposition (Andary et al, 1989).
    3) A method to measure bipyridines in human plasma by gas chromatography was developed by Brash (1976) but has NOT yet been reported as used in the diagnosis or management of Cortinarius poisoning (Brash et al, 1976).
    4) The cortinarius toxins have also been identified in methanalic extracts of the mushrooms (fruiting bodies) by thin layer chromatography. High performance liquid chromatography has also been used to identify these toxins (Tebbett & Caddy, 1983).
    5) Rapior et al (1989) detected orellanine in biological fluids by direct spectrofluorometry on two-dimensional thin-layer chromatograms after specific photo decomposition to orelline (Rapior et al, 1989).
    6) Rohrmoser et al (1997) described a method to use thin layer chromatography (TLC) technique to detect orellanine in renal biopsy material; this technique however, was NOT found to be beneficial in detecting toxin in urine or blood samples (Rohrmoser et al, 1997).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with renal insufficiency or failure should be admitted to the hospital. Patients with recalcitrant gastritis should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Home management is not appropriate for confirmed cases of orellanine ingestion. Most patients with unknown mushroom species ingestions can be managed at home. Patients with delayed symptoms should be referred to a health care facility.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) A mycologist should be consulted when orellanine poisoning is considered and a mushroom is available for identification. A nephrologist should be consulted for any patient with renal failure.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with nausea and vomiting without renal insufficiency can be observed and managed with symptomatic care.

Monitoring

    A) A basic metabolic panel and hepatic enzymes, bilirubin and INR should be obtained in any patient with significant gastritis associated with mushroom ingestion and in patients with constitutional symptoms associated with subacute mushroom ingestion.
    B) An ECG should be obtained to screen for electrolyte abnormalities such as hypocalcemia or hyperkalemia.
    C) Renal biopsy will reveal a tubulo-interstitial nephritis in most cases with fibrosis in approximately 1/3 of the cases.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) No prehospital decontamination is indicated.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: In general, decontamination is impractical because of the delayed presentation of poisoned patients. Patients that present within a few hours of ingestion due to recognition of their mistake should be given activated charcoal.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) A basic metabolic panel and hepatic enzymes, bilirubin and INR should be obtained in any patient with significant gastritis associated with mushroom ingestion and in patients with constitutional symptoms associated with subacute mushroom ingestion.
    2) An ECG should be obtained to screen for electrolyte abnormalities such as hypocalcemia or hyperkalemia.
    3) Renal biopsy will reveal a tubulointerstitial nephritis in most cases with fibrosis in approximately 1/3 of the cases.
    B) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    C) TRANSPLANTATION
    1) Kidney transplants may be required in those who do not regain renal function. Five such transplants were reported by Holmdahl & Blohme (1992) (Holmdahl & Blohme, 1992).
    D) EXPERIMENTAL THERAPY
    1) CYCLOPHOSPHAMIDE: Nieminen et al (1976) reported that a single dose of cyclophosphamide (150 milligrams/kilogram) given at the same time as an oral dose of C. orellanoides (= C. speciosissimus) prevented the renal inflammation in the treated male rats. No evidence could be found that this has been tried in humans after an ingestion.
    2) STEROIDS AND ANTIOXIDANT THERAPY: A 66-year-old previously healthy female developed acute renal failure following intoxication by Cortinarius orellanus and was treated with hemodialysis and started on 60 mg prednisolone once daily along with intravenous N-acetylcysteine using the standard administration for acetaminophen poisoning (150 mg/kg over 15 minutes, then 50 mg/kg over 4 hours followed by 100 mg/kg over 16 hours). The patient recovered and was dialysis-free by day 17.
    a) RATIONALE: In vitro studies suggest that when orellanine is exposed to oxidizing agents it can result in a large oxygen consumption and depletion of glutathione that can render cells more susceptible to oxidant damage.
    1) Cortinarius poisoning often results in interstitial nephritis. Steroids have been used frequently for other forms of interstitial nephritis. Despite some success with corticosteroid use, further investigation is warranted (Kilner et al, 1999). Benjamin (1995) states that steroids have NO proven benefit.
    b) In a case series of 8 patients with acute renal injury after ingesting a meal containing C. orellanus mushrooms, 6 patients received N-acetylcystine and corticosteroid treatment. A beneficial effect of this combination was not demonstrated in patients with either acute renal injury or chronic renal disease. Overall, the ingested amount of C. orellanus correlated with the severity of both acute renal injury or chronic renal disease (Grebe et al, 2013).
    3) ANTIOXIDANT THERAPY (NAC and SELENIUM): In another study, two adults were inadvertently poisoned after eating mushrooms containing cortinarius speciosissimus and developed the characteristic symptoms of toxicity including acute renal failure. The first patient was started on a regimen of IV N-acetylcysteine (following the standard acetaminophen poisoning administration schedule) with the addition of selenium 1,000 mcg bolus; followed by 1,000 mcg/24 hours. NAC was continued at a dose of 600 mg twice a day and selenium, 500 mcg daily. The patient still required dialysis for worsening renal function, but was weaned 9 days later and laboratory parameters slowly returned to normal over the next three months. The second patient was also treated with IV NAC and selenium and did not require dialysis and was discharged within a few days with improved laboratory parameters. It is not clear if this therapy had any impact on the recovery of renal function (Wornle et al, 2004).

