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toxidrome
Pyrrolizidine alkaloids toxidrome
botanicals

definition

pyrrolizidine alkaloids toxidrome
the following toxicity information is largely derived from poisonings, misidentified herbs, overdoses and research on isolated constituents; used with appropriate clinical judgment and cautious prescribing, herbs are safe and efficacious

plants included:
» Borago officinalis: small amounts
» Eupatorium perfoliatum, Eupatorium purpurea: small amounts
» Lithospermum spp.
» Symphytum officinale
» Senecio spp.
» Pulmonaria officinalis, Sticta pulmonaria
» Tussilago farfara

• pyrrolizidine alkaloids have caused hepatic occlusive disease in humans and cancer in rats; long-term use (over 10 days) is contraindicated as well as use during pregnancy and nursing and use in malnourished patients (e.g. Crohn's disease); for the most safety, external use only is recommended; young leaves are highest in the alkaloid
• potential hepatocarcinogen (Keeler and Tu, p. 248-249; 638; 646)
• chronic use may result in Budd-Chiari syndrome: hepatic venothrombosis leading to apathy, emaciation, and cirrhosis; patient presents with ascites, hepatosplenomegaly, anorexia, nausea, vomiting, and diarrhea (AMA, pp. 154-155; Brinker, p. 91; Cheeke)
• acute reactions present with signs of hepatic necrosis and veno-occlusive disease; ascites occurs along with abdominal pain, nausea, vomiting, bloody diarrhea, and headache (Brinker, p. 91; Cheeke)
• hepatotoxic effects may potentiated by copper intake (Brinker, p. 91)
Note: Outside of issues arising from the occurrence of pyrrolizidine alkaloids in traditional foods, such as various legumes, the hepatic veno-occlusion potentially due to medicinal herbs in the U.S. and Europe is more often associated with radiation, chemotherapeutic agents, such as dactinomycin and vincristine, and oral contraceptives than with chronic use of these herbs.

footnotes

Almer S, Bodemar G, Ryden BO, Elfstrom J, Franzen L, Ihse I, Resjo M. [Oral contraceptives and blood diseases are the most common causes of Budd-Chiari syndrome]. Lakartidningen 1989 Nov 15;86(46):4002-4008 [Article in Swedish]

Arseculeratne SN, Gunatilaka AA, Panabokke RG. Studies on medicinal plants of Sri Lanka: occurrence of pyrrolizidine alkaloids and hepatotoxic properties in some traditional medicinal herbs. J Ethnopharmacol 1981 Sep;4(2):159-177.
Abstract: There is a paucity of data on the occurrence of hepatotoxic and hepatocarcinogenic pyrrolizidine alkaloids in medicinal plants, and there are no data on the hepatotoxic properties of herbal medicines that are used in the traditional pharmacopoiea of Sri Lanka and other Asian and African countries. In view of the extensive consumption of these herbs and the occurrence of chronic liver diseases including hepatocellular cancer in this and other countries of South Asia, we have screened fifty medicinal plants for pyrrolizidine alkaloids and have obtained positive results with three species, namely Crotalaria verrucosa L., Holarrhena antidysenterica (L.) Br., and Cassia auriculata L. Feeding trials in rats with materials from these three species produced liver lesions--disruption of the centrilobular veins, congestion or haemorrhage in the centrilobular sinusoids, centrilobular or focal hepatocellular necrosis--and histopathology in the lungs and kidneys which were compatible with the action of pyrrolizidine alkaloids. The presence of alkaloids in C. auriculata has not been previously reported nor has the presence of pyrrolizidine alkaloids in H. antidysenterica. It is suggested that the consumption of herbal medicines that contain pyrrolizidine alkaloids could contribute to the high incidence of chronic liver disease including primary hepatocellular cancer in Asian and African countries.

Brauchli J, Luthy J, Zweifel U, Schlatter C. 1982. Pyrrolizidine alkaloids from Symphytum officinale L. and their percutaneous absorption in rats. Experientia, 38:1085-7.

