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PLANTS-PYRROLIZIDINE ALKALOIDS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pyrrolizidine alkaloids are responsible for significant economic losses in livestock. The extent of human poisoning is just now being understood. Plants responsible for poisonings have been mainly Heliotropium, Senecio, and Crotalaria species. The pyrrolizidine alkaloids are distributed in many plant families all over the world and poisonings have been reported in the United States, India, the Middle East, Africa, Jamaica, and Afghanistan.

Specific Substances

    A) CONSTITUENTS OF THE GROUP
    1) Senecio alkaloids
    2) Echium
    3) PAs
    4) Pyrrolizidine alkaloids
    5) Heliotrine
    6) Hydrophylline
    7) Intergerrine
    8) Jacobine
    9) Jacoline
    10) Jaconine
    11) Jacozine
    12) Lasiocarpine
    13) Monocrotaline
    14) Neoplatphylline
    15) Otosenine
    16) Platphylline
    17) Retrorsine
    18) Riddelline
    19) Senecio
    20) Sesbania
    21) Senecionine
    22) Seneciphylline
    23) Senkirkine
    24) Spartloidine
    25) Symphytum
    26) Yamataimine

Available Forms Sources

    A) FORMS
    1) Over 200 pyrrolizidine alkaloids have been identified (Moore et al, 1989; Mattocks, 1986).
    2) PLANT PARTS: Usually all parts of the plant contain pyrrolizidine alkaloids (Nelson et al, 2007). These plants may be ingested unintentionally, or be contaminants in food stuffs. There are a number of cases where plant parts, especially seeds, have been mixed in with grains and ingested (Huxtable, 1979b).
    3) Alkaloid content varies considerably, harvesting and processing methods will alter alkaloid content (Ciarrallo, 1992).
    4) CONTAMINANTS: Anticholinergic effects have been reported from a contaminant of comfrey tea, possibly due contamination of the comfrey plant with Atropa belladonna or Datura stramonium (Routledge & Spriggs, 1989; Awang & Kindack, 1989).
    B) SOURCES
    1) HERBAL TEAS
    a) Many herbal teas either contain or are contaminated with pyrrolizidine alkaloids. Hill et al (1951) found this to be true in Jamacia, Watt & Breyer-Brandwijk (1961) noted it in Africa, and Huxtable & Stillman (1977) found cases in Arizona.
    b) Common herbal teas contaminated with pyrrolizidine alkaloids in the United States are gordolobo yerba, yerba de pasmo (Huxtable, 1979a), matarique (Sullivan, 1980) and "bush teas" of Jamaica and Barbados (Anon, 1984a).
    c) Comfrey root tea may have 8.5 to 26 mg of pyrrolizidine alkaloids per cup (Roitman, 1981), and has caused veno-occlusive disease (Weston et al, 1987).
    2) COMFREY
    a) Comfrey species contain symphytine, echimidine, symglandine, and lycopsamine (Ciarallo, 1992).
    b) The fresh leaf of S. uplandicum Nyman (Russian comfrey) contain about 0.01 to 0.15% alkaloids. The primary alkaloids are echimidine (24%) and 7-acetyllycopsamine, 24 and 32% of total alkaloid, respectively.
    c) Comfrey has been used by the herbalist and the lay public to treat broken bones, tendon damage, gastrointestinal ulcers and lung congestion. A typical daily dose of the leaf ranges from 5 to 30 g, and daily doses of the root are usually 0.5 to 10 g. Comfrey can be applied externally to purportedly promote wound healing or reduce joint inflammation (Rode, 2002).
    d) AVAILABILITY: Because of the potential risk associated with oral consumption of comfrey because of the presence of pyrrolizidine alkaloids, its use has been restricted in several countries (Rode, 2002):
    1) Canada - distribution is restricted
    2) Germany - use is limited to topical products only with daily exposure of less than 100 mcg pyrrolizidine alkaloids
    3) US - the FDA has requested voluntary compliance with the removal of products containing comfrey
    e) Comfrey-pepsin food supplements are currently sold under a number of brand names and were found to contain several pyrrolizidine alkaloids (Huxtable et al, 1986). These preparations contained about 2.9 mg pyrolizidine per gram of plant material.
    1) In England, tablets and capsules (not tinctures, teas, or external-use products) are being voluntarily withdrawn from the market (Anon, 1993).
    f) The root contains higher concentrations than the leaves. A cup of root tea may contain 26 mg (Ciarrallo, 1992).
    3) HONEY
    a) Pyrrolizidine alkaloids have been found in honey made from flowers of the Senecio species. Human poisonings have not been reported, possibly due to the low concentration of pyrrolizidine alkaloids in the honey, the off color, and bitter taste (Deinzer et al, 1977).
    4) SENECIO
    a) GENERAL - In a study of South American Senecio species, the most common pyrrolizidine alkaloids found were retrorsine, senecionine, nitegerrimine, neosenkirkine, and florosenine (Habermehl et al, 1988).
    b) SENECIO BRASILIENSIS - An example of pyrrolizidine alkaloid content from Senecio brasiliensis (Hirschmann et al, 1987):
    Plant PartAlkaloid (mg)
    Flowering tops591.0 - 969.7
    Leaves208.0 - 380.9
    Stems20.5 - 45.7
    Roots20.2 - 36.3

    c) SENECIO JACOBAEA: This biennial plant is also referred to as ragwort and contains pyrrolizidine alkaloids that include jacobine, jacodine, jaconine and retrosine. All parts of the plant are poisonous, and can retain its toxicity when dried in hay or silage. The plant is most toxic during the first stage of growth. It is thought that the active ingredients are metabolized in the liver to toxic pyrrole derivatives which can affect hepatic mitosis (Noonan, 2001).
    C) USES
    1) MEDICINAL USES: Indicine N-oxide is being investigated for use as an antineoplastic agent (King et al, 1987).

