Orellanine Mushroom Toxicity

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Practice Essentials

Cortinarius orellanus, the poznan cort mushroom, is one of the few types of mushrooms that can cause fatal poisonings. Of the thousands of mushroom species that are increasingly studied and collected by amateur mushroom hunters, about 100 can cause serious illness, but only about 10 cause death.

People become sick after ingesting mushrooms for several reasons. They may have ingested toxin-containing mushrooms or mushrooms that cause Antabuse-type reactions to alcohol; they may experience difficulty digesting large amounts of mushrooms or have immunologic reactions to mushroom-derived antigens.

Cortinarius species (corts) that may contain the orellanine toxin include the following:

The most common of these in North America is probably C gentilis, although C orellanus and C speciosissimus are most often implicated in documented exposures. Presence of C orellanus in North America remains unconfirmed.

Orellanine is the major toxin found in these mushrooms. Orellanine (3,3',4,4'-tetrahydroxy-2,2'-bipyridine-1,1'-dioxide) is a colorless, crystalline, nephrotoxic compound.[1, 2]  Orelline is a possibly toxic product of orellanine.

Three other polypeptides have been identified: cortinarin A, cortinarin B, and cortinarin C. At least two of those appear to be nephrotoxic in experimental animals.

Mushroom identification is beyond the scope of this text, but the existence of corts is one of the many reasons not to eat little brown mushrooms (LBMs).

Pathophysiology

Patients with orellanine exposure may experience early symptoms because of other components of the mushroom; orellanine appears to be renal specific. Inhibition of alkaline phosphatase decreases production of adenosine triphosphate and disrupts cellular metabolism. Reaction is specific to the epithelium of cells in the proximal tubules and results in tubulointerstitial nephritis and acute kidney injury, with concomitant symptoms and complications. Orellanine seems to cause almost no reaction in glomeruli, although in an animal model, elimination of orellanine was almost exclusively by glomerular filtration.[3]

Studies of orellanine poisoning in rats have shown no signs of acute toxicity apart from kidney injury, but a study of orellanine poisoning in mice showed tubular necrosis as well as effects on other organs, as follows[4] :

However, a study of 28 patients with orellanine poisoning noted that no signs of acute damage were present in any other organ except the kidney.[5]

Epidemiology

In 2021, 9 exposures of orellanine-containing mushrooms were reported to the American Association of Poison Control Centers' (AAPCC) Toxic Exposure Surveillance System.[6]  A range of 0-9 exposures per year have been reported over the past 14 years. The reports by year can be found at the APPC site.

Unknown mushroom type makes up most mushroom exposures each year, usually accounting for over 70% of mushroom exposures (eg, 4887 in 2021). However, deaths in this group remain remarkably low (0-2 per year since 1996).[6]

A study published in May 2000 that used data from the National Center for Health Statistics found no difference when compared with AAPCC data in numbers of deaths caused by mushroom exposures.[7]

No accurate global database exists, but mushroom gathering is more common in Eastern and Western Europe than in North America. Most documented cases of orellanine toxicity are from Europe.

Mushroom poisoning is the leading cause of foodborne disease outbreaks and foodborne-related deaths in China. The Chinese Foodborne Disease Outbreak Surveillance System reported a total of 10,036 mushroom poisoning outbreaks in 2010-2020. These outbreaks resulted in a cumulative 38,676 illnesses and 788 deaths during that period. In 2020, 2075 mushroom outbreaks were reported.[8] Three outbreaks and no deaths were attributed to Cortinarius species, but over 60% of the outbreaks involved unidentified mushrooms.[9] The majority of the outbreaks (84.6%) were associated with consumption in the home and were related to self-harvesting of wild mushrooms.[8, 9]

Prognosis

A short latent period before onset of illness and kidney injury portends more severe renal insult and prolonged period of renal failure than delayed onset of illness. Relatively mild degrees of kidney insufficiency may resolve within weeks to months. Some patients may be treated expectantly without need for hemodialysis. In more severe cases, kidney failure can persist months to years requiring chronic hemodialysis or kidney transplantation.[5]

Few data are available to estimate incidence of orellanine poisoning. Most reported cases of kidney failure are from Europe. The AAPCC last reported a recognized Cortinarius exposure with a major effect in outcome (ie, exposure resulted in life-threatening signs or symptoms or resulted in significant residual disability) in 1999. Since 1999 no outcomes have occurred in the major category and only 3 total in the moderate class (ie, signs or symptoms more pronounced, more prolonged, or more systemic in nature than minor symptoms usually indicating the need for some form of treatment, but the patient had no residual disability).[6]

History

History of exposure is of utmost importance; without it, diagnosing mushroom or orellanine poisoning is unlikely. History of mushroom ingestion may be remote, particularly with orellanine, since early gastrointestinal symptoms may not be severe enough for patients to seek medical attention. Patients with symptomatic acute kidney injury may not present until 1-3 weeks after exposure. The emergency physician should routinely inquire about mushroom ingestion whenever a patient presents with gastroenteritis. A shorter latent period before onset of illness suggests more severe toxicity and greater risk of more severe kidney failure than delayed onset of illness.