Brinker F. 1995. Botanical Medicine Research Summaries. (from Eclectic Dispensatory of Botanical Therapeutics, vol.11), Sandy, Oregon: Eclectic Medical Publications.

Brinker F. 1996. The Toxicology of Botanical Medicines, rev. 2nd ed., Sandy, Oregon: Eclectic Medical Publications.

Chan MY, Zhao XL, Ogle CW. A comparative study on the hepatic toxicity and metabolism of Crotalaria assamica and Eupatorium species. Am J Chin Med 1989;17(3-4):165-170.
Abstract: The oral LD50 of Crotalaria assamica, which contains mainly monocrotaline, was found to be 154 mg/kg in mice. Neither liver necrosis nor morbidity was demonstrated with
Eupatorium extract at a dose level of 144 mg/kg, which was equivalent to the LD20 of Crotalaria. Pretreatment with phenobarbitone enhanced the toxicity of both plant extracts in mice. In in vitro studies, "metabolic pyrrole" was formed by incubating Eupatorium japonicum extracts with liver microsomes. The rate of "pyrrole" formation was similar to that of Crotalaria extract and pure monocrotaline alkaloid, but was much slower than
retrorsine. The rate of N-oxide formation was, in descending order, retrorsine, Eupatorium japonicum and Crotalaria/monocrotaline. It is concluded that the alkaloid in Eupatorium species is metabolized to "pyrrole" and an N-oxide metabolite in the liver, but hepatotoxicity is much lower when compared with that caused by Crotalaria.

Cheeke, P.R. 1979. Symposium on Pyrrolizidine Alkaloids: Toxicity, Metabolism, and Poisonous Plant Control Measures. Corvallis, OR: Nutrition Research Institute, Oregon State University.

Cheeke PR. Toxicity and metabolism of pyrrolizidine alkaloids. J Anim Sci 1988 Sep;66(9):2343-2350. (Review)
Abstract: Pyrrolizidine alkaloids (PA) are found mainly in plants of three families: boraginaceae, Compositae and Leguminosae. In North America, PA poisoning of livestock is caused primarily by consumption of Senecio and Crotalaria spp. The PA of Senecio spp. Cause irreversible hepatic damage; toxicity signs are a consequence of impaired liver function. Crotalaria intoxication leads to pulmonary damage as a primary effect; hepatic effects are less prominent. Large species differences exist in susceptibility to PA toxicosis. Small herbivores such as sheep, goats, rabbits, guinea pigs and other herbivorous laboratory animals are highly resistant to PA toxicity, associated with a low rate of hepatic production of reactive metabolites (pyrroles) and(or) a high rate of activity of detoxifying enzymes. Diester PA common to Heliotropium and Echium spp. are metabolized in the ovine rumen to 1-methyl metabolites, whereas the macrocyclic ester PA of Senecio spp. are not. Exposure to PA results in high concentrations of liver Cu, reduced liver Zn, and abnormal Fe metabolism with hematopoiesis markedly impaired. Pyrrolizidine alkaloid toxicity alters vitamin A metabolism in rats, depressing plasma and liver levels of vitamin A. Synthetic antioxidants in the diet confer protective activity in laboratory animals (e.g., rats, mice) against PA toxicoses. The PA and their metabolites are secreted in the milk of lactating animals, but this probably does not represent a significant human health hazard.

Datta DV, Khuroo MS, Mattocks AR, Aikat BK, Chhuttani PN. Herbal medicines and veno-occlusive disease in India. Postgrad Med J 1978 Aug;54(634):511-515.
Abstract: Six cases are described of veno-occlusive disease (VOD) after medicinal herb ingestion. The herb Heliotropium eichwaldii, taken by three patients, was found to contain the toxic pyrrolizidine alkaloid, heliotrine. Two patients presented with fulminant hepatic failure while the other four patients had a clinical picture suggestive of decompensated cirrhosis. The medical use of this herb may possibly be responsible for a significant proportion of acute and chronic liver disease in India, making it of public health importance.

