Toxicology of Plants

Amanita phalloides

Etiology

A. phalloides is the most toxic of the world’s cyclopeptide-containing mushrooms.

• Also known as “death cap” mushroom
• Responsible for 90% of fatal mushroom poisonings worldwide
• Appearance:
  • Pale, yellowish, or olive-green
  • Symmetric cap and stem
  • Bulbous base
  • Free, white lamellae
  • Resemble several edible mushrooms

Pathophysiology

The toxicity of A. phalloides is caused by amatoxins and phallotoxins. 

Amatoxins:

• Cyclic octapeptide (primarily alpha-amanitin)
• Heat stable and water insoluble
• Inhibit RNA polymerase II → interfere with protein synthesis → apoptosis
• Responsible for hepatic, renal, and encephalopathic effects 

Phalloidin:

• Cyclic heptapeptide
• Interrupts the actin polymerization–depolymerization cycle and impairs cell membrane function
• Causes self-limited gastroenteritis-like effects 6–12 hours after ingestion

Clinical presentation

Toxicity occurs over several days and usually develops in 3 characteristic stages:

Stage I: 

• Occurs 6–12 hours after ingestion and appears to resolve within 24 hours
• Symptoms: 
  • Abdominal cramping
  • Vomiting
  • Profuse watery diarrhea (may contain blood and mucus) 
• Potential consequences:
  • Dehydration
  • Hypovolemia
  • Acute renal failure
  • Shock

Stage II:

• May appear to improve clinically
• Ongoing liver damage is occurring, as seen by laboratory abnormalities.
• This stage may last 2–3 days.

Stage III:

• Liver failure:
  • Hypoglycemia
  • Coagulopathy
  • Encephalopathy
• Multiorgan dysfunction:
  • Renal failure
  • Pancreatitis
• Death may occur 1–2 weeks after the ingestion.

Diagnosis

The diagnosis typically relies on the history and presentation.

Laboratory abnormalities:

• Stage I (dehydration):
  • Hypokalemia
  • Metabolic acidosis
• Stages II and III (multiorgan dysfunction):
  • ↑ Serum aminotransferase levels 
  • ↑ PT and aPTT
  • ↑ Lipase and amylase
  • ↑ Creatinine

Amatoxin levels:

• Not routinely available, but may be available through reference laboratories
• Urine testing is preferred.

Management

No definitive antidote is available, so management is largely supportive.

• Consultation with poison control
• Gastric decontamination (activated charcoal)
• Aggressive IV fluid hydration for gastroenteritis
• Correct electrolyte abnormalities
• Therapy to decrease amatoxin uptake:
  • Silibinin dihemisuccinate
  • Penicillin G
• Antioxidant therapy for hepatotoxicity:
  • N-acetylcysteine
  • Cimetidine
  • Vitamin C
• Liver transplantation for liver failure

Tropane Alkaloid Plants

Etiology

• The tropane alkaloids include:
  • Atropine
  • Scopolamine
  • Hyoscyamine
• Tropane alkaloid plants represent a very diverse group:
  • Datura species (jimson weed, angel’s trumpet, thorn apple)
  • Hyoscyamus niger (henbane)
  • Atropa belladonna (deadly nightshade)
  • Mandragora officinarum (mandrake)
• These plants have historically been used for their hallucinogenic and medicinal properties.

Pathophysiology

Toxicity from tropane alkaloids causes anticholinergic poisoning through antagonism of central and peripheral muscarinic receptors.

Clinical presentation

Symptoms usually occur 30–60 minutes after ingestion and may continue for 24–48 hours, manifesting as a classic anticholinergic toxidrome.

• Tachycardia
• Hyperthermia
• Dilated pupils → blurred vision
• Urinary retention
• Hot, dry, flushed skin
• Dry mucous membranes
• Neurologic signs and symptoms:
  • Disorientation
  • Delirium
  • Hallucinations
  • Psychosis
  • Seizures

Mnemonic:

The presentation of an anticholinergic toxidrome can be remembered with:

• “Red as beet” (flushed skin)
• “Blind as a bat” (mydriasis)
• “Dry as a bone” (dry mucous membranes)
• “Hot as a hare” (anhidrosis)
• “Mad as hatter” (altered mental status)
• “Full as a flask” (urinary retention)

Diagnosis

The diagnosis of tropane alkaloid toxicity is clinical.

