Hepatotoxins manifest their effects by one or more mechanisms: centrilobular necrosis, midzonal necrosis, periportal necrosis, cholestasis, biliary hyperplasia, fatty or hydropic change near necrotic zones, or venous occlusion. Fatal hepatic insufficiency may result if the initial injury is acute and severe. More commonly, the hepatic damage from toxins is subacute or chronic. In chronic processes, the longterm result may be cirrhosis. Many hepatotoxins, especially those in plants, exert toxic effects on multiple organs, particularly the kidneys, lungs, and GI tract.
Definitive diagnosis of hepatotoxicosis may be difficult because the plant exposure may be intermittent and inapparent at the time of presentation. Careful history, inspection of the environment, plasma laboratory evaluation, liver ultrasonography and biopsy, and/or necropsy may be needed to document the offending agent. With acute plant toxicities, evidence of hepatotoxic plants may be present in the gastric contents or rumen, or may not be observed at all clinically.
Specific antidotes for hepatotoxins are limited. Removal of the animals from the source is essential to prevent additional exposure. Administration of an adsorbent (eg, activated charcoal, mineral oil) or laxatives (eg, mineral oil, magnesium sulfate) or rumenotomy may decrease the absorption of toxic elements in acute poisonings. These techniques may not be helpful in chronic intoxications (eg, pyrrolizidine alkaloid toxicosis), in which the toxic agent has been ingested over weeks to months before clinical signs of toxicosis are evident. Supportive care includes correction of electrolyte, metabolic, and glucose disorders via fluid treatment and dietary management. Hepatic encephalopathy must be controlled. Sunlight should be avoided if photosensitization is present. Topical or systemic antimicrobials may be used to prevent or treat secondary pyoderma. The prognosis is guarded and depends on the particular hepatotoxin.
Chemical and Drug-related Causes of Toxic Hepatopathy
Iron Toxicosis as a Cause of Toxic Hepatopathy in Large Animals
Newborn foals (< 3 days old) are especially sensitive to iron overload because of their high serum iron concentrations, increased ability to absorb iron, and oversaturation of transferrin at birth. In adult horses, injectable iron increases body iron concentration more substantially than do most oral supplements; liver biopsy will document increased iron stores, but these are rarely, if ever, associated with clinical signs of liver disease. Iron toxicosis has been reported in calves and young bulls injected with a ferric ammonium citrate alone or in combination with ferrous gluconate.
Foals given iron at birth, especially before receiving colostrum, or given multiple blood transfusions, may develop acute iron toxicosis with clinical signs of hepatic encephalopathy in 2–5 days and a fatal outcome. Plasma bilirubin and blood ammonia concentrations are high, and prothrombin time is prolonged. Alterations in plasma hepatic enzymes vary. In adult horses, acute toxicosis, although less common, may cause enteric irritation and cardiovascular collapse with sudden death. Clinical signs of more chronic hepatic failure, including weight loss, icterus, and depression, may occur with repeated oral administration of iron. Possible sources of excess iron include inappropriate supplementation, forages high in iron, injectable iron, and leaching of iron into water or feed. Calves with iron toxicosis show trembling, vocalizing, bruxism, colic, and seizures.
Hepatic lesions vary. Most livers are friable and are swollen or shrunken. The liver is pale tan or mottled red-brown in color. Hemorrhages may be present in the stomach, intestines, and bladder.
Diagnosis is based on history of iron supplementation, clinical signs, and necropsy lesions. Serum and liver iron concentrations may be normal or increased. Normal iron concentrations in horses are 66–204 mcg/dL in serum and 100–300 ppm in liver tissue. Because serum iron concentration correlates poorly with total iron stores, serum ferritin concentrations are better used as an estimate of total iron.
Treatment is generally supportive, with administration of fluids and nutritional supplementation. Chelation treatment with deferoxamine is unlikely to be successful in acute iron toxicosis. The prognosis is poor.