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: Pyrrolizidine alkaloids are found in about 3% of flowering plants worldwide. Some of these plants are used in herbal teas and for medicinal purposes. Significant economic losses in livestock have occurred secondary to ingestion of plants containing these alkaloids.
    B) TOXICOLOGY: The alkaloids that are thought to cause toxicity are unsaturated pyrrolizidine alkaloids and their N-oxides. Conversion of alkaloids to a pyrrole derivative results in an alkylating agent that attacks the liver and other toxicity are unsaturated pyrrolizidine alkaloids and their N-oxides. Conversion of alkaloids to a pyrrole derivative results in an alkylating agent that attacks the liver and other cell components. Extensive destruction of small branches of the hepatic venous system may result, leading to a veno-occlusive disease of the liver. Other types of toxicity seen in various animal species include pulmonary toxicity, skin lesions, hematologic abnormalities, CNS depression, and renal damage.
    C) EPIDEMIOLOGY: Known cases of pyrrolizidine alkaloids toxicity in humans are extremely rare. However, pyrrolizidine alkaloids are responsible for significant economic losses in livestock worldwide.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Acute dosing of large amounts of pyrrolizidine alkaloids produce primary liver disease (acute hepatitis) in humans, but gastroenteritis may also be seen. Patients may present with vomiting and severe abdominal pain. Hepatomegaly, splenomegaly, right upper quadrant abdominal pain, and ascites may follow. Jaundice is seen inconsistently. Diagnosis is often difficult, because pyrrolizidine alkaloids are usually excreted within 24 hours, but symptoms may not appear for days to weeks. Diagnosis is usually established by hepatotoxicity indicative of pyrrolizidine alkaloids, especially veno-occlusive disease similar to Budd-Chiari syndrome, pathognomonic changes in liver structure and histology, and analysis of any plant material available.
    2) Toxicity may result from both subacute and chronic exposures, is more likely to occur in children, and may be passed transplacentally from mother to fetus.
    0.2.20) REPRODUCTIVE
    A) Transplacental pyrrolizidine poisoning has been reported. Venoocclusive disease of the liver has been reported in 2 infants whose mothers ingested herbal medicines containing pyrrolizidine alkaloid.
    0.2.21) CARCINOGENICITY
    A) PAs have been shown to produce various tumors in mice and rats including rhabdomyosarcomas. Most authors conclude that pyrrolizidine alkaloids are carcinogenic and mutagenic, at least in the animals studied.

Laboratory Monitoring

    A) Therapeutic or toxic levels of pyrrolizidine alkaloids have not been established. Though methods exist for their detection, these tests are not useful for immediate clinical care, as these alkaloids are generally excreted within 24 hours.
    B) Liver damage is seen days to months post ingestion, so initial liver function tests may only serve to establish baseline laboratories. Depending on the degree of hepatic damage, ancillary labs such as a basic chemistry panel and coagulation studies may be useful.
    C) Doppler ultrasound can help assess for alterations of blood flow in the liver.
    D) The severity of a patient's symptoms may require studies such as a head CT to monitor for cerebral edema.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Supportive care is the mainstay of treatment. Cessation of ingestion of the pyrrolizidine alkaloids and treatment for resultant symptoms are the main therapies available.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. For patients that progress to liver failure, it is likely too late to protect the liver. Possible treatments early in intoxication would be to block metabolism of the alkaloids or add reactive substrates with sulfhydryl groups (eg, methionine, cysteine, ethoxyquin, glutathione and dichlorobenzenethiol). Patients with liver failure may require invasive treatments such as portal-systematic shunt placements for hepatic and portal decompression or liver transplantation.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital activated charcoal may be considered, but only if the patient is awake and cooperative and the ingestion is relatively recent (ie, within an hour of ingestion). However, most exposures are usually due to chronic ingestion, so it is unlikely that activated charcoal would have any benefit.
    2) HOSPITAL: Activated charcoal is unlikely to be of benefit in the setting of chronic ingestion. It may be considered in patients with a recent ingestion (within an hour) in patients that are awake and alert. There is no evidence for the use of gastric lavage or whole bowel irrigation, but both therapies could be considered in a massive ingestion of pyrrolizidine alkaloids.
    D) ANTIDOTE
    1) No specific antidote exists for pyrrolizidine alkaloid poisoning.
    E) ENHANCED ELIMINATION
    1) There is no evidence for the use of dialysis, hemoperfusion, urinary alkalinization, or multiple dose charcoal. However, hemodialysis has been used in patients who become critically ill with hepatic and renal failure.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with accidental or single ingestion of plants or herbal products that contain pyrrolizidine alkaloids may likely remain at home especially if they have no significant symptoms.
    2) OBSERVATION CRITERIA: Patients who develop any concerning symptoms or had an intentional self-harm exposure should be sent to a health care facility for observation until symptoms are clearly improving and they are cleared from a psychiatric standpoint.
    3) ADMISSION CRITERIA: Patients who develop hepatotoxicity or worsening symptoms should be admitted to the hospital. Depending on the severity of their symptoms, they may require ICU care (eg, patients with fulminant hepatic failure). Patients should not be discharged from the hospital until they are medically stable and with clearly improving symptoms.
    4) CONSULT CRITERIA: Patients with significant hepatotoxicity may benefit from consultation from a hepatologist and even a transplant surgeon if they develop signs of liver failure. Patients with fulminant hepatic failure likely will require the care of an intensivist. A toxicologist or poison center can be contacted for advice for any exposures at any time.
    G) PITFALLS
    1) One pitfall is not considering the diagnosis in a patient who presents with hepatotoxicity and not asking about a patient's use of herbal products or alternative medications.
    H) TOXICOKINETICS
    1) Percutaneous absorption in rats resulted in 0.1 to 0.4% of the dose excreted, which was 20 to 50 times less than oral dosing. Absorption is generally rapid with the greatest concentrations at 3 to 4 hours in the liver, kidney and stomach; however, only the liver had significant amounts at 72 hours in one study. These alkaloids are metabolized in the liver via the P450 system and other metabolic enzymes and most pyrrolizidine alkaloids are excreted within 24 hours.
    I) PREDISPOSING CONDITIONS
    1) Extremes of age may predispose patients to toxicity; a report exists of veno-occlusive disease of the liver in 2 infants via transplacental pyrrolizidine poisoning.
    J) DIFFERENTIAL DIAGNOSIS
    1) Toxicity of pyrrolizidine alkaloids can resemble other causes of liver failure, especially those causing Budd-Chiari syndrome. Causes of Budd-Chiari syndrome include primary obstruction (eg, thrombosis, phlebitis, stenosis) and secondary obstruction by external compression or invasion of the portal venous system by abscesses, tumors or cysts.