Management

• Assess and address the patient’s airway, breathing, and circulation (ABC assessment).
• Consider gastric decontamination.
• Benzodiazepines for seizure and agitation
• Physostigmine is the antidote.

Toxicodendron Plants

Etiology

• Members of the plant genus, Toxicodendron
• In North America, this includes:
  • Poison ivy (T. rydbergii, T. radicans)
  • Poison oak (T. diversilobum, T. toxicarium)
  • Poison sumac (T. vernix)

Pathophysiology

• Toxicodendron species contain the oleoresin urushiol.
• Contact with the skin → type IV hypersensitivity reaction

Clinical presentation

An acute allergic dermatitis generally occurs within 4–96 hours, and complete resolution is expected within 7–21 days. Characteristics of the rash include:

• Intense pruritus
• Erythematous papules, plaques, vesicles, or bullae
• Linear arrangement

Diagnosis

The diagnosis of Toxicodendron dermatitis is based on exposure history and physical exam.

Management

• Clean all clothing and objects that may be contaminated with urushiol.
• Soothing measures
  • Oatmeal baths
  • Cold compresses
  • Calamine (a combination of zinc oxide and ferric oxide)
  • Burow’s solution (an aqueous solution of aluminum triacetate)
• Oral antihistamines
• Topical corticosteroids
• Systemic steroids for severe dermatitis

Cyanide Plants

Etiology

Many plants contain cyanogenic glycosides, such as amygdalin.

• Pits or seeds from: 
  • Cherry
  • Apricot
  • Peach
  • Plum
  • Pear
  • Apple
• Lima beans
• Clover
• Sorghum
• Almonds

Pathophysiology

• Chewing seeds and pits is required for toxicity.
• Amygdalin is ingested → converted to hydrogen cyanide by gut bacteria → enters bloodstream
• Inactivates cytochrome oxidase → inhibits aerobic metabolism and ATP production
• Tissues cannot use available oxygen → functional hypoxia 
• Anaerobic metabolism takes over → lactic acid production

Clinical presentation

Signs and symptoms of cyanide poisoning are delayed until several hours after ingestion, but may include:

• Cardiovascular:
  • Initial tachycardia → bradycardia → circulatory collapse
  • Hypotension
  • Dysrhythmias
• Respiratory:
  • Hyperventilation (attempted compensation for metabolic acidosis)
  • Respiratory depression and failure 
• Neurologic:
  • Headache
  • Dizziness
  • Seizures
  • Coma
  • Anoxic brain injury
• GI:
  • Nausea and vomiting 
  • Abdominal pain
• Other:
  • Renal failure
  • Hepatic necrosis
  • Rhabdomyolysis
  • Pink or cherry-red skin (uncommon)

Diagnosis

The diagnosis is generally based on the clinical history and examination. The following may support the diagnosis.

• Anion gap metabolic acidosis
• ↑ Lactic acid
• Cyanide level: 
  • Usually not available in time to be of benefit
  • Confirms cyanide toxicity

Management

• ABC assessment
• Supportive management:
  • IV fluid hydration
  • Vasopressors for hypotension
  • Benzodiazepines for seizures
• Gastric decontamination
• Antidotes:
  • Hydroxocobalamin (1st-line treatment) 
    • Precursor of vitamin B₁₂
    • Binds cyanide
  • Amyl nitrite or sodium nitrite
    • Induce methemoglobinemia
    • Provide alternative binding site for cyanide 
  • Sodium thiosulfate
    • ↑ Availability of sulfur donors for rhodanese
    • Transforms cyanide to thiocyanate → excreted by kidneys

Cardiac Glycoside Plants

Etiology

Cardiac glycosides are found in a number of plants, including:

• Foxglove (Digitalis purpurea and D. lanata)
• Oleander (Nerium oleander and Thevetia peruviana)
• Lily of the valley (Convallaria majalis)
• Squill (Urginea maritima and U. indica)
• Ouabain (Strophanthus gratus)
• Dogbane (Apocynum cannabinum)
• Wallflower (Cheiranthus cheiri)

Pathophysiology

Consuming plant parts or teas brewed from these plants can lead to toxicity.