Davies TC. Liver damage caused by extracts of "rattlebox" seeds (Crotalaria). J S C Med Assoc 1969 Jun;65(6):201-202

De Smet PAGM et al. (eds.). 1993. Adverse Effects of Herbal Drugs 2, Berlin: Springer-Verlag

Edgar JA, Lin HJ, Kumana CR, Ng MM. Pyrrolizidine alkaloid composition of three Chinese medicinal herbs, Eupatorium cannabinum, E. japonicum and Crotalaria assamica. Am J Chin Med 1992;20(3-4):281-288.
Abstract: The pyrrolizidine alkaloid composition of three Chinese herbs, "pei lan", "cheng gan cao" and "zi xiao rong," identified respectively as Eupatorium cannabinum, Eupatorium japonicum (Compositae) and Crotalaria assamica (Leguminosae), were studied by fast atom bombardment mass spectrometry and gas chromatography-electron impact mass spectrometry. Viridiflorine, cynaustraline, amabiline, supinine, echinatine, rinderine and isomers of these alkaloids were found in the Eupatorium species. Monocrotaline was the only pyrrolizidine alkaloid detected in the Crotalaria species.

Feigen M. Fatal veno-occlusive disease of the liver associated with herbal tea consumption and radiation. Aust N Z J Med 1984 Feb;14(1):61-62.

Jones JG, Taylor DE. Hepatic veno-occlusive disease and herbal remedies. Ann Rheum Dis 1989 Sep;48(9):791. (Letter)

Keeler, R.F., and Tu, A.T. 1983. Handbook of Natural Toxins. New York: Marcel Dekker, Inc.

Kumana CR, Ng M, Lin HJ, Ko W, Wu PC, Todd D. Hepatic veno-occlusive disease due to toxic alkaloid herbal tea. Lancet 1983 Dec 10;2(8363):1360-1361. (Letter)

Kumana CR, Ng M, Lin HJ, Ko W, Wu PC, Todd D. Herbal tea induced hepatic veno-occlusive disease: quantification of toxic alkaloid exposure in adults. Gut 1985 Jan;26(1):101-104.
Abstract: Four young Chinese women took daily doses of an unidentified 'Indian' herbal tea as treatment for psoriasis. Three (one of whom died), developed ascites, hepatomegaly and biochemical abnormalities within 19-45 days. The fourth patient discontinued herbal tea after 21 days when she developed a skin rash. Two patients had portal hypertension, while all had liver histology showing features of veno-occlusive disease. Pyrrolizidine alkaloids were identified spectrophotometrically in the brewed tea, and in the chopped leaves of the herbal mixture; the mean dose in the tea prepared for consumption being 12 mg/day of alkaloid base and 18 mg/day of N-oxide. The mean cumulative dose of alkaloids (base + N-oxide) before onset of symptoms (three patients), was estimated to be 18 mg/kg. In the asymptomatic patient with histological liver disease only, the corresponding dose was 15 mg/kg. These cases thus provide some measure of pyrrolizidine alkaloid toxicity in adults.

Lampe, K.F., and McAnn, M.A. 1985. AMA Handbook of Poisonous and Injurious Plants. Chicago: American Medical Association.

