- Chemical and Drug-related Causes of Toxic Hepatopathy
- Blue-green Algae Intoxication
- Hepatotoxic Plants
Hepatotoxins in Large Animals
Hepatotoxins manifest their toxicity by one or more mechanisms: periacinal (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 may be difficult. Careful history, inspection of the environment, laboratory evaluations, liver biopsy, or necropsy may be needed to determine the offending agent. With acute plant toxicities, evidence of hepatotoxic plants may be seen in the stomach contents or rumen.
Specific antidotes for hepatotoxins are limited. Removal of the animals from the source is essential to decrease additional exposure. Administration of an absorbent (eg, activated charcoal, mineral oil) or laxatives (eg, mineral oil, magnesium sulfate) or rumenotomy may decrease absorption of toxic elements in acute poisonings. These may not be helpful in chronic intoxications (ie, pyrrolizidine alkaloid toxicity), in which the toxic agent has been ingested over weeks to months before signs of toxicosis are evident. Supportive care includes correction of electrolyte, metabolic, and glucose disorders via fluid therapy and dietary management. Hepatic encephalopathy must be controlled. Sunlight should be avoided if photosensitization is present. Antimicrobials may be considered to prevent secondary pyoderma. Prognosis is guarded and depends on the particular hepatotoxin.
For coal-tar poisoning, see Coal-Tar Products Poisoning.
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 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, may develop acute toxicity with clinical signs of hepatic encephalopathy in 2–5 days and a fatal outcome. Serum bilirubin and blood ammonia concentrations are high, and prothrombin time is prolonged. Alterations in serum hepatic enzymes are variable. In adult horses, acute toxicosis, although less common, may cause enteric irritation and cardiovascular collapse with sudden death. Signs of more chronic hepatic failure, including weight loss, icterus, and depression, may be seen 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 have trembling, vocalizing, bruxism, colic, and convulsions.
Hepatic lesions are variable. 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 levels are better used as an estimate of total iron.
Treatment is generally supportive with fluids and nutritional supplementation. Chelation therapy with deferoxamine is unlikely to be successful in either acute iron toxicosis or chronic hemochromatosis. Repeated phlebotomy has been attempted for hemochromatosis. The prognosis is poor.
Acute copper toxicosis with severe hepatic necrosis and death may be seen in cattle 1–4 days after injection of copper salt. Copper toxicosis is seen 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 iron concentrations resulted in acute death with few premortem signs and no evidence of hemolytic crisis. (Also see Copper Poisoning.)
Exposure to carbon tetrachloride, chlorinated hydrocarbons, hexachlorethane, 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. Active hepatitis to cirrhosis may be seen 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.
Aflatoxins and fumonisins can cause hepatic injury and failure in ruminants, swine, and horses. Fusarium toxicosis is the most common mycotoxicosis causing liver failure in horses, whereas aflatoxins only sporadically cause hepatic failure in this species. (See Mycotoxicoses.)
Acute hepatotoxicosis may be seen after ingestion of hepatotoxic cyanobacteria. (See Algal Poisoning.)
Kleingrass (Panicum coloratum) can produce toxicosis in horses and ruminants. Kleingrass toxicosis is a problem in the southwestern USA from late spring to early fall. Young growing plants are most hazardous because of their high sapogenin content, believed to be the toxic principle. A similar syndrome is seen in horses in the eastern USA grazing pasture or fed hay containing high concentrations of fall Panicum.
Clinical signs 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, γ-glutamyl transpeptidase or transferase (GGT), and blood ammonia concentrations are increased. Sheep with photosensitivity caused by kleingrass ingestion commonly have a crystalline material in the bile ducts, canaliculi, and macrophages.
Presumptive diagnosis of plant-induced hepatopathy is based on history of exposure to plants and multiple affected animals on a farm or in an area. Affected animals should be removed from the kleingrass source, fed good-quality hay, and protected from sunlight. Local treatment of the photodermatitis with antimicrobial or softening creams may be needed in severe cases.
Alsike clover (Trifolium hybridum) causes two syndromes in horses in the USA and Canada: photosensitivity (trifobiasis) and Alsike clover poisoning (“big liver disease”). Alsike clover grows well on heavy clay soil, and an increased incidence of toxicosis is reported during wet seasons. The disease is seen mostly when the blossom of the plant is eaten and the predominant forage being fed is the Alsike clover. The toxic principle is an unidentified phototoxin. Photosensitivity has been reported in horses, sheep, cattle, and pigs.
Alsike photosensitivity is also known as “dew poisoning” because it is seen mostly when pastures of clover are wet and horses’ skins are moist. It is characterized by reddened skin after exposure to sun, followed by dry necrosis of the skin or edema and serous discharge. The muzzle, tongue, and feet are frequently affected. If the stomatitis is severe, anorexia and weight loss develop.
Alsike clover poisoning may be fatal, with progressive loss of condition and signs of hepatic failure and neurologic disturbances. Colic, diarrhea, and other signs of GI disturbances have been noted. Affected horses may be markedly depressed or excited. Prolonged exposure is usually required before signs of hepatic insufficiency are evident. Serum chemistry alterations include increased GGT and AST activities and hyperbilirubinemia, with direct bilirubin frequently being ≥25% of the total.
Presumptive diagnosis of plant-induced hepatopathy is based on history of exposure to plants and multiple animals on a farm or in an 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.
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 for clinical findings, diagnosis, and control.
Cockleburs, including Xanthium strumarium, may be found throughout the world. Poisoning is most frequent after ingestion of the palatable two-leaf seedling stage or ground seeds. The burs are highly toxic but rarely eaten. The mature plant is less toxic and generally unpalatable. The toxic principle is carboxyatractyloside, which directly affects the liver.
Within hours of toxin ingestion, swine, cattle, and horses develop signs of depression, nausea, weakness, ataxia, and subnormal temperature. Spasms of the cervical muscles, vomiting, dyspnea, and convulsions may occur. Death may occur within hours of the onset of signs. Animals that survive initial acute poisoning frequently develop chronic liver disease.
Affected animals require intensive supportive care. Mineral oil or activated charcoal may be given orally to delay absorption of the toxic principle. Physostigmine (5–30 mg, IM) has also been recommended.