Range Of Toxicity

    A) TOXIC DOSE: PEDIATRIC: Between 70 to 147 mg of pyrrolizidine alkaloids administered in an herbal tea for 2 weeks to a 6 month-old infant produced toxicity. In another case, a 2 month-old infant ingested approximately 66 mg over 5 to 7 days which resulted in hematemesis, liver injury and death. ADULT: Four women who ingested approximately 570 to 1380 mg of pyrrolizidine alkaloids, found in a contaminated tea, over 19 to 45 days developed ascites and liver failure; one woman died.

Clinical Effects

Summary Of Exposure

    A) USES: Pyrrolizidine alkaloids are found in about 3% of flowering plants worldwide. Some of these plants are used in herbal teas and for medicinal purposes. Significant economic losses in livestock have occurred secondary to ingestion of plants containing these alkaloids.
    B) TOXICOLOGY: The alkaloids that are thought to cause toxicity are unsaturated pyrrolizidine alkaloids and their N-oxides. Conversion of alkaloids to a pyrrole derivative results in an alkylating agent that attacks the liver and other toxicity are unsaturated pyrrolizidine alkaloids and their N-oxides. Conversion of alkaloids to a pyrrole derivative results in an alkylating agent that attacks the liver and other cell components. Extensive destruction of small branches of the hepatic venous system may result, leading to a veno-occlusive disease of the liver. Other types of toxicity seen in various animal species include pulmonary toxicity, skin lesions, hematologic abnormalities, CNS depression, and renal damage.
    C) EPIDEMIOLOGY: Known cases of pyrrolizidine alkaloids toxicity in humans are extremely rare. However, pyrrolizidine alkaloids are responsible for significant economic losses in livestock worldwide.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Acute dosing of large amounts of pyrrolizidine alkaloids produce primary liver disease (acute hepatitis) in humans, but gastroenteritis may also be seen. Patients may present with vomiting and severe abdominal pain. Hepatomegaly, splenomegaly, right upper quadrant abdominal pain, and ascites may follow. Jaundice is seen inconsistently. Diagnosis is often difficult, because pyrrolizidine alkaloids are usually excreted within 24 hours, but symptoms may not appear for days to weeks. Diagnosis is usually established by hepatotoxicity indicative of pyrrolizidine alkaloids, especially veno-occlusive disease similar to Budd-Chiari syndrome, pathognomonic changes in liver structure and histology, and analysis of any plant material available.
    2) Toxicity may result from both subacute and chronic exposures, is more likely to occur in children, and may be passed transplacentally from mother to fetus.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) FIBROSIS
    1) WITH THERAPEUTIC USE
    a) Fibrosis of the superior vena cava was seen in one patient who had been ingesting "bush tea" made in Trinidad. Biopsy of the affected vessels showed medial fibrosis with fibrosis and calcification.
    1) Unfortunately the bush tea was not analyzed, so a direct, proven relationship cannot be assumed (Mehta et al, 1986).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PULMONARY HYPERTENSION
    a) Ventricular hypertrophy thought to be due to pulmonary arterial hypertension has been seen in animals poisoned chronically with pyrrolizidine alkaloids (Huxtable, 1979).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PLEURAL EFFUSION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Right pleural effusion was seen in a 6 month-old given pyrrolizidine alkaloid-containing herbal tea (Huxtable et al, 1977).
    b) Large single doses, or chronic small doses may eventually lead to pulmonary arterial hypertension (Turner & Lalich, 1965; Chesney & Allen, 1973).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPERTENSION PULMONARY
    a) Pulmonary hypertension has been seen in mice given doses of 14 mg/kg of monocrotaline (Shubat et al, 1989).
    2) RESPIRATORY DISORDER
    a) Animal studies have shown lung endothelial damage (Huxtable, 1979).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported (Kingsbury, 1964).
    B) MALAISE
    1) WITH POISONING/EXPOSURE
    a) Lassitude is often present (Mohabbat et al, 1976).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia is common (Mohabbat et al, 1976).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) VENO-OCCLUSIVE DISEASE OF THE LIVER
    1) WITH THERAPEUTIC USE
    a) There have been cases of veno-occlusive hepatic disease caused by food products contaminated with pyrrolizidine alkaloid containing seeds (Selzer & Parker, 1951; Savvina, 1952; Huxtable, 1979a). Chronic daily use of comfrey tea over a period of several days to several months has resulted in liver disease (Zuckerman et al, 2002; Sperl et al, 1995; McDermott & Ridker, 1990; Bach et al, 1989; Ridker & McDermott, 1989) Yeong et al, 1990).