Larrey D. [Liver involvement in the course of phytotherapy]. Presse Med 1994 Apr 16;23(15):691-693. (Editorial, Review) [Article in French]
Abstract: The development of herbal medicine has follow in line with increased popular interest in ecology. Emphasis has been placed on the safety of natural herbs in contrast with the risks involved with "classical" medicines. But recent publications have revealed that several herbal medicines are toxic for the liver. For example, in France we have observed cases of hepatitis after ingestion of germander (Teucrium chamaedrys). Clinicians should also be aware of other well documented toxic effects of herbs used in popular medicines in Africa, Asia or Central America. The toxicity of pyrrolizidine alkaloids was recognized over 40 years ago. More than 300 plant species, including Heliotropium, Crotalaria, Senecio and Symphytum, are implicated. In Africa or Central America, intoxication is sometimes endemic since these plants are often used for making tea. In Western countries, cases of herb-induced hepatitis have been observed after use of preparations containing Symphytum or Chinese herbs. Pyrrolizidine alkaloids cause obstruction of the hepatic venous system and can lead to hepatonecrosis. Clinical manifestations include abdominal pain, ascitis, hepatomegaly and raised serum transaminase levels. Prognosis is often poor with death rates of 20 to 30% being reported. Atractylis gummifera is another example of herbal toxicity. Twenty-six species of this plant are used for medicinal purposes or for chewing gum. Intoxication usually occurs in the spring and is related to chewing the roots of these plants. Severe hepatocellular lysis may occur less than 24 hours after ingestion. Clinical manifestations are related to the induced hypoglycemia and neurovegetative disorders or subsequent renal failure. These compounds have an inhibitor effect on the Krebs cycle and can lead to severe or fatal liver failure. Other similar cases of fatal liver accidents have been reported after ingesting Callilepis laureola, a herb used by the Zoulous in Natal for medicinal purposes or after use of products containing extracts of Teucrium chamaedrys, which was nevertheless authorized in France in 1986 for use in preparations for weight loss. These examples emphasize the importance of remembering that herbal medicine is not harmless. Faced with the extensive distribution of many herbal preparations and the risk of self-medication, consumers and clinicians alike should be increasingly vigilant with these potentially hepatotoxic products.

Lyford CL, Vergara GG, Moeller DD. Hepatic veno-occlusive disease originating in Ecuador. Gastroenterology 1976 Jan;70(1):105-108.
Abstract: A case of hepatic veno-occlusive disease manifested by massive ascites is described in a 35-year-old female. She had consumed an herbal tea containing a Crotalaria plant species for 6 months prior to evaluation. Inferior vena cava and hepatic veins were patent by angiography. Liver biopsy showed histological changes typical of hepatic veno-occlusive disease, consisting of centrilobular congestion and sublobular hepatic vein obstruction. Complete clinical, biochemical, and histological recovery was documented 1 year after ingestion of the brew was discontinued. This is the first case known to be reported from Ecuador and the first to be diagnosed in the United States.

Mahran G, Wassel G, El-Menshawi B, El-Hossary G, Saeed A. Pyrrolizidine alkaloids of Crotalaria aegyptiaca and Crotalaria madurensis. Acta Pharm Suec 1979;16(5):333-338.

McGee J, Patrick RS, Wood CB, Blumgart LH. A case of veno-occlusive disease of the liver in Britain associated with herbal tea consumption. J Clin Pathol 1976 Sep;29(9):788-794.
Abstract: Veno-occlusive disease of the liver with clinical and pathological features similar to those of the condition occurring in the Caribbean is described in a young woman resident in Britain. The diagnosis was made from liver biopsies and hepatic venography and was confirmed at necropsy. Small amounts of pyrroliziding alkaloids were recovered from a sample of mate (Paraguay) tea, owned by the patient, to which she was addicted. It seems probable that the consumption of large amounts of this tea over a period of years was the cause of the hepatic disease.

Pauwels A, Mostefa-Kara N. [Hepatotoxicity of medicinal plants and plant-based preparations]. Gastroenterol Clin Biol 1993;17(5 Pt 2):H79-H85. [Article in French]

Roulet M, Laurini R, Rivier L, Calame A. Hepatic veno-occlusive disease in newborn infant of a woman drinking herbal tea. J Pediatr 1988 Mar;112(3):433-436

Safouh MA, Shehata A, Milad M. Experimental study on hepatic vein occlusion disease. The hepatotoxic effect of Senecio plant. J Egypt Med Assoc 1968;51(6):479-489

Sommer M. Hepatic veno-occlusive disease and drinking of herbal teas. J Pediatr 1989 Oct;115(4):659-660. (Letter)

