Pyrrolizidine Alkaloid Toxicity

John R. Elliott, DVM; Perry J. Bain, DVM, PhD; Kenneth S. Latimer, DVM, PhD

Class of 2005 (Elliott) and Department of Pathology (Bain, Latimer), College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388

Introduction

Pyrrolizidine alkaloids (PAs) are hepatotoxins found in many species of plants throughout the world. Plants of primary importance in the United States are Amsinckia spp. (e.g. fiddleneck), Crotalaria spp. (e.g., Rattlebox), Cynoglossum spp. (e.g., hound’s tongue), Echium spp. (e.g., Salvation Jane), Heliotropium spp. (e.g., common heliotrope), and Senecio spp. (e.g., ragwort, groundsel, and tar weed) (Figs. 1 through 4). Plants containing PAs are distributed throughout the United States and are most prevalent in the northwest regions.^{4, 6} These plants are not palatable to livestock and are avoided when better quality grazing is available. Most cases of PA toxicosis occur when pastures are overgrazed and in early spring when there is a limited supply of green forage. The PA concentrations in plants are not substantially decreased if fed fresh or dried. Therefore, toxicity can occur from contaminated hay, silage, or grain; and may be seen at any time of the year. ² All livestock are susceptible to PA toxicity. Horses and cattle are at greater risk while small ruminants, especially sheep, are less susceptible.⁶ PA toxicity has historically been a significant problem, but with modern herbicides and better grazing management practices this problem has been minimized in some areas.

Figure 1 Scientific Name: Amsinckia spp. Common Name: Fiddleneck © Br. Alfred Brousseau, Saint Mary's College

Figures 2a and 2b. Scientific Name: Senecio spp. Common Name: Senecio, Groundsels, and Ragworts. Courtesy of Cornell University

Figure 3. Scientific Name: Cynoglossum officinale L. Common Name: Hound’s tongue. © John M Randall The Nature Conservancy.	Figure 4. Scientific Name: Crotalaria spp. Common Name: Rattlebox.

Toxicity

Pyrrolizidine alkaloid concentrations vary among plants but, historically, Senecio spp have presented the greatest risk to livestock. It has been estimated that ingestion of Senecio plant material equivalent to 1% to 5% body weight daily will cause hepatic disease within a few weeks in horses and cattle. It has been demonstrated that ingestion of one plant of Cynoglossum spp. (hound’s tongue) per day for two weeks can cause clinical disease in a 500-kg horse. Amsinckia spp, Crotalaria spp, Echium spp, and Heliotropium spp poisonings are less prevalent in the United States.²

Cattle and horses are thirty to forty times more susceptible to PA poisoning than sheep and goats. This difference in susceptibility to development of toxicosis is related to the fact that sheep and goats have a greater ability to detoxify PAs in the liver.⁵

Mechanism of Action

Pyrrolizidine alkaloids are absorbed in the intestine and transported to the liver where they are metabolized to pyrroles. Pyrroles are toxic metabolites that are very reactive chemically and cross link with double stranded DNA. They bind both proteins and nucleic acids within hepatocytes. Upon binding DNA, the toxin has an antimitotic effect on hepatocytes resulting in megalocyte formation. As the megalocytes die, these cells are replaced with fibrous tissue instead of normal hepatocytes. Ultimately, the liver fails due to hepatocellular death and fibrosis.^1,2,3 While the liver is the primary organ effected, reactive metabolites may also damage the lung, leading to cor pulmonale or right heart failure. Renal damage may result in megalocytosis of renal tublar epithelium and glomerulosclerosis.⁷

Ingestion of large doses of PAs results in acute toxicosis and most commonly produces centrilobular necrosis with hemorrhage. Chronic ingestion usually produces hepatocellular necrosis in the portal areas, megalocytosis, fibrosis, biliary hyperplasia and obstruction of hepatic veins.¹

Clinical Signs

Clinical signs of pyrrolizidine alkaloid toxicosis are consistent with signs of liver failure. The underlying lesion develops slowly in most cases (weeks to months), and clinical signs generally appear suddenly. The most common clinical signs are weight loss, icterus, behavioral abnormalities due to hepatoencephalopathy, and photosensitive dermatitis.⁵

Cattle exhibit signs of toxicosis such as a sudden onset of depression and decreased reactivity to stimuli. Intermittent outbursts of excitability and aggressive behavior, profuse diarrhea, and tenesmus possibly resulting in a rectal prolapse may be seen. Other clinical signs include abdominal pain, circling, and blindness. Death usually occurs 2-3 days after the onset of clinical signs.⁵

Signs of PA toxicosis in horses include weight loss, icterus, decreased reactivity to stimuli, and abnormal behavior. Poisoned horses may appear blind and walk into or through objects or fences, and loose their sense of purpose by walking aimlessly in circles or straight lines. Head pressing and ataxia are common. Episodes of spontaneous, uncontrolled galloping may be seen and often result in trauma to the animal. Death is frequently the sequela to clinical signs.⁵