• Cardiac glycosides bind to a cell membrane → reversible inhibition of the Na–K–adenosine triphosphatase pump
• This process leads to:
  • ↑ Intracellular Na → ↑ intracellular calcium → dysrhythmia
  • ↓ Intracellular K

Clinical presentation

Signs and symptoms of cardiac glycoside toxicity include:

Cardiac:

• Palpitations
• Bradycardia
• Arrhythmia:
  • Premature ventricular contractions
  • Atrioventricular block
  • Junctional rhythms
  • Ventricular tachycardia or fibrillation
• Chest pressure
• Dyspnea
• Light-headedness

GI symptoms: 

• Nausea and vomiting
• Abdominal pain

Neurologic symptoms: 

• Weakness
• Altered mental status

Diagnosis

The diagnosis will be suspected because of the history and clinical presentation and supported by the workup.

• Digoxin level:
  • Some plant glycosides can cross-react with digoxin assays.
  • A negative level does not rule out cardiac glycoside exposure.
• Hyperkalemia
• ECG to assess for arrhythmia

Management

• ABC assessment
• Supportive management:
  • Cardiac monitoring
  • Atropine for symptomatic bradycardia
  • Appropriate management of life-threatening arrhythmias
  • Electrolyte monitoring and correction of life-threatening hyperkalemia
• Gastric decontamination
• Antidote: digoxin-specific antibody fragments (Fab)

Comparative Chart of Toxic Plants

Differential Diagnosis

• Gastroenteritis: inflammation of the stomach and intestines, commonly caused by infections from bacteria, viruses, or parasites. Common clinical features of gastroenteritis include abdominal pain, diarrhea, vomiting, fever, and dehydration. Diagnostic testing with stool analysis or culture is not always required, but it can help determine the etiology in certain circumstances. Most cases are self-limited; therefore, the only required treatment is supportive therapy (fluids). 
• Acetaminophen toxicity: A toxic ingestion of acetaminophen may lead to severe hepatotoxicity. Patients may initially present with symptoms similar to those of gastroenteritis. Acetaminophen toxicity may progress to liver failure, renal failure, and pancreatitis. An acetaminophen level can help confirm the diagnosis. Gastric decontamination should be attempted, along with N-acetylcysteine therapy. Liver transplantation may be required for fulminant liver failure.
• Viral hepatitis: liver inflammation caused by infection with hepatitis virus: Patients may present with a viral prodrome of fever, anorexia, and nausea. RUQ abdominal pain, jaundice, and transaminitis also occur. The diagnosis is made with viral serologic testing. Management of acute hepatitis is supportive.
• Amphetamine toxicity: intoxication with amphetamines causing a sympathomimetic response. Patients may have tachycardia, hyperthermia, mydriasis, delirium, seizures, rhabdomyolysis, and renal failure. Unlike with anticholinergic toxicity, patients are diaphoretic. The diagnosis is often made clinically and confirmed with a drug screen. Management includes supportive care and benzodiazepines.
• Hyperthyroidism: Elevated levels of free thyroid hormones can result in hypermetabolism. Patients can have tachycardia, palpitations, anxiety, tremor, diaphoresis, and diarrhea. The diagnosis is confirmed with thyroid studies. Management depends on the etiology, but it may include methimazole, beta-blockers, radioactive iodine, and surgery.
• Contact dermatitis: inflammation of the skin in response to irritants. Pruritus, pain, microvesiculation (formation of small vesicles), and a burning sensation may occur. The diagnosis is clinical. Management involves removing the offending agent and reducing skin inflammation with steroids or topical calcineurin inhibitors.
• Bullous pemphigoid: autoimmune blistering disease caused by antibodies against hemidesmosomes. Patients are usually elderly and present with pruritic, tense, bullous lesions and spared mucosal surfaces. Triggers include medications, trauma, skin conditions, and systemic disease. Biopsy with immunofluorescent staining is used for diagnosis. Management includes steroids, immunosuppressants, and antiinflammatory medications.
• Carbon monoxide poisoning: Inhalation of carbon monoxide causes displacement of oxygen from the hemoglobin, interfering with aerobic metabolism. Patients may suffer from headache, nausea, dyspnea, loss of consciousness, and seizures. Skin color may be cherry-red, though this is usually seen postmortem. An elevated carboxyhemoglobin level can provide the diagnosis. Management requires 100% oxygen or hyperbaric oxygen.