Acute and chronic copper poisoning (toxicosis) can affect animals in most parts of the world. Sheep are most frequently affected, although other species are also susceptible. In various breeds of dogs, notably Bedlington Terriers, an inherited sensitivity to copper toxicosis similar to Wilson disease in humans has been identified. Chronic copper poisoning has been reported in other breeds of dogs, including Labrador Retrievers, West Highland White Terriers, Skye Terriers, Keeshonds, American Cocker Spaniels, and Doberman Pinschers. Acute signs of poisoning are usually seen after accidental administration of excessive amounts of soluble copper salts, which may be present in orally administered liquid anthelmintics, mineral supplement mixes, or improperly formulated feed rations.
Many factors that affect the metabolism of copper metabolism influence the likelihood of an animal developing chronic copper toxicosis via effects on absorption or retention of copper. Decreased concentrations of molybdenum or sulfate in the diet are important examples. Primary chronic copper toxicosis occurs most commonly in sheep when excessive amounts of copper are ingested over a prolonged period. The disease remains subclinical until copper that accumulates in the liver is released in massive amounts into the bloodstream. Increased liver enzyme concentrations may provide an early warning of the pending crisis. Serum copper concentrations increase acutely, causing lipid peroxidation and intravascular hemolysis. This hemolytic crisis may be precipitated by numerous factors, including transportation, handling, weather conditions, pregnancy, lactation, strenuous exercise, or a deteriorating nutrition. In sheep, dog or coyote attacks have been associated with sudden outbreaks of chronic copper poisoning.
Ingestion of certain plants such as subterranean clover (Trifolium subterraneum), cause a mineral imbalance and excessive copper retention, resulting in chronic copper toxicosis (phytogenous toxicosis). The ingestion of plants such as Heliotropium europaeum or Senecio spp for several months may cause hepatogenous chronic copper toxicosis. These plants (with normal concentrations of copper and low concentrations of molybdenum) contain hepatotoxic alkaloids, which causes retention of excessive copper in the liver.
In dogs with liver diseases such as chronic active hepatitis, the primary clinical signs may resemble those of chronic copper poisoning, which can be attributed to liver damage and subsequent retention of excessive copper; however, it is not clear whether chronic active hepatitis causes the accumulation of copper in the liver or is the result of such accumulation.
Acute poisoning may follow intakes of 20–100 mg/kg of copper in sheep and young calves and of 200–800 mg/kg in mature cattle. Chronic poisoning of sheep may occur with daily intakes of 3.5 mg/kg of copper when grazing pastures that contain 15–20 ppm (dry matter) of copper and low concentrations of molybdenum. Clinical signs of disease may occur in sheep or camelid species that ingest feed intended for cattle, which typically contain higher concentrations of copper than is appropriate for these species. Signs of toxicosis may also develop when water is supplied via copper plumbing. In general, cattle and goats are more resistant to copper poisoning than sheep. It is important that species-specific diets are fed to minimize the risk of chronic copper poisoning.
Breed differences related to the susceptibility for chronic copper poisoning have been reported in sheep and goats. Jersey dairy cattle are reportedly more susceptible than other breeds of cattle. Young calves or sheep injected with soluble forms of copper may develop acute clinical signs without evidence of a hemolytic crisis. Copper is used as a feed additive for pigs at 125–250 ppm; concentrations >250 ppm are potentially toxic—although as for sheep, other factors may be protective, eg, high concentrations of protein, zinc, or iron. Chronic copper toxicosis is more likely to occur with low dietary intake of molybdenum and sulfur. Decreased formation of copper molybdate or copper sulfide complexes in tissues impairs the excretion of copper in urine or feces.
Acute copper toxicosis causes severe gastroenteritis characterized by anorexia, signs of abdominal pain, diarrhea, dehydration, and shock. Hemolysis and hemoglobinuria may develop after 3 days if the animal survives the initial event. The sudden onset of clinical signs in chronic copper poisoning is associated with a hemolytic crisis. Clinical and laboratory signs in affected animals include depression, lethargy, weakness, recumbency, rumen stasis, anorexia, thirst, dyspnea, pale mucous membranes, hemoglobinuria, and jaundice. Several days or weeks before the hemolytic crisis, liver enzyme concentrations, including ALT and AST, are usually increased. During the hemolytic crisis, laboratory testing will often indicate methemoglobinemia, hemoglobinemia, and decreases in PCV and blood glutathione concentration. In camelid species such as alpacas or llamas, no hemolytic crisis is seen, although extensive liver necrosis remains a consistent manifestation.