Diagnosis

Diagnosis of pyrrolizidine alkaloid toxicosis is based on history, clinical signs, clinical laboratory abnormalities, and liver biopsy. Clinical laboratory abnormalities are elevations in gamma-glutamyl transferase, alkaline phosphatase, aspartate aminotransferase activities, and an increase in bile acid concentration. Hyperbilirubinemia, hypoproteinemia, hyperammonemia, an inflammatory leukogram, and abnormal liver function tests are commonly seen. Ultrasonographic or necropsy examination reveals a small, firm, pale liver. Liver biopsy abnormalities in PA toxicosis include megalocytosis, centrilobular and periportal fibrosis, and biliary hyperplasia (Figs. 5 and 6).^1,2

Figure 5. Megalocytosis of hepatocytes in the liver parenchyma of a horse with pyrrolizidine alkaloid toxicosis from ingestion of Crotalaria spectabilis (Hematoxylin and eosin stain).	Figure 6. Liver biopsy from a horse with Crotalaria sp. toxicosis. A megalocyte is present at right. Hepatic fibrosis (left) and bile duct hyperplasia also are present (Hematoxylin and eosin stain).

Treatment

There is no definitive treatment for pyrrolizidine alkaloid toxicosis. Further exposure to plants containing PAs must be prevented. Treatment consists of supportive care to allow time for liver regenerate and restoration function, if possible. Supportive care includes administration of intraveneous fluid administration to correct dehydration and electrolyte abnormalities, glucose to provide basic energy requirements, and antibiotics and wound care if photodermatitis is present.^1,2,5

Prevention

Livestock management techniques can minimize exposure to pyrrolizidine alkaloid-containing plants. Plants containing PAs are unpalatable and are not usually consumed when quality forage is available. Therefore, overgrazing of pastures must be avoided to minimize the risk of PA toxicosis. Biological control of PA-containing plants has proven to be beneficial. The cinnabar moth, T. jacobaeae, and the flea beetle, Longitarsus jacobaeae, feed on plants containing PAs and inhibit their proliferation in pastures. Sheep also have proven to be efficient biological controls. Given the sheep’s high resistence to PA toxicosis, they are used to control moderate infestations of these plants with little risk of poisoning. Broad leaf herbicides may be indicated for dense stands of noxious plants, but is probably not economically feasible for large areas of pasture. Good management techniques and knowledge of toxic plants are essential to prevent PA poisonings.³

References

1. Schmitz DG: Toxicologic Problems. In: Reed SM, Bayly WM (eds): Equine Internal Medicine. Philadelphia, W.B. Saunders Co., 1998, pp. 1024-1025.

2. Talcott P: Pyrrolizidine Alkaloid Poisoning. In: Robinson NE (ed): Current Therapy in Eqine Medicine, 5th Edition. Philidelphia, W.B. Saunders Co., 2003, pp. 788-790.

3. Cheeke PR: Natural Toxicants in Feeds, Forages, and Poisonous Plants, 2nd Edition. Danville, Interstate Publishers, Inc., 1998, pp. 338-352.

4. Savage CJ: Diseases of the Liver. In: Colahan PT, Mayhew IG, Merritt AM, Moore JN (eds): Equine Medicine and Surgery, vol 1, 5th ed. St. Louis, Mosby, Inc., 1999, pp. 829-830.

5. Radostits OM, Gay CC, Blood DC, Hinchcliff KW: Veterinary Medicine, A Textbook of the Diseases of Cattle, Sheep, Pigs, Goats, and Horses, 9th Edition. Philidelphia, W.B. Saunders Co., 2000, pp. 1661-1664

6. Galey FD: Plants and Other Natural Toxicants. In: Smith BP (ed): Large Animal Internal Medicine, 3rd Edition, St. Louis, Mosby, Inc., 2002, pp. 1616-1618.

7. Jones TC, Hunt RD, King NW: Veterinary Pathology, 6th Edition. Baltimore, Williams & Wilkins, 1997, p. 712-718.

Acknowledgements

Figure 1 courtesy of Saint Mary’s College of California
http://elib.cs.berkeley.edu/cgi/img_query?seq_num=6318&one=T

Figure 2 courtesy of Cornell University
http://www.ansci.cornell.edu/plants/comlist.html

Figure 3 courtesy of UC Davis and The Nature Conservancy
http://tncweeds.ucdavis.edu/photos/cynof01.jpg

Figure 4 courtesy of Institute for Systematic Botany
http://www.plantatlas.usf.edu/images.asp?plantID=1449#

"A Group of Cows" by Zhang Guan is from the website Chinese Paintings by Zhang Guan and is used with permission..

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