    b) RISK FACTORS - Children may be at increased risk of developing alkaloid-induced veno-occlusive liver damage (Sperl et al, 1995).
    c) CLINICAL FEATURES - Veno-occlusive liver disease is characterized by portal hypertension with severe ascites due to obliteration of centrilobular or sublobular hepatic veins. There is perivenular congestion with sinusoidol dilatation, occlusion of small terminal hepatic venules by loose convective tissue, and fibrosis extending from the perivenular areas (Ciarallo, 1992; Sperl et al, 1995).
    d) LABORATORY FEATURES: Lab abnormalities include: an elevated AST and bilirubin and a prolonged INR (Nelson et al, 2007).
    e) STAGES OF ILLNESS
    1) Stages of veno-occlusive illness have been identified following exposure (Steenkamp et al, 2000):
    1) Acute - Abdominal swelling, hepatomegaly and ascites
    2) Subacute - Persistent hepatomegaly
    3) Chronic - Septal cirrhosis (centrilobular type)
    f) CASE SERIES
    1) In a series of 20 pediatric patients with veno-occlusive disease following pyrrolizidine exposure from South African traditional therapies, every patient had extensive ascites, with significant hepatomegaly in 94% of the patients. Eighty-two percent had splenomegaly, and jaundice was observed in 55% of patients. Hyperbilirubinemia (greater than 21 micromol/L) occurred in 91% of patients. Ultrasound and liver biopsy confirmed the clinical features in all patients. Mortality rate was 45% (n=9) (Steenkamp et al, 2000).
    2) 22.6% of 7200 villagers who ate Heliotropium contaminated wheat developed veno-occlusive disease over a 3 to 9 month period (Mohabbat et al, 1976).
    3) Kumana et al (1985) reported a mean cumulative alkaloid (base and N-oxide) dose of 18 mg/kg in 3 surviving women who drank an herbal tea over 19 to 45 days before developing symptoms of veno-occlusive liver disease. A fourth woman died from hepatic failure, portal hypertension, and terminal gastrointestinal hemorrhage.
    g) CASE REPORTS
    1) CASE REPORT: In a fatally poisoned Arizona child, the initial presentation closely mimicked Reye's syndrome (Fox et al, 1978).
    2) CASE REPORT: Irreversible veno-occulsive disease (VOD) was reported in a 3.5 month old infant following administration of a herbal medicine containing the pyrrolizidines retrorsine, seneciphylline, and platyphylline daily for one week. Clinical effects included ascites and elevated liver enzymes. The infant died 3 months after admission, after the development of Streptococcus pneumoniae peritonitis and septicemia. Postmortem liver histology confirmed the diagnosis of VOD (Zuckerman et al, 2002).
    3) CASE REPORT: Veno-occlusive disease has been reported with the use of comfrey root herbal tea (Weston et al, 1987).
    4) CASE REPORT: Reversible veno-occlusive liver disease was reported in an 18 month-old infant following the daily ingestion, for 15 months, of comfrey tea containing an estimated 60 mcg/kg of body weight per day of pyrrolizidine alkaloid (Sperl et al, 1995).
    5) CASE REPORT: Yeong et al (1990) reported a 23-year-old man who developed hepatic veno-occlusive disease with severe portal hypertension and subsequent death due to liver failure. The patient had ingested 4 to 5 comfrey leaves daily for 1 to 2 weeks prior to symptoms.
    B) HEPATOSPLENOMEGALY
    1) WITH POISONING/EXPOSURE
    a) Hepatosplenomegaly may occur following exposure
    b) CASE SERIES: Hepatosplenomegaly developed in the majority of 61 people who ate wheat flour and linseed oil contaminated with pyrrolizidine alkaloid containing seeds (Allen et al, 1979). In another series of 20 pediatric exposures, hepatomegaly developed in 94% of patients (Steenkamp et al, 2000).
    C) CIRRHOSIS OF LIVER
    1) WITH THERAPEUTIC USE
    a) Liver cirrhosis often occurs early, and is accompanied by megalocytosis (Van der Watt et al, 1971). Cirrhosis is associated with the ingestion of "bush teas" in Jamaica (Bras et al, 1961).
    D) ASCITES
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Ascites developed in the majority of 61 people who ate wheat flour and linseed oil contaminated with pyrrolizidine alkaloid containing seeds. This process took 10 to 12 months (Allen et al, 1979). In another series, extensive ascites was present in each patient (n=20) that developed veno-occlusive disease following pyrrolizidine exposure (Steenkamp et al, 2000).
    b) CASE REPORTS: Ascites was seen in a 6 month-old who had been given pyrrolizidine alkaloid containing teas (Huxtable et al, 1977); in 3 of 4 women who drank a pyrrolizidine alkaloid containing tea for 19 to 45 days (Kumana, 1983); and villagers in India who ingested grain contaminated with Crotalaria species (Tandon et al, 1976).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATIC FUNCTION ABNORMAL
    a) Russian comfrey root has been shown in animal studies to affect GOT and GLDH, illustrating impaired liver function (Calvenor et al, 1980).

