Courtesy of Dr. Cecil Brownie.
Courtesy of Dr. Cecil Brownie.
Pyrrolizidine alkaloidosis is typically a chronic toxicosis that results in hepatic failure. It is caused by many toxic plants, most commonly of the genera Senecio, Crotalaria, Heliotropium, Amsinckia, Echium, Cynoglossum, and Trichodesma. These plants grow mainly in temperate climates; however, some (eg, Crotalaria spp) require tropical or subtropical climates. The plants most often implicated include ragwort (S jacobea), groundsel (S riddellii, S longilobus), rattleweed (Crotalaria retusa), and seeds of yellow tarweed (A intermedia).
Cattle, horses, farmed deer, and pigs are most susceptible; sheep and goats require ~20 times more plant material than cattle before a fatal poisoning develops. Individual susceptibility varies greatly within species; young growing animals are most susceptible.
Etiology and Pathogenesis of Pyrrolizidine Alkaloidosis in Animals
More than 350 toxic factors (alkaloids with a pyrrolizidine base) have been found in plants, with some plants containing several pyrrolizidine alkaloid toxins. Senecio jacobaea contains jacobine; other pyrrolizidine alkaloids frequently incriminated in toxicities include retrorsine, seneciphylline, and monocrotaline.
These plants, which under normal conditions are avoided by grazing animals, may be eaten during drought conditions. Some animals may eat these plants preferentially as roughage when they are available on extremely lush pasture. Animals are also poisoned by eating the plant material in hay, silage, or pellets. At least some of the toxic compounds are known to survive drying. Seeds from Crotalaria, Amsinckia, and Heliotropium spp, which have been harvested with grain, have caused disease in horses, cattle, pigs, and poultry.
Toxicokinetics
Absorption. Pyrrolizidine alkaloids undergo rapid absorption via the GI tract.
Distribution. Pyrrolizidine alkaloids undergo distribution to liver via the portal vein. They are found in fetal tissues, milk, and eggs from affected animals.
Metabolism. Pyrrolizidine alkaloids undergo hepatic metabolism.
Elimination. Pyrrolizidine alkaloids undergo rapid urinary excretion.
Mechanism of action. The toxic alkaloids are metabolized in the liver to highly reactive pyrroles, which produce cytotoxic effects on target sites, most commonly the nuclei of hepatocytes. Other target sites may include the epithelial and vascular tissues of the kidneys and lungs. The pyrroles crosslink DNA strands and also unite DNA with nucleoproteins such as actin. These molecular alterations are presumed to create the antimitotic and megalocytic effects characteristic of pyrrolizidine alkaloidosis. There is good evidence that a few of the adducts formed promote development of hepatic neoplasms.
Clinical Findings of Pyrrolizidine Alkaloidosis in Animals
Hepatic disease with associated clinical signs is the most common manifestation of pyrrolizidine alkaloidosis in domestic animal species. Acute intoxication is characterized by sudden death from hemorrhagic hepatic necrosis and visceral hemorrhages. This is a rare event because the poor palatability of these plants makes rapid ingestion of large quantities of the toxins uncommon. More chronic exposure is typical, and the liver reflects the cumulative and progressive effects of repeated ingestion of small doses of toxin. Consequently, clinical signs may not occur for several weeks or months after initial exposure. Consumption of the offending plant may even have ceased months earlier. The ongoing hepatic damage in these instances is suspected to be due to the recycling of toxic pyrroles as they are released from one dying cell and taken up by another. Clinical progression may also be altered by concurrent hepatic disease; a hemolytic crisis may be precipitated in sheep with excessive hepatic copper stores.
In horses and cattle, clinical signs include loss of condition, anorexia, dullness, and constipation or diarrhea. Tenesmus and passing of bloodstained feces may be followed by rectal prolapse, especially in cattle. Ascites and icterus may be present, and cattle and sheep sometimes show intermittent photosensitization. Some animals become progressively weaker and reluctant to move. Others, especially horses, exhibit signs of hepatic encephalopathy such as head-pressing, yawning, aimless wandering, or even frenzied and aggressive behavior. Pica may occur. Death may occur suddenly or after prolonged recumbency with hepatic coma and high concentrations of ammonia in the blood.