Improvement in kidney injury may occur within several weeks to months; however, kidney injury may last months to years and patients may require long-term hemodialysis or kidney transplantation.

Important details of ingestion include the following:

Gastrointestinal signs and symptoms are usually mild and observed 24-48 hours postingestion. They may include the following:

Renal manifestations may include the following:

Systemic manifestations may include the following:

Neurologic manifestations may include the following:

Physical Examination

Patients with orellanine-induced acute kidney injury (AKI) may have a paucity of findings on physical examination, as follows:

Volume status: With anorexia and polyuria, volume depletion may be present. With anuric AKI, volume overload is possible.

Neurologic: With modest degrees of renal dysfunction, mental status may be relatively preserved. With more advanced AKI, depressed mentation, confusion, or coma may occur. Myoclonus and asterixis suggest uremia in this setting.

Gastrointestinal: By time of presentation, abdominal symptoms may have resolved.

Renal: Flank tenderness may be present.

Other findings: Signs of uremia (eg, pericarditis, pleuritis, volume overload) may be present.

Laboratory Studies

Blood studies may include the following:

On urinalysis, microscopic hematuria and leukocyturia is common. Gross hematuria is rare. Albuminuria may be present.

Other Tests

A 12-lead electrocardiogram is useful if hyperkalemia or other comorbidity is suspected.

Assistance by an experienced mycologist is essential for mushroom identification. A regional poison center or local university may be able to assist in this regard. A reference lab may be able to test for orellanine if a food specimen is available.

Since a considerable delay between ingestion and presentation (days) usually exists, gastric specimens are unlikely to be of any use. Examine for mushroom type or orellanine toxin if any prepared food is still available. It may be possible to have additional mushrooms collected and identified if patient is able to describe area where the mushrooms were foraged.

Emergency Department Care

Stabilize acute life-threatening conditions with resuscitative measures. Correct shock and dehydration. Monitor urine output.[10]

Since patients often present days after ingestion, there is little value in acute gastrointestinal decontamination measures such as activated charcoal or lavage. Activated charcoal might be of benefit in the event of very recent orellanine mushroom ingestion. Contraindications and cautions include delayed presentation, multiple episodes of emesis, and depressed level of consciousness. Consider an antiemetic for ongoing nausea and vomiting.

Seizures occur very rarely but, when present, the treatment of choice is a benzodiazepine followed by phenytoin.

Urgent hemodialysis may be necessary for significant kidney injury or electrolyte disturbances. Early hemoperfusion or hemodialysis, soon after ingestion and before any evidence of kidney injury, has been advocated. Scant data exist on this early intervention and its clinical efficacy is uncertain. 

Admit all symptomatic patients for further management and observation. Intermittent hemodialysis may be necessary if kidney failure is severe. Patients should be in a facility that has nephrology specialists and hemodialysis capability.

Early management of an orellanine exposure without signs of kidney injury is undefined. Consider outpatient management only after careful consultation with a toxicologist and/or nephrologist and if close follow-up is possible.

Consultations

Consult nephrology for urgent hemodialysis, if needed, and for ongoing assistance with inpatient management. Consult regional poison control center for assistance in locating a mycologist. Expert assistance from a mycologist may be useful in mushroom identification. A toxicology consultation, if available, is useful.

Medication Summary

Pharmacologic treatment is rarely indicated. Gastrointestinal decontamination may be appropriate if the patient presents very soon after ingestion. Anticonvulsant therapy is indicated for seizures.

Activated charcoal (Liqui-Char)

Clinical Context:  Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.

For maximum effect, administer within 30 min after ingesting poison.

Class Summary

Empirically used to adsorb toxin in GI tract. A cathartic is used to enhance movement of toxin through the GI tract. However, no evidence indicates that cathartics increase the efficacy of activated charcoal.

