FRANK J. MILNE STATE-OF-THE-ART LECTURE


with plant ingestion. There is little doubt that pyr- rolizidine alkaloid (PA)–containing plants are the most common plants, worldwide, causing toxic liver failure in horses. There is a long list of PA- containing plants, but Amsinckia intermedia (tar- weed), Cynoglossum officinale (hound’s tongue), Heliotropium europaeum (heliotrope), Senecio jaco- baea (tansy ragwort), Senecio vulgaris (common groundsel), Senecio riddellii (sand groundsel), Sene- cio flaccidus (threadleaf groundsel), and Echium plantagineum (Patterson’s curse) are some the more common species reported as causing hepatotoxicity in horses in North America.114 Recent reported outbreaks of Crotalaria species hepatotoxicity in horses have mostly been from Brazil and Austra- lia.115 The incidence of Crotolaria toxicosis in the southeastern, central, and mid-Atlantic states, ar- eas where the plant is found, seems low in compar- ison with toxicity from other PA-containing plants found in the western United States and parts of Canada. All parts of PA-containing plants, fresh or dried, are toxic but toxin concentrations may vary during the course of the growing season and for the perennial Senecio jacobaea and many other PA- containing plants, toxin concentration is highest during budding and flowering; the onset of flowering heralds the period of greatest risk for toxicity for those plants.116 Threadleaf groundsel is an ever- green and maintains foliage throughout the year. For Crotolaria, the seeds are most toxic.116 Most PA-containing plants have a bitter taste and, there- fore, variable palatability. Hepatotoxicity from plant ingestion is usually associated with chronic feeding of contaminated hay but with drought con- ditions and sparse grasses these same toxic plants will be consumed in the pasture. The liver is important in both toxic pyrroles for-


mation and in detoxification of PAs. The parent PAs in the plants are relatively unreactive but when metabolized by the horse can produce highly toxic pyrroles.114 Pyrrolizidine alkaloids are absorbed and metabolized in the hepatocytes, especially in the zone 3 region with more acute intoxication, where hepatocytes with the highest level of drug- metabolizing enzymes are located.7 PAs are dehy- drogenated to yield pyrroles which cross-link DNA and thus impair hepatic cell division and protein synthesis hence causing megalocytosis.7 Another important toxic metabolite is trans-4-hydroxy-2- hexenal, a reactive aldehyde that causes lipid peroxidation.117 Other than megalocytosis, charac- teristic pathologic and histopathologic lesions with chronic ingestion include karyomegaly, progressive fibrosis, variable nodular regeneration, bile duct proliferation, and veno-occlusion. With chronic disease, the liver may eventually become small and fibrotic.115 Horses that ingest large amounts of PA plants over a few days, usually in contaminated alfalfa hay, may die from subacute liver disease and hepatic lesions in these cases might have diffuse centrilobular necrosis118 and, unless megalocytes


80 2015  Vol. 61  AAEP PROCEEDINGS


are observed, lesions could look similar to Theiler’s disease pathology. Megalocytes may not be seen in the liver on microscopic exam until 30 days or more after exposure to the PA.119 The effect of PA toxins on the liver is cumulative


and it is estimated that horses must ingest approx- imately 2% or more of their body weight to develop hepatic failure.119 In many instances, by the time clinical signs develop weeks or months later, con- taminated hay is often long gone from the property. If confirmation of the diagnosis cannot be made by investigation of the feeds or from histopathology of the liver, chromatography/mass spectrometry test- ing of frozen liver could be performed to detect py- rollic metabolites.119 Although the disease is chronic, acute onset of neurologic signs (HE) is a common presentation and onset may be precipitated by a number of stressors. Weight loss, diminished appetite, jaundice, and photosensitization can be early clinical findings, followed by acute onset of neurologic signs due to hepatic encephalopathy. Weight loss and decline in appetite often go unde- tected in many cases. Laryngeal paralysis and gas- tric impaction also occur in a small percentage of affected horses.120–122 Horses with PA-induced hepatic failure have a guarded-to-poor prognosis due to the extensive fibro- sis that occurs in most cases prior to the develop- ment of any clinical signs. Treatments for hepatic encephalopathy (page 92), antioxidant therapy with vitamin E, S-adenosyl methionine (SAMe) and milk thistle extract, anti-inflammatory/anti-fibrosis treatment with pentoxifylline, supportive care with fluid therapy, and nutritional management provid- ing a high-energy and adequate-protein diet (page 95) are, to my knowledge, the most frequent treat- ments provided to horses with PA toxicity and liver failure. There is minimal proof of efficacy for those treatments in affected horses but most of the treat- ments seem reasonable based upon pathophysiology of the disease. The addition of dietary supplements of cysteine, butylated hydroxyanisole, 200 micro-


grams of vitamin B12/kg of feed, and 5 mg of folic acid/kg of feed did not alter toxicity in ponies fed tansy ragwort.123 A recent study in rats found that administration of SAMe and vitamin E adminis- tered before and after monocrotoline pyrrole expo- sure modulated the hepatic oxidative stresses induced by that toxic PA pyrrole.124 Unfortu- nately, pharmacokinetic and efficacy studies on SAMe are not available in horses and bioavailablity of silymarin in horses may be less than 1%.125 When the above treatments are administered rela- tively early in the course of the disease, and with a dose of luck, a moderate percentage of clinically affected horses (including even a few with signs of HE), will have transient resolution of clinical signs and survive for several months or have complete recovery.126,127 I suspect that earlier detection of disease, increased antioxidant therapies, and better nutritional management including provision of


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