Sperl W, Stuppner H, Gassner I, Judmaier W, Dietze O, Vogel W. Reversible hepatic veno-occlusive disease in an infant after consumption of pyrrolizidine-containing herbal tea. Eur J Pediatr 1995 Feb;154(2):112-116.
Abstract: Veno-occlusive disease was diagnosed in an 18-month-old boy who had regularly consumed a herbal tea mixture since the 3rd month of life. The boy developed portal hypertension with severe ascites. Histology of the liver showed centrilobular sinusoidal congestion with perivenular bleeding and parenchymal necrosis without cirrhosis. The tea contained peppermint and what the mother thought was coltsfoot (Tussilago farfara). The parents believed the tea aided the healthy development of their child. Pharmacological analysis of the tea compounds revealed high amounts of pyrrolizidine alkaloids. Seneciphylline and the corresponding N-oxide were identified as the major components by thin-layer chromatography, mass spectrometry and NMR spectroscopy. We calculated that the child had consumed at least 60 micrograms/kg body weight per day of the toxic pyrrolizidine alkaloid mixture over 15 months. Macroscopic and microscopic analysis of the leaf material indicated that Adenostyles alliariae (Alpendost) had been erroneously gathered by the parents in place of coltsfoot. The two plants can easily be confused especially after the flowering period. The child was given conservative treatment only and recovered completely within 2 months. CONCLUSION: In all cases of veno-occlusive disease pyrrolizidine alkaloids ingestion should be excluded. The identity of collected plant material should be verified by pharmaceutically trained experts and information of composition, dosage and mode of administration should be included in guidelines for herbal preparations.

Stillman AS, Huxtable R, Consroe P, Kohnen P, Smith S. Hepatic veno-occlusive disease due to pyrrolizidine (Senecio) poisoning in Arizona. Gastroenterology 1977 Aug;73(2):349-352.
Abstract: An infant with documented hepatic veno-occlusive disease due to ingestion of pyrrolizidine alkaloids is presented. The alkaloids were ingested in the form of an herbal tea commonly used as a folk remedy among the Mexican-American population. Among these people, this herb is known as gordolobo yerba. The patient presented with acute hepatocellular disease and portal hypertension which progressed over 2 months to extensive hepatic fibrosis. Other potential causes of hepatic venous occlusion were absent.

Tandon HD, Tandon BN, Mattocks AR. An epidemic of veno-occlusive disease of the liver in Afghanistan. Pathologic features. Am J Gastroenterol 1978 Dec;70(6):607-613.
Abstract: A large outbreak of veno-occlusive disease occurred in Afghanistan in which approximately 7,800 in a population of 35,000 subjects were estimated to have been affected. It was caused by consumption of wheat flour heavily contaminated with seeds of a plant of the heliotropium species. These were found to contain pyrrolizidine alkaloids, chiefly heliotrine. Fourteen percutaneous liver biopsies, representing different stages of diseases and liver tissue from eight autopsies were studied. Morphological changes in the liver were characteristic. Centrilobular hemorrhagic necrosis was followed by occlusive changes in the hepatic veins, finally resulting in nonportal cirrhosis. The sequence of changes observed suggests primary parenchymal injury and possibly obstructive lesions at the sinusoidal level. Collagenization of the sinusoids and reorganization of the lobular reticulin begin early in disease. Occlusive changes in the efferent veins apparently follow.

Talalaj S, Czechowicz A. Cautions in the use of herbal remedies during pregnancy and for small children. Med J Aust 1990 Jan 1;152(1):52.(letter)