Copper Toxicosis as a Cause of Toxic Hepatopathy in Large Animals
Acute copper toxicosis with severe hepatic necrosis and death may occur in cattle 1–4 days after injection of copper salt. Copper toxicosis occurs in sheep and young calves after excess dietary intake of copper and in young goat kids fed calf milk replacer containing copper. The primary conditions associated with copper toxicosis are hemolytic anemia and liver damage. In camelids, ingestion of inappropriate dietary copper concentrations can result in acute death with few antemortem clinical signs and no evidence of hemolytic crisis. (Also see Copper Poisoning Copper Poisoning .)
Miscellaneous Chemicals and Drugs Associated with Hepatotoxicosis in Large Animals
Exposure to carbon tetrachloride, chlorinated hydrocarbons, hexachloroethane, carbon disulfide, arsenic, monensin, pentachlorophenols, phenol, paraquat, halothane (goats, llamas), isoflurane, phenobarbital, tannic acid, copper disodium edetate, and high doses of ivermectin may cause centrilobular necrosis and hepatic failure. Phosphorus causes primarily periportal changes. Changes from active hepatitis to cirrhosis may occur after use of isoniazid, nitrofuran, halothane, aspirin, or dantrolene in large animals. Erythromycin, rifampin, anabolic steroids, phenothiazine tranquilizers, some diuretics, quinidine sulfate, and diazepam have been associated with cholestasis and icterus.
Blue-green Algae Toxicosis
Pyrrolizidine Alkaloid Toxicosis in Large Animals
Pyrrolizidine alkaloid-containing plants are common in certain geographic areas (eg, the northwestern region of the United States) and can be the most common cause of liver disease regionally. Common examples include Senecio (ragwort), Amsinckia (fiddleneck), and Crotalaria (rattlebox). Like many of the plants that lead to toxicoses, pyrrolizidine alkaloid plants usually are ignored by grazing large animals until conventional grasses become scarce in pastures—ie, late in the growing season or under drought conditions. Large animals foraging for food may then seek out other weedy plants, including this group. Toxins also survive the drying process and remain active in baled hay. Chronic ingestion results in hepatic megalocytosis, biliary hyperplasia, and periportal fibrosis. Horses acutely affected by pyrrolizidine alkaloid toxicosis may present with diarrhea, and occasionally with dyspnea. Chronic signs are of liver failure. Biopsy or necropsy is diagnostic. (See Pyrrolizidine Alkaloidosis Mitral Valve Dysplasia in Animals Mitral valve dysplasia is a congenital malformation of the mitral valve leaflets or any other component(s) of the mitral valve complex. This condition occurs in dogs and is a common defect of... read more .)
Panicum Grass Toxicosis in Large Animals
Three species of Panicum grasses have been linked to liver failure in horses and/or ruminants: kleingrass (Panicum coloratum), switchgrass (P virgatum), and P dichotomiflorum (fall Panicum). Panicum toxicosis is a problem in horses, sheep, and goats in the southwestern US (particularly Texas, where it was introduced from South Africa in the 1950s) from late spring to early fall, whereas fall Panicum cases occur after new hay is fed to horses in the late fall and early winter. Young, growing plants are the most hazardous because of their high saponin content, believed to be the toxic principle, possibly in conjunction with other known hepatotoxins, such as mycotoxins.
Clinical signs of Panicum grass toxicosis include icterus, photosensitivity, intermittent colic and fever, weight loss, and hepatic encephalopathy. Photosensitivity may develop around the coronary band and cause lameness. Lesions include hepatic and portal fibrosis and biliary hyperplasia. Bilirubin, gamma-glutamyl transferase (GGT), and blood ammonia concentrations are increased. Sheep with photosensitivity due to Panicum ingestion commonly have a crystalline material in the bile ducts, canaliculi, and macrophages.
A presumptive diagnosis of plant-induced hepatopathy is based on a history of exposure to plants and multiple affected animals on a given farm or in a defined area. Affected animals should be removed from the Panicum source, fed good-quality hay, and protected from sunlight. Local treatment of photodermatitis with antimicrobial or softening creams may be needed in severe cases.
