Acute or chronic copper poisoning is encountered in most parts of the world. Sheep are affected most often, although other species are also susceptible. In various breeds of dogs, especially Bedlington Terriers, an inherited sensitivity to copper toxicosis similar to Wilson disease in people 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 poisoning is usually seen after accidental administration of excessive amounts of soluble copper salts, which may be present in anthelmintic drenches, mineral mixes, or improperly formulated rations.
Many factors that alter copper metabolism influence chronic copper poisoning by enhancing the absorption or retention of copper. Low levels of molybdenum or sulfate in the diet are important examples. Primary chronic poisoning is seen most commonly in sheep when excessive amounts of copper are ingested over a prolonged period. The toxicosis remains subclinical until the copper that is stored in the liver is released in massive amounts. Increased liver enzymes may provide an early warning of the pending crisis. Blood copper concentrations increase suddenly, causing lipid peroxidation and intravascular hemolysis. The hemolytic crisis may be precipitated by many factors, including transportation, handling, weather conditions, pregnancy, lactation, strenuous exercise, or a deteriorating plane of nutrition.
Phytogenous and hepatogenous factors influence secondary chronic copper poisoning. Phytogenous chronic poisoning is seen after ingestion of plants, such as subterranean clover (Trifolium subterraneum), that produce a mineral imbalance and result in excessive copper retention. The plants that are not hepatotoxic contain normal amounts of copper and low levels of molybdenum. The ingestion of plants such as Heliotropium europaeum or Senecio spp (see Pyrrolizidine Alkaloidosis) for several months may cause hepatogenous chronic copper poisoning. These plants contain hepatotoxic alkaloids, which result in retention of excessive copper in the liver. In dogs with liver diseases such as chronic active hepatitis (CAH), the primary clinical signs may resemble those of chronic copper poisoning, which can be attributed to the liver damage and subsequent retention of excessive copper; however, it is not clear whether CAH causes the accumulation of copper in the liver or is the result of accumulation.
Acute poisoning may follow intakes of 20–100 mg of copper/kg 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 of copper/kg when grazing pastures that contain 15–20 ppm (dry matter) of copper and low levels of molybdenum. Clinical disease may occur in sheep or camelid species that ingest cattle rations, which normally contain higher levels of copper, or when their water is supplied via copper plumbing; cattle and goats are more resistant to copper poisoning than sheep and thus are not affected in these instances. Species-specific diets with respect to copper are recommended to minimize the occurrence of chronic copper poisoning. Breed differences related to the suceptibility to chronic copper poisoning have been reported in sheep and goats. Young calves or sheep injected with soluble forms of copper may develop acute clinical signs of toxicity without evidence of a hemolytic crisis. Copper is used as a feed additive for pigs at 125–250 ppm; levels >250 ppm are dangerous—although as for sheep, other factors may be protective, eg, high levels of protein, zinc, or iron. Chronic copper toxicosis is more likely to occur with low dietary intake of molybdenum and sulfur. Reduced formation of copper molybdate or copper sulfide complexes in tissues impairs the excretion of copper in urine or feces.
Acute copper poisoning causes severe gastroenteritis characterized by abdominal pain, diarrhea, anorexia, dehydration, and shock. Hemolysis and hemoglobinuria may develop after 3 days if the animal survives the GI disturbances. The sudden onset of clinical signs in chronic copper poisoning is associated with the hemolytic crisis. The time of onset is influenced by the concentration of copper in the diet. 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 enzymes, including ALT and AST, are usually increased. During the hemolytic crisis, methemoglobinemia, hemoglobinemia, and decreases in PCV and blood glutathione are usually seen. In camelid species such as alpacas or llamas, no hemolytic crisis is seen, although extensive liver necrosis remains a consistent manifestation. Morbid animals often die within 1–2 days. Herd morbidity is often <5%, although usually >75% of affected animals die. Losses may continue for several months after the dietary problem has been rectified. Severe hepatic insufficiency is responsible for early deaths. Animals that survive the acute episode may die of subsequent renal failure. Photosensitization may occur in association with chronic copper poisoning, reflecting the hepatotoxicity common to both syndromes. Cirrhosis of the liver is also associated with the syndrome in dogs.
Acute copper poisoning produces severe gastroenteritis with erosions and ulcerations in the abomasum of ruminants. Icterus develops in animals that survive >24 hr. 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 significant in acute copper poisoning. In chronic poisoning, blood and liver copper concentrations are increased during the hemolytic period. Blood concentrations often rise to 5–20 mcg/mL, as compared with normal levels of ~1 mcg/mL. Liver concentrations >150 ppm (wet wt) are significant in sheep. The concentration of copper in the tissue must be determined to eliminate other causes of hemolytic disease. Molybdenum tissue concentrations should be evaluated to determine whether the syndrome is due to primary or secondary chronic copper poisoning.
Often, treatment is not successful. The prognosis is poor in all species. GI sedatives and symptomatic treatment for shock may be useful in acute toxicity. Penicillamine (50 mg/kg/day, PO, for 6 days) or calcium versenate may be useful if administered in the early stages of disease to enhance copper excretion. Vitamin C (500 mg/day/sheep, SC) has been shown to reduce oxidative damage to RBCs during the 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 wk reduces losses in affected lambs. Dietary supplementation with zinc acetate (250 ppm) may 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 poisoning 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 molybdenum supplementation or restriction of copper intake. High-risk flocks of sheep may be supplemented with sodium thiosulfate in the diet to prevent or control chronic copper poisoning. In dogs, genetic testing is available to identify carriers of the autosomal recessive gene associated with abnormal copper accumulation, although the mode of inheritance is not known for all susceptible breeds. Periodic liver biopsies, tissue copper determination, and liver enzyme assessment 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.