Reproductive

    3.20.1) SUMMARY
    A) Transplacental pyrrolizidine poisoning has been reported. Venoocclusive disease of the liver has been reported in 2 infants whose mothers ingested herbal medicines containing pyrrolizidine alkaloid.
    3.20.3) EFFECTS IN PREGNANCY
    A) VENOOCCLUSIVE LIVER DISEASE
    1) CASE REPORT - Transplacental pyrrolizidine poisoning is reported. A newborn infant, whose mother showed no signs of toxicity, died of veno-occlusive disease after its mother ingested an herbal medicine containing pyrrolizidine alkaloid. This report suggests that infants may be more sensitive (Roulet et al, 1988).
    2) CASE REPORT - Another case of a newborn infant with venoocclusive disease of the liver has been reported. The infant developed liver failure with severe coagulopathy and portal hypertension which may have been responsible for the ileal perforation found on autopsy. The mother used a herbal mixture containing pyrrolizidine alkaloids from Turkey for daily cooking. Analysis of the herbal mixture showed toxic alkaloids such as lycopsamine, acetyl lycopsamine, acetyl intermedine and senkirine in amounts surpassing the legally allowed quantities 20- to 30-fold, taking into account the amounts used for cooking (Rasenack et al, 2003).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) PAs have been shown to produce various tumors in mice and rats including rhabdomyosarcomas. Most authors conclude that pyrrolizidine alkaloids are carcinogenic and mutagenic, at least in the animals studied.
    3.21.3) HUMAN STUDIES
    A) SARCOMA
    1) As yet, there have been no cases of human cancers attributed to these alkaloids (Abbott, 1988). Although there is a concern for hepatic carcinoma if cirrhosis develops (Nelson et al, 2007).
    3.21.4) ANIMAL STUDIES
    A) TUMORS
    1) Dehydroretronecine has been shown to produce various tumors in mice and rats including rhabdomyosarcomas (Allen et al, 1979). Most authors conclude that pyrrolizidine alkaloids are carcinogenic and mutagenic, at least in animals studied (Huxtable, 1979b).
    2) Hirono et al (1978) found that the roots and leaves of Symphytum officinale, when added to the diets of rats chronically, induced hepatocellular adenomas and bladder cancers.
    3) Lasiocarpine (Sroboda & Reddy, 1972) and symphytine (Hirono, 1979) have been shown to be carcinogenic in animals.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Therapeutic or toxic levels of pyrrolizidine alkaloids have not been established. Though methods exist for their detection, these tests are not useful for immediate clinical care, as these alkaloids are generally excreted within 24 hours.
    B) Liver damage is seen days to months post ingestion, so initial liver function tests may only serve to establish baseline laboratories. Depending on the degree of hepatic damage, ancillary labs such as a basic chemistry panel and coagulation studies may be useful.
    C) Doppler ultrasound can help assess for alterations of blood flow in the liver.
    D) The severity of a patient's symptoms may require studies such as a head CT to monitor for cerebral edema.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Therapeutic or toxic levels of pyrrolizidine alkaloids have not been established.
    2) Levels are not helpful, since the liver damage is seen days, weeks, or months from the ingestion, and the alkaloids are generally excreted within 24 hours (Ciarallo, 1992).

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Methods for isolation and identification of pyrrolizidine alkaloids have been described by Segall (1979) and Ramsdell & Buhler (1979).
    a) Mass spectrophotometry, reverse phase high pressure liquid chromatography and cation exchange, gas, liquid, paper and thin layer chromatography methods have been used.
    B) COLORIMETRIC SCREENING
    1) Two nonspecific colorimetric screening methods have been described to detect for the presence of pyrrolizidine alkaloids (Steenkamp et al, 2000; Zuckerman et al, 2002):
    a) BIRECKA method can detect the presence of alkaloids in urine up to 72 hours after ingestion, but cannot identify alkaloids as pyrrolizidines or differentiate between toxic and nontoxic compounds. However, the test is rapid and simple to perform.
    b) MATTOCKS method can confirm the presence of toxic unsaturated pyrrolizidines in plant material, but due to its lack of sensitivity it is not appropriate for urine samples from small children.
    C) GAS CHROMATOGRAPHY/MASS SPECTROMETRY
    1) Zuckerman et al (2001) described the use of a HP6890 gas chromatograph equipped with an HP 7683 auto injector and HP 5973 mass selective detector to analyze Senecio latifolius. In a dried specimen of S latifolius, pyrrolizidines retrorsine, seneciphylline and platyphylline were identified. The authors concluded that this test could be used retrospectively to identify alkaloids in a urine specimen (Zuckerman et al, 2002).
    D) BIOASSAY
    1) Various methods have been used to detect PA hepatotoxicity including primary cultures of rat hepatocytes, subchronic intraperitoneal administration to weanling rats and adult rats, phenobarbital pretreatment, subchronic oral administration, and intravenous administration to dogs.
    a) No single animal model was predictive for hepatotoxicity in humans.