Alsike Clover Toxicosis in Large Animals
Alsike clover (Trifolium hybridum) causes two syndromes in horses: photosensitivity (trifoliosis) and hepatopathy (“big liver disease,” a term coined in Ontario). It is a common pasture- and hay-associated hepatotoxicosis in the northeastern US; in Ontario, Quebec, and Alberta in Canada; and in Europe. Alsike clover grows well on heavy clay soil, and an increased incidence of toxicosis is reported during wet seasons. The disease occurs mostly when the blossom of the plant is eaten and the predominant forage being fed is alsike clover. The toxic principle is an unidentified phototoxin. Photosensitivity has been reported in horses, sheep, cattle, and pigs.
Alsike clover photosensitivity is a dermatitis/stomatitis characterized by reddened skin after exposure to sun, followed by dry necrosis of the skin or edema and serous discharge. The muzzle, tongue, and coronary bands are also frequently affected; lameness is not unexpected. If the stomatitis is severe, anorexia and weight loss develop.
Alsike clover hepatopathy may be fatal, with progressive loss of condition and clinical signs of hepatic failure and hepatic encephalopathy. Colic, diarrhea, and other clinical signs of GI disturbances have been noted. Affected horses may manifest hepatic encephalopathy by being markedly depressed or excited. Compared to the more acute photosensitivity, hepatic encephalopathy is thought to occur after a longer period of ingestion. Plasma chemistry alterations include increased GGT and AST activities, as well as hyperbilirubinemia, with direct bilirubin frequently making up ≥ 25% of the total.
A presumptive diagnosis of plant-induced hepatopathy is based on history of exposure to plants and multiple affected animals on a given farm or in a defined affected area. Horses in which photosensitivity is the primary finding may recover quickly after being removed to alsike-free pasture. Those with severe stomatitis or dermatitis require supportive care and local treatment of the stomatitis until they heal. Horses with clinical signs of hepatic encephalopathy may be difficult to save.
Mycotoxic Lupinosis in Large Animals
Mycotoxic lupinosis is a worldwide disease of sheep and cattle that consume lupines containing a hepatic mycotoxin produced by the fungus Phomopsis leptostromiformis. See Mycotoxic Lupinosis Mycotoxic Lupinosis in Animals Lupinosis is a liver disease or hepatotoxicosis caused by ingestion of lupine plants infected with Diaporthe toxica (previously identified as Phomopsis leptostromiformis). Lupinosis... read more in the chapter "Mycotoxicoses" for clinical findings, diagnosis, and control.
Xanthium (Cocklebur) Toxicosis in Large Animals
Cockleburs, including Xanthium strumarium, may be found throughout the world. Poisoning is most frequent after ingestion of the more palatable two-leaf seedling stage or ground seeds. The burs are highly toxic but rarely eaten, because of their spiny outer coating. The mature plant is less toxic and generally unpalatable. The toxic principle is carboxyatractyloside, which directly affects the liver.
Within hours of ingesting cockleburs, swine, cattle, and horses develop clinical signs of depression, nausea, weakness, ataxia, and subnormal temperature. Spasms of the cervical muscles, vomiting, dyspnea, and seizures may occur. Death may occur within hours of the onset of clinical signs. Animals that survive initial acute poisoning frequently develop chronic liver disease.
Animals suffering from Xanthium toxicosis require intensive supportive care. Mineral oil or activated charcoal may be given orally to adsorb toxins and decrease intestinal absorption of the toxic principle. Administration of physostigmine (0.06–0.08 mg/kg, IV, slowly) or neostigmine (0.022–0.025 mg/kg, IV) may also be helpful to increase GI motility and hasten elimination of any toxic plant matter remaining in the colon.
Miscellaneous Plant Hepatotoxicoses in Large Animals
Hepatotoxins are found in numerous plants, including Nolina texana, Agave lechuguilla, Phyllanthus abnormis, and Lantana camara. (See Range Plants of Temperate North America Range Plants of Temperate North America Poisonous plants are among the important causes of economic loss to the livestock industry and should be considered when evaluating illness and decreased productivity ( see Table: Poisonous... read more .)