Enhanced Elimination

    A) HEMOPERFUSION
    1) Extracorporeal hemoperfusion over resin filters has been recommended by some authors in patients seen within 1 week of ingestion (Schumacher & Hoiland, 1983). Two cases treated with combined hemoperfusion and hemodialysis had normal creatinine values (Heath et al, 1980).
    2) Some authors suggest that early treatment with hemodialysis or hemoperfusion may prevent irreversible renal failure (Holmdahl et al, 1984).
    3) There is no controlled clinical data to evaluate the efficacy of early hemoperfusion or hemodialysis. Routine use of these modalities is generally not recommended (Benjamin, 1995).
    B) HEMODIALYSIS
    1) May be necessary to correct fluid and electrolyte imbalance either as continued intermittent dialysis or until kidney transplant is available (Bouget et al, 1990). Spontaneous diuresis has been reported following hemodialysis (9 days) and hydration in an adult; irreversible renal damage did occur (Calvio et al, 1998).
    2) Of six cases of C. orellanoides (= C. speciosissimus) poisoning treated in Finland with hemodialysis alone, four required transplants and only one returned to normal health (Heath et al, 1980).
    3) Long term dialysis may be required to manage these patients (Colon et al, 1982; Horn et al, 1997).
    C) DIURESIS
    1) Forced diuresis should NOT be done because it may increase renal damage (Michelot & Tebbett, 1990).
    D) PERITONEAL DIALYSIS
    1) Peritoneal dialysis has been used successfully (Myler et al, 1964), but hemodialysis and hemoperfusion are preferred treatment.