Affected animals often die within 1–2 days. Herd morbidity is often <5%, although usually >75% of affected animals die. Deaths may continue for several months after the dietary problem has been rectified. Severe hepatic insufficiency is responsible for early deaths. Animals that survive the initial episode may die of subsequent renal failure. Photosensitization may occur in association with chronic copper poisoning, reflecting the hepatotoxicity common to both acute and chronic toxicosis. Cirrhosis of the liver also occurs in affected dogs.
Acute copper poisoning produces severe gastroenteritis, with erosions and ulcerations in the abomasum of ruminants. Icterus develops in animals that survive >24 hours. Tissues discolored by icterus and methemoglobin are characteristic of chronic poisoning. Swollen, gunmetal-colored kidneys, port-wine-colored urine, and an enlarged spleen with dark brown-black parenchyma are manifestations of the hemolytic crisis. The liver is enlarged and friable. Histologically, there is centrilobular hepatic and renal tubular necrosis.
Evidence of blue-green ingesta and increased fecal (8,000–10,000 ppm) and kidney (>15 ppm, wet wt) copper levels are considered notable in acute copper poisoning. In chronic poisoning, blood and liver copper concentrations are increased during the hemolytic period. Serum concentrations often increase to 5–20 mcg/mL, as compared with the normal reference range of ~1 mcg/mL. Liver concentrations >150 ppm (wet wt) are clinically relevant in sheep. The concentration of copper in the tissue must be determined to eliminate other causes of hemolytic disease, which may include zinc, chlorate, red maple, or onion poisoning. Other diagnoses to be ruled out may include bacillary hemoglobinuria, leptospirosis, babesiosis and postparturient hemoglobinuria. Liver damage associated with metal exposure, ingestion of pyrrolizidine alkaloids, mycotoxins, or various drugs such as acetaminophen should also be considered. Molybdenum tissue concentrations should also be determined.
Often, treatment for copper poisoning is not successful. Prognosis is poor in all species. Supportive treatment for shock and gastrointestinal signs may be useful in animals with acute toxicity. Penicillamine (50 mg/kg per day, PO, for 6 days) or calcium versenate may also be useful to enhance copper excretion if administered in the early stages of disease. Vitamin C (500 mg/day per sheep, SC) may potentially reduce oxidative damage to RBCs during hemolytic crisis. Ammonium tetrathiomolybdate (1.7 mg/kg, IV, every other day for 6 days) is effective for the treatment and prevention of copper poisoning. This treatment, which reduces copper absorption and enhances copper elimination, should be used conservatively. A withdrawal period of ~10 days is required for this medication. Daily oral administration of ammonium molybdate (100 mg) and sodium thiosulfate (1 g) for 3 weeks may reduce deaths in affected lambs. Dietary supplementation with zinc acetate (250 ppm) may also be useful to reduce the absorption of copper.
Plant eradication or reducing access to plants that cause phytogenous or hepatogenous copper poisoning is desirable. Primary chronic or phytogenous copper toxicosis may be prevented by top-dressing pastures with 1 oz of molybdenum per acre (70 g/hectare) in the form of molybdenized superphosphate or by use of molybdenum supplementation or restriction of copper intake.
High-risk flocks of sheep may be supplemented with dietary sodium thiosulfate to prevent or control chronic copper toxicosis. In addition, with molybdenum or thiosulfate supplementation, the prevention of chronic copper poisoning may be enhanced by routine evaluation of the copper and molybdenum concentrations in feed and avoiding provision of cattle feeds to supplement susceptible species such as sheep. Oversupplementation of animals with chelated minerals should also be avoided. Water is generally not an important source of copper for most food producing animals, although water standards exist for most species: cattle (1.0 ppm), swine (5.0 ppm), sheep (0.5 ppm). In dogs, genetic testing is available to identify carriers of the autosomal recessive gene associated with abnormal copper accumulation; however, the mode of inheritance is not known for all susceptible breeds. Periodic liver biopsies for evaluation of tissue copper concentration and testing of liver enzymes may also be useful to evaluate disease status. In addition to previously described treatments, zinc supplementation and prednisone or prednisolone administration enhance copper excretion and limit development of liver disease.
Copper poisoning, particularly chronic toxicosis, is a common occurrence in many animal species.
The insidious onset accompanied by high mortality and a poor response to treatment emphasizes the need to focus on prevention of the disease.
Marked differences in species and breed susceptibility should be considered in control strategies.