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


mild-to-moderate-protein diet might have improved the prognosis since my internship year in California in the mid-1970s when the outcome of treatment was generally poor. One of the more favorable out- comes I know of was from cases that Dr. Karen Unger managed in 2013. Although some horses died from PA toxicity, four horses with persistent and marked increases in AST, GGT, and bile acids (up to 108 mol/L) for 3–4 weeks survived and ap- peared clinically normal 3 years later. Serum bile acid concentrations greater than 50 umol/L gener- ally indicate a poor prognosis for long-term life.118 When a case of PA toxicity is confirmed or suspected on a farm, measurement of GGT in other horses on the farm is a sensitive, although not 100% sensitive, test to detect subclinical cases.16 GGT testing of horses potentially exposed to plant or environmental hepatotoxins, such as alsike clover, Panicum spp. should be routinely recommended.


Alsike Clover Poisoning


Alsike clover (Trifolium hybridum) poisoning is one of the most common pasture-associated hepatotoxic- ities seen in some areas of the northeastern United States and in some provinces of Canada (Ontario, Que


´bec, Alberta); it is also seen in Europe.128–130


Much of the original description of the disease came from outbreaks of hepatic failure in horses in On- tario where the disease was called “big liver dis- ease.”128 The disease most often occurs when horses graze pastures or are fed hay containing large amounts of alsike clover. An increased inci- dence of poisoning is reported during wet seasons when the clover grows luxuriantly on heavy clay soil. Two presentations of the disease have been described.128 The first is dermatitis-stomatitis, previously referred to as trifoliosis or clover disease. The second presentation of the disease, believed to be associated with more long-term consumption of the plant, is hepatic dysfunction, characterized by icterus, colic, and nervous system signs. It remains unproven whether photosensitivity without signs of liver failure is really a primary photosensitivity or whether it is secondary to biliary disease that per- mits phylloerythrin accumulation without other signs of liver failure. We have found marked ele- vations in GGT in exposed, asymptomatic, horses grazing fields of alsike clover that might support the latter suggestion. The liver of horses that die from the disease may be noticeably enlarged with rounded edges, sometimes weighing 5% of body weight or 25 kg in a 500-kg horse. Other cases may have normal or even smaller-than-normal livers if there is extensive fibrosis. Characteristically there is little inflammation in the liver and the paren- chyma is mostly intact except where it collapses by expanding fibrosis. Bile duct proliferation and fi- brosis, most severe in the portal areas, is found in all cases but these two findings are common to several other toxins including PA toxicity (however, PA tox- icity and most other hepatotoxins will cause more


severe parenchymal disease). Both biliary and hepatocellular enzymes are increased in horses with alsike clover–associated liver failure, as are serum bile acids and direct and indirect bilirubin. Despite the consistent and often severe portal bile duct pro- liferation and fibrosis there is little evidence of bile stasis, which helps explain why this, a predominant biliary disease, may not have the typical high per- cent of conjugated bilirubin in the serum that is expected with an obstructive biliary diseases. In- terestingly, we have found that horses exposed to the same alsike clover fields as horses exhibiting liver failure, have moderate-to-marked elevations in GGT with normal SDH, suggesting that the disease begins as a predominant biliary toxicity. The toxic principle in alsike clover has yet to be identified. It is not known whether the agent is a toxic metabolite from the plant itself or a mycotoxin produced by a fungus (Cymodothea trifolii) living on the plant.131 We have noticed a pattern where no cases will occur for many years followed by several cases occurring in other years, suggesting that the toxicity may be related to a mycotoxin that may grow best on the alsike clover under certain climatic conditions. Treatment would be the same as for PA toxicity except the antifibrotic drug colchicine (0.03 mg/kg PO once daily) could be used and might have some additional benefit in inhibiting fibrosis.


Panicum Toxicity


Three different Panicum sp. (panic grasses) have been found to cause outbreaks of liver failure in horses. The first outbreak132 involved Panicum coloratum (kleingrass), a species introduced to Texas in 1952 from Kimberly, Union of South Africa, and subsequently widely planted in the state. The second involved Panicum virgatum (switchgrass), and occurred in eastern Nebraska.133 In the au- tumn of 2004, Dr. Melinda Freckleton discovered 14 horses in a single stable in Virginia that were clin- ically affected with liver disease, some with failure resulting in death, shortly after being fed a new shipment of hay.134 We had, anecdotally, on two other prior occurrences (1 and 3 years earlier), re- ceived information on outbreaks of hepatotoxicosis in horses in the mid-Atlantic area and had become suspicious of fall panicum toxicity based upon lim- ited testing of the hay from those prior outbreaks but were unable to acquire a sufficient volume of the presumed toxic hay for a feeding trial. Thanks to Dr. Freckleton’s efforts, we were finally able to ob- tain hay from the third outbreak, conducted a feed- ing trial, and confirmed the hepatotoxicity of Panicum dichotomiflorum (fall Panicum). The on- set of severe hepatotoxicosis after fall Panicum hay exposure was rapid (1–2 weeks) in both the natu- rally occurring cases and in the experimental horses. Horses with Panicum coloratum hepato- toxicosis had either prolonged grazing on the klein- grass pasture or were fed hay for 150 days before showing signs of liver failure.132 Hepatic pathology


AAEP PROCEEDINGS  Vol. 61  2015 81


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