Less common clinical signs that have been described with pyrrolizidine toxicoses include inspiratory dyspnea in ponies due to laryngeal and pharyngeal paralysis, dyspnea due to interstitial pneumonia in horses, and renal disease in pigs.
Lesions
In acute cases, the liver may be enlarged, hemorrhagic, and icteric. In chronic cases, it is atrophied, fibrous, finely nodular, and usually pale with a glistening surface due to fibrous thickening of the capsule. Other livers are markedly icteric. The gallbladder is often edematous and grossly distended with thick, mucoid bile. Edema of the abomasum and segments of the bowel, mesentery, and associated lymph nodes is common, and there may be ascites. In some cases, numerous small hemorrhages are present in the abdominal serous membranes.
Characteristic histopathologic changes often occur in the liver; however, the wide array of potentially damaging pyrrolizidine alkaloids means such changes represent an unreliable diagnostic feature. Irreversible enlargement of individual hepatocytes (megalocytosis) may occur; it is conspicuous in horses and sheep but less pronounced in cattle. In cattle, marked perivenous fibrosis of sublobular veins is usually present; however, this is not a consistent finding in horses and sheep. In all species, increases in connective tissue, both within and around the lobules, can be marked. Single cell necrosis (piecemeal necrosis) of hepatocytes may be present. Bile duct hyperplasia is variable, although it may be the most striking microscopic change that occurs in some livers. Pulmonary changes that occur in horses exposed to some Crotalaria spp may include hyperplasia of bronchioloalveolar epithelium, congestion, septal fibrosis, and emphysema. Renal tubular lining cells and glomerular epithelial cells also may be individually enlarged in pigs.
Diagnosis of Pyrrolizidine Alkaloidosis in Animals
Presumptive diagnosis is made based on clinical signs, compatible changes in biochemical parameters, and a history of exposure. Chemical analysis of whole blood for toxic metabolites can confirm recent exposure; however, analysis is dependent on the half-life of erythrocytes to which these pyrroles are bound. This has typically been performed by use of high-performance liquid chromatography (HPLC) and mass spectrometry and thus restricted to toxicology laboratories. However, concerns regarding the potential for pyrrolizidine alkaloids in foodstuffs such as honey, grains, and milk have promoted the development of immunoassays to detect pyrrole-protein adducts. These assays will likely become commercially available for the analysis of blood samples, although only the most common pyrrolizidine alkaloids will be targeted.
When hepatic cirrhosis is extensive, hypoalbuminemia and hyperglobulinemia develop. Serum fibrinogen concentration, bilirubin concentration, gamma-glutamyltransferase (GGT) activity, and glutamate dehydrogenase (GDH) activity may be increased; however, this disease is insidious and serum biochemical changes can be surprisingly mild. Hepatic biopsy is often useful, especially if megalocytic changes occur. Other hepatotoxins (eg, copper or aflatoxin) as well as infections such as chronic fascioliasis must be considered before making the diagnosis.
At postmortem examination, the diagnosis can often be made based on gross findings plus characteristic histopathologic changes in hepatic, pulmonary, or renal tissues. Hepatic tissue assays for pyrrolic metabolites and pyrrole-DNA adducts on unfixed biopsy samples or hepatic tissue collected at postmortem examination can provide a definitive confirmation of toxin exposure, in some instances even when the pyrrolizidine alkaloid ingestion occurred months earlier.
Treatment and Control of Pyrrolizidine Alkaloidosis in Animals
Further intake of toxic plant material must be prevented. Animals showing clinical signs rarely recover, and lesions present in subclinically affected animals may progress and result in further losses over several months. Because high protein intake may precipitate clinical signs, rations high in carbohydrates are indicated. Supportive treatment for dehydration and photosensitization may be needed.
Prevention of further outbreaks by decreasing exposure should be stressed.
Sheep are commonly used for grazing control of these plants; however, this practice carries risks unless the sheep used are destined for early slaughter. Biological control of plants with predator moths, flea beetles, and seed flies has met with variable success. Senecio and related toxic species in pastures have been controlled satisfactorily by annual herbicide applications, preferably in spring before hay or silage conservation.
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