Re: Enlargement of the spleen following pyrrolizidine alkaloid ingestion

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Enlargement of the spleen following pyrrolizidine alkaloid ingestion has been noted, for more info find attached file

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Mohammad Bashaar

From: Fatai FEHINTOLA <fentolamine@...>Subject: Re: Pyrrolizidine Alkaloid Toxicity & mechanism of actionnetrum Date: Sunday, July 6, 2008, 11:15 PM

Thanks very much, Bashaar for the well written piece.fatai fehintola, Ibadan, Nigeria>> Pyrrolizidine Alkaloid Toxicity> > 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.> 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 hepatoencephalopath y, 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> Treatment> > > > > > Note: Treatment of animals should only be performed by a licensed veterinarian. Veterinarians should consult the current literature and current pharmacological formularies before initiating any treatment protocol.> 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: SM, Bayly WM (eds): Equine Internal Medicine. Philadelphia, W.B. Saunders Co., 1998, pp. 1024-1025.> 2. Talcott P: Pyrrolizidine Alkaloid Poisoning. In: 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, 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: BP (ed): Large Animal Internal Medicine, 3rd Edition, St. Louis, Mosby, Inc., 2002, pp. 1616-1618.> 7. TC, Hunt RD, King NW: Veterinary Pathology, 6th Edition. Baltimore, & Wilkins, 1997, p. 712-718.> > Source: http://www.vet. uga.edu/VPP/ clerk/elliott/ index.php> > Best> > Bashaar> > > >