Abstracts

Case Reports

    A) SPECIFIC AGENT
    1) C. ORELLANOIDES (= C. SPECIOSISSIMUS)
    a) A 30-year-old patient ate C. orellanoides (speciosissimus) in a stew on 2 consecutive days. Forty-eight hours later he developed nausea, vomiting, and anorexia. During the first week postexposure severe thirst, myalgia, and bilateral lumbar pain were noted.
    1) He was also oliguric from day 6. On day 10 he appeared well, being afebrile and anicteric with just a trace of edema. Urinalysis showed a trace of blood, a small number of RBC's, plasma urea of 42 mmol/L, sodium of 137 mmol/L, potassium of 5.5 mmol/L, bicarbonate of 19 mmol/L, and creatinine of 1925 mcmol/L.
    2) LFT's, hemoglobin, and WBC were normal. Hemodialysis was required. Severe renal failure persisted and kidney transplantation was done 9 months postingestion (Short et al, 1980).
    2) C. ORELLANUS
    a) A 31-year-old ate two Cortinarius orellanus mushrooms. Nine days later, when symptoms appeared, she was admitted to the hospital. Acute renal damage (creatinine of 1100 micromoles/liter) was the diagnosis.
    b) Hemodialysis and plasmapheresis with hemodialysis were used to recover partial renal function. No liver abnormalities were seen. Other treatment included furosemide, diltiazem, dopamine, vitamin C, and amino acid mixtures.
    c) A biopsy done on the fourth day showed tubular necrosis and interstitial fibrosis. By day 13, the patient was discharged with normal renal function (Andary et al, 1989). The plasma level in this patient (first level) was 6 mg/L (0.02 mmol/L).
    d) After the first hemodialysis, no levels could be found. Renal tissues assayed found 7 micrograms per 25 microliters in the first biopsy and 24 mcg in 8 microliters in the second.
    3) MIXED INGESTION
    a) Two cases of suspected Cortinarius poisoning were reported in the Pacific Northwest. Abdominal pain, dry mouth, nausea, vomiting, diarrhea, and polyuria and anuria were seen.
    b) In both cases several different mushrooms were ingested, confusing the picture as to which particular species caused the symptoms. Cortinarius was identified by genus, but NOT by species.
    c) Orellanine was isolated from these patients, but the laboratory test employed a potentially doubtful standard (Moore et al, 1991).

Range Of Toxicity

Summary

    A) TOXICITY: The toxic dose of mushrooms containing orellanine is unknown largely due to patient variability in susceptibility to the toxin and variability of the amount of toxin between mushrooms. Mortality is rare if renal replacement therapy is provided.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) A mortality of 15% occurred in the first series of poisonings reported (Grzymala, 1965) and has been quoted ever since (Short et al, 1980; Marichael et al, 1977). The other series are too small to be statistically significant.
    2) With modern management no early fatalities should occur but continued intermittent dialysis and/or kidney transplants are the only alternatives in a significant number of cases.
    B) ACUTE
    1) LETHAL DOSE/TOXIN CONTENT
    a) Orellanine is found as 1.5% to 2% in the dried mushroom (Richardson et al, 1988; (Prast & Pfaller, 1988).
    b) Cortinarin A concentrations have ranged from 0.47% [(dry weight of C. speciosissimus) to 0.0004% (C. croceifius) (Tebbett & Caddy, 1984a).
    c) Cortinarin B concentrations have ranged from 0.6% (C. speciosissimus) to 0.52% (C. orellanus) and 0.47% (C. orellanoides) (Tebbett & Caddy, 1984a).
    C) ANIMAL DATA
    1) RATS: Great individual variation was found in the susceptibility of rats to these toxins. As many as 20% to 30% of the animals were resistant, even with large doses. Not enough poisonings have been seen in humans to evaluate whether this variation occurs in humans as well (Nieminen & Pyy, 1976).
    2) One study found that 2 grams of dried Cortinarius orellanus/kilogram in male Sprague Dawley rats caused acute kidney malfunction within 48 hours (Prast & Pfaller, 1988).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Outcome is based on the amount of toxin ingested, but a great deal of individual variability exists (i.e., the degree of renal failure present). A shorter latent period is also considered a poorer prognosis (Benjamin, 1995).
    B) CASE REPORTS
    1) Acute renal failure has been described in the literature following orellanine ingestion. Hemodialysis is an effective therapy, but permanent dialysis or renal transplant may be necessary following exposure for persistent renal dysfunction (Holzl et al, 1997; Horn et al, 1997; Eivindson et al, 2000).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) In one case where orellanine levels were measured during tubulointerstitial nephritis, the plasma level 10 days after exposure was 6.12 milligrams/liter.
    b) A renal biopsy 13 days postingestion showed orellanine concentrations of 7 micrograms/25 cubic millimeters, and 24 micrograms per 8 cubic meters at 6 months (Rapior et al, 1989).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ORELLANINE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 12.5 mg/kg (RTECS , 2001)
    2) LD50- (ORAL)MOUSE:
    a) 33 mg/kg (RTECS , 2001)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 8.3 mg/kg (RTECS , 2001)