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 who develop hepatotoxicity or worsening symptoms should be admitted to the hospital. Depending on the severity of their symptoms, they may require ICU care (eg, patients with fulminant hepatic failure). Patients should not be discharged from the hospital until they are medically stable and with clearly improving symptoms.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with accidental or single ingestion of plants or herbal products that contain pyrrolizidine alkaloids may likely remain at home especially if they have no significant symptoms.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Patients with significant hepatotoxicity may benefit from consultation from a hepatologist and even a transplant surgeon if they develop signs of liver failure. Patients with fulminant hepatic failure likely will require the care of an intensivist. A toxicologist or poison center can be contacted for advice for any exposures at any time.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients who develop any concerning symptoms or had an intentional self-harm exposure should be sent to a health care facility for observation until symptoms are clearly improving and they are cleared from a psychiatric standpoint.

Monitoring

    A) Therapeutic or toxic levels of pyrrolizidine alkaloids have not been established. Though methods exist for their detection, these tests are not useful for immediate clinical care, as these alkaloids are generally excreted within 24 hours.
    B) Liver damage is seen days to months post ingestion, so initial liver function tests may only serve to establish baseline laboratories. Depending on the degree of hepatic damage, ancillary labs such as a basic chemistry panel and coagulation studies may be useful.
    C) Doppler ultrasound can help assess for alterations of blood flow in the liver.
    D) The severity of a patient's symptoms may require studies such as a head CT to monitor for cerebral edema.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Most toxicity has been reported after chronic use.
    B) ACTIVATED CHARCOAL
    1) Activated charcoal is only useful if plant material is still expected to be in the stomach or GI tract.
    2) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    3) 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).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) Activated charcoal is probably only useful if an ingestion is recent and expected to be still in the stomach. Most toxicity has been in the setting of chronic use. Often the symptoms of pyrrolizidine alkaloids do not appear for some days or weeks after the initial ingestion.
    2) 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.
    3) 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) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY: Supportive care is the mainstay of treatment. Cessation of ingestion of the pyrrolizidine alkaloids and treatment for resultant symptoms are the main therapies available.
    2) MANAGEMENT OF SEVERE TOXICITY: Treatment is symptomatic and supportive. For patients that progress to liver failure, it is likely too late to protect the liver. Possible treatments early in intoxication would be to block metabolism of the alkaloids or add reactive substrates with sulfhydryl groups (eg, methionine, cysteine, ethoxyquin, glutathione and dichlorobenzenethiol). Patients with liver failure may require invasive treatments such as portal-systematic shunt placements for hepatic and portal decompression or liver transplantation.
    B) MONITORING OF PATIENT
    1) Therapeutic or toxic levels of pyrrolizidine alkaloids have not been established.
    2) Though methods exist for their detection, these tests are not useful for immediate clinical care, as these alkaloids are generally excreted within 24 hours. Liver damage is seen days to months postingestion, so initial liver function tests may only serve to establish baseline laboratories.
    3) Depending on the degree of hepatic damage, ancillary labs such as a basic chemistry panel and coagulation studies may be useful.
    4) Doppler ultrasound can help assess for alterations of blood flow in the liver.
    5) The severity of a patient's symptoms may require studies such as a head CT to monitor for cerebral edema.
    C) LIVER DAMAGE
    1) HEPATIC INJURY: A portal - systemic shunt to bypass the obstruction may be required in some patients (Ciarallo, 1942). Hepatic and portal decompression has been shown to be effective in some cases of veno-occlusive hepatic disease induced by pyrrolizidine alkaloids (McDermott & Ridker, 1990).
    2) Liver transplantation may be an option as part of the symptomatic care of the patient with cirrhosis or severe hepatotoxicity (Nelson et al, 2007).
    D) EXPERIMENTAL THERAPY
    1) SULFHYDRYL GROUPS
    a) Addition of sulfhydryl groups has been tried in animal models. Substances used include methionine, cysteine, ethoxyquin, glutathione, and dichlorobenzenethiol.
    b) Results were unpredictable and seemed of little protective value in these preliminary studies (Eisenstein & Huxtable, 1979).
    c) Work done by Kim (1984) on mice did show a protective effect by simultaneously feeding thiol containing compounds with pyrrolizidine alkaloids. The practical significance of this finding for human cases is doubtful.
    2) INHIBITION OF METABOLISM
    a) Inhibition of the microsomal P450 mixed function oxidase system may be effective if given EARLY. Most of the alkaloids will be excreted in the first 24 hours if not metabolized, and will cause little harm.
    b) Animal test models using allylisopropyl acetamide were minimally successful, metyrapone (Metapirone(R) - Ciba) and SKF 525A (proadifen hydrochloride) prevented ventricular hypertrophy in exposed animals.
    c) These substances have not been tested in humans. The limited availability of these substances and the necessity of early treatment may limit the usefulness of these substances as treatment agents (Eisenstein & Huxtable, 1979).