Midazolam (Versed)

Clinical Context:  Used as alternative in termination of refractory status epilepticus. Because water soluble, it takes approximately 3 times longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose. Has twice the affinity for benzodiazepine receptors than diazepam. May be administered IM if unable to obtain vascular access.

Diazepam (Valium)

Clinical Context:  First-line therapy for seizure control. Can be given by ET/PR (not FDA approved) in an emergency.

Lorazepam (Ativan)

Clinical Context:  Sedative hypnotic with short onset of effects and relatively long half-life.

By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.

Monitoring patient's blood pressure after administering dose is important. Adjust prn. Alternative to diazepam. Can be given IM/ET (not FDA approved) in emergency.

Class Summary

Depresses all levels of CNS (eg, limbic formation, reticular formation), possibly by increasing activity of GABA.

Author

Reed Brozen, MD, Director of Air Transport, Associate Professor, Department of Emergency Medicine, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

Disclosure: Nothing to disclose.

Chief Editor

Sage W Wiener, MD, Assistant Professor, Department of Emergency Medicine, State University of New York Downstate Medical Center; Director of Medical Toxicology, Department of Emergency Medicine, Kings County Hospital Center

Disclosure: Nothing to disclose.

Additional Contributors

Miguel C Fernandez, MD, FAAEM, FACEP, FACMT, FACCT, Associate Clinical Professor, Department of Surgery/Emergency Medicine and Toxicology, University of Texas School of Medicine at San Antonio; Medical and Managing Director, South Texas Poison Center

Disclosure: Nothing to disclose.

Acknowledgements

Michael Hodgman, MD Assistant Clinical Professor of Medicine, Department of Emergency Medicine, Bassett Healthcare

Michael Hodgman, MD is a member of the following medical societies: American College of Medical Toxicology, American College of Physicians, Medical Society of the State of New York, and Wilderness Medical Society

Disclosure: Nothing to disclose.

References

  1. Herrmann A, Hedman H, Rosén J, Jansson D, Haraldsson B, Hellenäs KE. Analysis of the mushroom nephrotoxin orellanine and its glucosides. J Nat Prod. 2012 Oct 26. 75(10):1690-6. [View Abstract]
  2. Dinis-Oliveira RJ, Soares M, Rocha-Pereira C, Carvalho F. Human and experimental toxicology of orellanine. Hum Exp Toxicol. 2016 Sep. 35 (9):1016-29. [View Abstract]
  3. Najar D, Haraldsson B, Thorsell A, Sihlbom C, Nyström J, Ebefors K. Pharmacokinetic Properties of the Nephrotoxin Orellanine in Rats. Toxins (Basel). 2018 Aug 17. 10 (8):[View Abstract]
  4. Anantharam P, Shao D, Imerman PM, Burrough E, Schrunk D, Sedkhuu T, et al. Improved Tissue-Based Analytical Test Methods for Orellanine, a Biomarker of Cortinarius Mushroom Intoxication. Toxins (Basel). 2016 May 21. 8 (5):[View Abstract]
  5. Hedman H, Holmdahl J, Mölne J, Ebefors K, Haraldsson B, Nyström J. Long-term clinical outcome for patients poisoned by the fungal nephrotoxin orellanine. BMC Nephrol. 2017 Apr 3. 18 (1):121. [View Abstract]
  6. Gummin DD, Mowry JB, Beuhler MC, Spyker DA, Rivers LJ, Feldman R, et al. 2021 Annual Report of the National Poison Data System(©) (NPDS) from America's Poison Centers: 39th Annual Report. Clin Toxicol (Phila). 2022 Dec. 60 (12):1381-1643. [View Abstract]
  7. Hoppe-Roberts JM, Lloyd LM, Chyka PA. Poisoning mortality in the United States: comparison of national mortality statistics and poison control center reports. Ann Emerg Med. 2000 May. 35(5):440-8. [View Abstract]
  8. Li W, Pires SM, Liu Z, Liang J, Wang Y, Chen W, et al. Mushroom Poisoning Outbreaks - China, 2010-2020. China CDC Wkly. 2021 Jun 11. 3 (24):518-522. [View Abstract]
  9. Li H, Zhang H, Zhang Y, Zhou J, Yin Y, He Q, et al. Mushroom Poisoning Outbreaks - China, 2020. China CDC Wkly. 2021 Jan 15. 3 (3):41-45. [View Abstract]
  10. Jaeger A. Orellanine Mushrooms. Rumack BH, Spoerke DG, eds. Handbook of Mushroom Poisoning Diagnosis and Treatment. 2nd ed. CRC Press LLC; 1994. 249-64.