Tomioka M, Calvo F, Siguas A, Sanchez L, Nava E, Garcia U, Valdivia M, Reategui E. [Hepatic veno-occlusive disease associated with ingestion of Senecio tephrosioides]. Rev Gastroenterol Peru 1995 Sep;15(3):299-302. [Article in Spanish]
Abstract: A case of hepatic veno-occlusive disease (HVOD) in a 38 year-old woman is reported. She had occasionally consumed "Huamanrripa" (Senecio tephrosioides) as a cough remedy for many years. She was hospitalized because she had presented abdominal pain, jaundice and anasarca during 10 weeks. The histological studies of hepatic biopsy showed pronounced congestion to centrilobulillar predominance, focus of necrosis and a reversed lobulation pattern in some areas. In the next 13 months she was hospitalized four times due to complications of portal hypertension. This is the first reported case of HVOD associated with S tephrosioides ingestion. It is very probable that this plant used in peruvian traditional medicine contains pyrrolizidine alkaloids, hepatic and nephrotoxic substances that are present in other species of Senecio genus. Due to present popularity of alternative medicine, an increment in HVOD incidence is expected.

Wichtl M (ed.). 1994. Herbal Drugs and Phytopharmaceuticals. Boca Raton, FL: CRC Press.

Winship KA. 1991. Toxicity of comfrey. Adverse Drug React. Toxicol. Tev., 10:47-59.

Yeong ML, Swinburn B, Kennedy M, Nicholson G. Hepatic veno-occlusive disease associated with comfrey ingestion. J Gastroenterol Hepatol 1990 Mar;5(2):211-214.
Abstract: A 23 year old man presented with hepatic veno-occlusive disease and severe portal hypertension and subsequently died from liver failure. Light microscopy and hepatic angiography showed occlusion of sublobular veins and small venous radicles of the liver, associated with widespread haemorrhagic necrosis of hepatocytes. The patient had been on a predominantly vegetarian diet and, prior to his illness, took comfrey leaves which are known to contain hepatotoxic pyrrolizidine alkaloids. Comfrey is widely used as a herbal remedy, but so far has only been implicated in two other documented cases of human hepatic veno-occlusive disease. A possible causal association of comfrey and this patient's veno-occlusive disease is suggested by the temporal relationship of the ingestion of comfrey to his presentation, the histological changes in the liver and the exclusion of other known causes of the disease.

Yeong ML, Clark SP, Waring JM, Wilson RD, Wakefield SJ. The effects of comfrey derived pyrrolizidine alkaloids on rat liver. Pathology 1991 Jan;23(1):35-38.
Abstract: Three groups of young adult rats were fed pyrrolizidine alkaloids derived from Russian comfrey to study the effects of the herb on the liver. Group I animals received a single dose of 200 mg/kg body wt, Group II 100 mg/kg three times a week for 3 weeks and Group III 50 mg/kg three times a week for 3 weeks. All rats showed light and electron-microscopic evidence of liver damage, the severity of which was dose dependent. There was swelling of hepatocytes and hemorrhagic necrosis of perivenular cells. There was a concomitant loss of sinusoidal lining cells with disruption of sinusoidal wall and the sinusoids were filled with cellular debris, hepatocyte organelles and red blood cells. Extravasation of red blood cells was evident. Terminal hepatic venules were narrowed by intimal proliferation, and in Group II and III, reiculin fibres radiated from these vessels. These appearances have been described in veno-occlusive disease due to pyrrolizidine alkaloids from other plant sources such as Senecio and Crotalaria. The safety of comfrey, a widely used herb, in relation to human consumption requires further investigation.

Zhao XL, Chan MY, Kumana CR, Ogle CW. A comparative study on the pyrrolizidine alkaloid content and the pattern of hepatic pyrrolic metabolite accumulation in mice given extracts of Eupatorium plant species, Crotalaria assamica and an Indian herbal mixture. Am J Chin Med 1987;15(1-2):59-67.
Abstract: Plants belonging to the Eupatorium species, E. japonicum Thunb, E. fortunei and E. chinense, were found to contain very low concentrations of pyrrolizidine alkaloid compared with a known hepatotoxic Indian herbal mixture and Crotalaria assamica. High concentrations of pyrrolic metabolite were detected in livers of mice given a single oral dose of extracts of Indian herbal mixture or C. assamica but not in the case of the Eupatorium species. Also, accumulation of pyrrole metabolites was not demonstrated with chronic administration of decoctions prepared from herbs of the Eupatorium species.