Enhanced Elimination

    A) HEMODIALYSIS
    1) There is no evidence for the use of dialysis, hemoperfusion, urinary alkalinization, or multiple dose charcoal. However, hemodialysis has been used in patients who become critically ill with hepatic and renal failure.
    2) Attempts to remove pyrrolizidine alkaloids by hemodialysis have not been reported. Hemodialysis may be effective in treating the patient with liver failure. One fatally poisoned child did have renal failure as well as hepatic failure (Fox et al, 1978).

Abstracts

Case Reports

    A) ADULT
    1) A 49-year-old woman who used various herbs & vitamins extensively developed abdominal swelling and edema of the extremities over a 4 month period. She was diagnosed as having veno-occlusive disease of the liver. Both her herbal tea and "comfrey-pepsin" pills contained pyrrolizidine alkaloids and resulted in a 15 microgram per kilogram per day ingestion. The minimum estimated dose taken was 85 mg.
    B) PEDIATRIC
    1) Over 2 to 3 years, a 13-year-old boy had regularly taken years an herbal tea containing comfrey leaf. The exact amount and frequency is unknown. He developed hepatomegaly and ascites and was diagnosed as having veno-occlusive liver disease (Weston et al, 1987).

Range Of Toxicity

Summary

    A) TOXIC DOSE: PEDIATRIC: Between 70 to 147 mg of pyrrolizidine alkaloids administered in an herbal tea for 2 weeks to a 6 month-old infant produced toxicity. In another case, a 2 month-old infant ingested approximately 66 mg over 5 to 7 days which resulted in hematemesis, liver injury and death. ADULT: Four women who ingested approximately 570 to 1380 mg of pyrrolizidine alkaloids, found in a contaminated tea, over 19 to 45 days developed ascites and liver failure; one woman died.

Minimum Lethal Exposure

    A) CASE REPORTS
    1) ADULT
    a) Four women who ingested a contaminated tea for 19 to 45 days developed ascites and liver failure; one woman died. The total amount of alkaloid ingested was estimated to be 570 to 1,380 mg (Anon, 1984).
    2) INFANT
    a) Between 70 to 147 mg of pyrrolizidine alkaloids administered in an herbal tea over 2 weeks to a 6 month-old infant produced hepatomegaly, ascites, right pleural effusion, and veno-occlusive disease of the liver (Huxtable, 1979a; Stillman et al, 1977).
    b) A 2 month-old infant ingested approximately 66 mg over 5 to 7 days which resulted in hematemesis, liver injury and death.

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) ADULT
    a) Hepatic disease was seen in a woman who ingested approximately 85 mg of alkaloid over 4 months (Ridker, 1985).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) Have not been established for the pyrrolizidine alkaloids in humans.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) RETRORSINE
    1) LD50- (INTRAPERITONEAL)RAT:
    a) 35 mg/kg -- over 72H, single injection (Huxtable, 1977a)
    B) SENECIONINE
    1) LD50- (INTRAPERITONEAL)RAT:
    a) 85 mg/kg -- over 72H, single injection (Huxtable, 1977a)

Pharmacology Toxicology

Toxicologic Mechanism

    A) The alkaloids which are thought to cause toxicity are unsaturated pyrrolizidine alkaloids and their N-oxides.
    1) The mechanism of action is assumed to be due to conversion of the alkaloids to a pyrrole derivative, which acts as an alkylating agent and attacks liver and other cell components.
    2) In vivo, this requires the alkloid to contain an unsaturated heterocyclic ring for conversion. Alkaloids without the ring have shown little hepatotoxicity (Roitman et al, 1979).
    3) Since activation is necessary, the amount of transformation is not only species, but even strain specific. Pan et al (1993) showed that two strains of rats had different responses to monocrotaline induced pulmonary vascular disease.
    B) Some of the reactive pyrrolic derivatives escape reaction in the liver and are carried in sinusoidal blood to other tissues like the lungs (Mattocks, 1972). Alkylating metabolites also bind to the thiol groups of hemoglobin in red blood cells (Mattocks & Jukes, 1990).
    C) Pyrrolizidine alkaloids that are unsaturated in the 1,2 position are hepatotoxins. Some of these are also pneumotoxins that produce pulmonary arterial hypertension and right ventricular hypertrophy (Huxtable & Awang, 1990).
    D) Bras et al (1954) has termed pyrrolizidine alkaloid toxicity as veno-occlusive due to the extensive destruction of small branches of the hepatic venous system.
    1) The pyrrole metabolites are capable of alkylating groups at the site of both ester linkages making it possible to link two DNA strands (Allen et al, 1979).