Pharmacology Toxicology

Toxicologic Mechanism

    A) Orellanine was the name given to the first toxin isolated from Cortinarius orellanus (Grzymala, 1962). It has a bipyridyl structure (Antkowiak & Gessner, 1979) and is extremely stable in the intact fruiting body even after 20 years in dried herbarium specimens.
    1) It is not destroyed by cooking or removed from the mushroom by parboiling and discarding the water (Benjamin, 1995).
    2) Scottish School: disagrees with a toxin that is bipyridyl in structure. Instead, they believe the agents are a series of compounds labeled cortinarins "A", "B", and "C", which are closely related to the amatoxin cyclopeptides. Cortinarin "B" is formed from "A" upon O-demethylation. Cortinarin "B" appears to be the most toxic, when it has been metabolized to its sulfozide form in the liver (Benjamin, 1995).
    B) When extracted from the mushroom, however, it rapidly decomposes into other compounds, especially when exposed to light, particularly ultraviolet light.
    1) Five to ten of these degradation products, one named orelline, have previously caused confusion in the literature (Kurnsteiner & Moser, 1981; Moser M, 1985).
    2) There are intermediaries in the conversion of orellanine which may bind covalently with proteins and glutathione to produce renal damage (Andary et al, 1989).
    C) Three other polypeptide nephrotoxin toxins, Cortinarin A, B, and C, have been isolated from Cortinarius speciosissimus.
    1) Cortinarin A & B are nephrotoxic in laboratory animals and their relationship to the orellanine and the nephrotoxicity from these mushroomsi is yet unclear (Tebbett & Caddy, 1984; Caddy et al, 1982; Holmdahl et al, 1987).
    D) Richard et al (1988) tested mice with pure orellanine and demonstrated similar toxicity as that seen when these mushrooms are taken orally. They found the nephrotoxicity to be related to a small molecule (molecular weight under 500) - namely orellanine.
    E) Pathological findings are limited to the kidney and primarily to the outer layer of the medulla and more specifically to the cells of the proximal tubules. This lesion has been called tubulointerstitial nephritis (Nieminen et al, 1975; Mottonen et al, 1975).
    1) The glomerulae show practically no damage except for slight mesangial cell reaction (Short et al, 1980).
    F) The pathogenesis of this renal damage is now known to be due to the orellanine inhibition of alkaline phosphatase which in turn interrupts the production of adenosine triphosphate upon which cellular metabolism depends (Moser M, 1985).
    G) When tested in cell cultures, orellanine caused a disruption of confluent monolayers and activity reductions in membrane bound alkaline phosphatase and cytosolic lactate dehydrogenase. The mechanism appears to be intracellular (Heufler et al, 1987).
    H) Orellanine is highly toxic to the duckweed (Lemma minor) (Hoiland, 1983) via inhibition of photosynthetic activity. Orellanine's structure is similar to that of paraquat and diquat, but the mechanism of action appears different.
    1) Orellanine can neither be reduced by electrons from water nor from NADPH whereas paraquat can (Richard et al, 1987; Richard et al, 1988).

Physicochemical

Physical Characteristics

    A) ORELLANINE: A crystalline, colorless compound; when heated above 27 degrees C or deoxidised under ultraviolet light, it decomposes to a yellow, stable, nontoxic, sublimable compound (orelline) (Tiecco et al, 1987; Andary et al, 1989).
    1) Orellanine is converted to orellinine and subsequently to orelline by heat and UV radiation (Antkowiak & Gessner, 1985).

Molecular Weight

    A) Not applicable

Animal Toxicology

Clinical Effects

    11.1.9) OVINE/SHEEP
    A) KIDNEY DAMAGE - Severe kidney damage was seen in 4 sheep examined post mortem. The sheep had been in pasture containing C. orellanoides (= C. speciosissimus). Similar damage was produced experimentally in a lamb, given suspensious of homogenized fruiting bodies (Overas et al, 1979).

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