Animal Toxicology

Clinical Effects

    11.1.2) BOVINE/CATTLE
    A) Senecio intoxication (pyrrolizidine alkaloids) may produce depression, anorexia, ataxia of the hind limbs, head pressing, recumbency, roughened coat, staggering walk, diarrhea, tenesmus and fixed, staring faces (Craig et al, 1991). Vital signs may reveal subnormal temperature and elevated heart rate. Hairless perivulval skin may reveal petechiae and vaginal mucosa may show pinpoint ecchymotic hemorrhages. Serum chemistry may reveal severe liver damage and an increased bilirubin level (Brodrick, 1997).
    1) Borsberry (1999) reported presenting signs after ragwort ingestion of loss of condition (greyhound-look), cessation of milk production, watery scour without tenesmus, depression, major appetite for minerals, drinking urine and dirty water.
    2) Ascites and edema of the abomasum may be seen. The liver has been reported to be swollen and mottled, with fibrotic sections (Molyneaux et al, 1991; Seawright et al, 1991).
    B) Case mortality in one South American outbreak of Senecio poisoning was virtually 100% (de Lombardo et al, 1992).
    C) Lactating cows seem to be particularly susceptible to poisoning, possibly due to the stress of lactation (Synge & Stephen, 1993).
    D) YAKS - Poisoning is characterized by anemia, emaciation, dermatosis, and chronic liver damage (Winter et al, 1990). Mondal et al (1999) reported anorexia, severe gingivitis with excessive bubbly salivation, swelling and discrete necrosis of the gums, ventral surface of the tongue and the buccal mucosa leading to painful mouth movements which produced a smacking sound. The tongue progressively discolored to a yellowish white. Ulcerative symptoms showed on the muzzles, teats, scrotums, hooves and coronets. A lag time of 25 to 30 days between consumption of the plant and onset of symptoms was reported.
    1) Dermatoses consisted of photosensitive symptoms and lesions on the skin with cracks and fissures, particularly on the nose, submandibular region, shoulder, rump, hip and thigh. At first, the skin becomes rough, and the hair would coalesce due to exudates forming a matted surface which eventually sloughs off and exposes a raw surface. These yaks prefer to be in dark places. Mucous membranes were not icteric (Mondal et al, 1999).
    2) Symptoms in terminal phases included profuse mucopurulent nasal discharge, regurgitation of foul smelling ruminal contents followed by hypovolemic shock, then coma and death (Mondal et al, 1999).
    11.1.3) CANINE/DOG
    A) Dogs exhibit mainly liver disease (Huxtable & Awang, 1990; Huxtable et al, 1986).
    11.1.5) EQUINE/HORSE
    A) Dyspnea, most likely due to laryngeal and/or pharyngeal paralysis from hepatic encephalopathy, was associated with pyrrolizidine alkaloid toxicosis (Pearson, 1991).
    B) PREGNANCY - Stillbirths and agalactia are seen in mares that ingest Acremonium coenophialum (endophyte) infected fescue (Festuca arundinacea) containing pyrrolizidine alkaloids (Putnam et al, 1991; Garrett & Heiman, 1980; Taylor et al, 1985).
    C) CNS depression is a common symptom seen in horses (Huxtable & Awang, 1990; Huxtable et al, 1986).
    D) Renal damage has been seen in horses after ingestion of pyrrolizidine alkaloid containing plants (Van der Watt, 1971).
    E) O'Scanaill (1998) reported respiratory distress, weakness, and severely injected mucous membranes following ragwort ingestions. Skin lesions similar to photosensitivity were observed. Pastern regions were grossly enlarged and edematous with a serous fluid leakage. Involvement of the coronary bands was also noted with a separation occurring between hair and hoof.
    1) Laboratory results revealed liver damage. Postmortem examinations revealed extensive pathological liver changes.
    11.1.9) OVINE/SHEEP
    A) Sheep exhibit primarily a hemolytic syndrome (Huxtable & Awang, 1990; Huxtable et al, 1986).
    11.1.10) PORCINE/SWINE
    A) Renal damage has been seen in pigs after ingestion of pyrrolizidine alkaloid containing plants (Van der Watt, 1971).
    11.1.13) OTHER
    A) OTHER
    1) MONKEYS -
    a) Veno-occlusive disease has been reproduced in monkeys using seeds of Crotalaria spectabilis (Allen et al, 1967).
    b) HEPATIC NECROSIS - Centrilobular hepatic necrosis was seen in monkeys given seeds of C. spectabilis over a 32 day period (Allen et al, 1971).
    c) Renal tubular megalocytosis and metaplasia of the parietal cells of Bowman's capsule was seen in monkeys.

Treatment

    11.2.1) SUMMARY
    A) CATTLE
    1) Brodrick (1997) has reported the use of fenestration of the rumen with removal of its contents followed by installation of 1.2 kilograms of activated charcoal in 3 liters of 50% propylene glycol daily for 3 days in an acutely ill cow.

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) CATTLE
    1) Cattle fed Senecio riddelli as a gavage, in doses of 45 mg of pyrrolizidine alkaloids per kilogram of body weight per day for 20 days, developed signs of intoxication and had 100% morbidity. Cattle receiving doses of 4.5 mg/kg/day for 20 days did not become toxic (Molyneaux et al, 1991).
    2) Calves became intoxicated and were euthanatized after ingestion of 1.3 mg of pyrrolizidine alkaloids/kilogram/day (Craig et al, 1991).

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) CATTLE
    1) Brodrick (1997) has reported the use of fenestration of the rumen with removal of its contents followed by installation of 1.2 kilograms of activated charcoal in 3 liters of 50% propylene glycol daily for 3 days in an acutely ill cow.

Kinetics

    11.5.1) ABSORPTION
    A) LACK OF INFORMATION
    1) There was no specific information on absorption at the time of this review.
    11.5.3) METABOLISM
    A) GENERAL
    1) Seawright et al (1991, 1991a) described a method of determining exposure to pyrrolizidine alkaloids by examining the sulfur-bound pyrroles on hemoglobin and in liver tissue. This aids in determining which animals have been exposed.

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