Copper poisoning

Copper poisoning  

            Copper is a metallic mineral that is an essential nutrient required in very minute amounts for all species of farm animals. Copper is an essential component of the animal system and play an important physiological role in haematopoiesis, myelin formation, phospholipids formation. Although it is an essential nutrient, copper can also be poisonous if ingested in amounts that exceed the animal’s requirement. There is a tremendous variation in the amount of copper needed by different species of farm animals. Similarly, there is tremendous variation in the susceptibility to copper poisoning among the farm animal species. What makes this problem confusing is that extra copper may need to be added to the diets of certain livestock species (pigs, poultry) to optimize health and performance, while the same feed can be lethal to other livestock species. Sheep are by far the most susceptible farm animal species to copper poisoning, with goats being less susceptible than sheep and cattle being less susceptible than either sheep or goats. Pigs are the least susceptible to copper poisoning, their rations often contain added copper (125-250ppm) in amounts that, if consumed by sheep, can cause acute copper poisoning. Many cases of poisoning occur when sheep or goats ingest small amounts of copper over a prolonged time period. Copper that is ingested is stored in the animal’s liver, and repeated ingestion of small amounts of copper above the animal’s requirement may cause accumulation of what eventually becomes a toxic amount of copper for the animal.

            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.

Sources of poisoning

            Sources of copper that can cause copper poisoning in sheep and goats

• Trace mineral-supplemented salt that is formulated for cattle or horses.

• Vitamin and mineral supplements intended for horses, cattle, swine, or poultry.

• Complete feeds for swine, horses, poultry, or cattle.

• Pasture that has been fertilized with swine manure.

• Pasture that has been fertilized with poultry litter.

•Copper-containing disinfectant foot baths for cattle.

            In addition to the consumption of feeds containing high concentrations of copper that cause poisoning in sheep, copper poisoning can occur when liver disease is present. Referred to as secondary copper poisoning, liver disease causes normally stored copper in the liver to be released into the blood stream where it causes destruction of the red blood cells (hemolysis). Certain plants (for example, Senecio species) that contain toxic alkaloids when eaten by sheep over a period of weeks can cause sufficient liver damage to precipitate a sudden release of stored copper from the liver to cause copper poisoning.

Toxicity may occur due to copper sulphate, copper chloride. Copper salts are mostly used in agriculture as plants fungicidal, so poisoning of animals can occur by grass pollution from its use in spraying of tree.

            Copper sulphate less threat to birds than to other animals. It is also toxic to fish and other aquatic invertebrates, such as crab, shrimp and oysters as well as earthworms in soil. Bees are endangered by strong, water-based compounds, such as a Bordeaux mixture of copper sulphate, lime and water.

            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. 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 susceptibility 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, e.g., 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.

Toxicokinetics

            After oral intake, copper is absorbed from intestine and then enters a carrier state in the blood. In the blood it is present in the erythrocytes. Liver removes most of the copper from the blood but other soft tissues also store some copper. The storages of copper in the liver is variable in different species. The liver excretes copper in the bile.

Clinical signs

            Symptoms of acute copper poisoning are nausea, vomition, salivation, purgation, violent abdominal pain, dehydration, tachycardia, shock and collapse, ending in death. Acute copper poisoning causes severe gastroenteritis characterized by abdominal pain, diarrhea, anorexia, dehydration, and shock. Haemolysis and haemoglobinuria 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, dyspnoea, pale mucous membranes, haemoglobinuria, and jaundice. Several days or weeks before the hemolytic crisis, liver enzymes, including ALT and AST, are usually increased. During the hemolytic crisis, methaemoglobinaemia, haemoglobinaemia, 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.

            Once copper has accumulated to a toxic amount in the liver, the sheep or goat can develop sudden and severe signs of disease.

            The signs of copper poisoning in sheep and goats include:

• Weakness, panting, and dull attitude

• Pale mucous membranes

• Yellow discoloration (jaundice) of the mucous membranes of the eyes, gums and genitalia

• Dark brown or red colored urine

• Abortion in pregnant ewes and does

• Death

            Clinical features of acute poisonings includes salivation, vomiting, watery diarrhoea that is grey-green in colour and often haemorrhagic, painful, severe colic and gastrointestinal effects. Neurological effects include convulsions, followed by paralysis, and decubitus. Death may occur within several hours to several days after ingestion.

            In chronic poisonings, sheep and cattle are most affected species, and copper is hepatotoxic. Clinical signs are bright yellow mucous membranes, yellow-coloured skin, haematuria, bloody nasal discharge, anaemia, anorexia, occasional convulsions, edema of the head and neck (presenting several hours before the onset of jaundice).

Lesions

            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 methaemoglobin are characteristic of chronic poisoning. Generalised yellowing of mucous membranes, swollen, gunmetal-colored kidneys that sometimes are mottled, port-wine-colored urine, friable, yellowish liver (or small, firm, pale liver), histologically, there is centrilobular hepatic and renal tubular necrosis, gallbladder distension and thick, greenish bile, enlarged spleen with a blackberry jam consistency with dark brown-black parenchyma are manifestations of the hemolytic crisis.

Diagnosis

            Diagnosis of copper poisoning can generally be made on the basis of the clinical signs, the observation of swollen, ‘gunmetal-colored’ kidneys, port-wine-colored urine, and an enlarged spleen on post mortem examination, and the detection of elevated concentrations of copper in the blood and liver. Blood copper concentrations above 2 micrograms/ml and liver copper concentrations above 150ppm (wet weight) are highly suggestive of copper toxicity.

            Evidence of blue-green ingesta and increased faecal (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.

Treatment

            Treatment of copper poisoning is very challenging, and severely affected animals often die despite treatment.

            There is no specific antidote. Symptomatic care include gastrointestinal demulcents, adsorbents (activated vegetable charcoal), cardiorespiratory stimulants and treatments to control convulsions (xylazine, diazepam), if necessary.

            Medications are administered to affected animals to increase the rate of excretion of copper from the liver.

            Oxygen administration and other supportive care may be required.

            When it is known that sheep have ingested feeds with toxic concentrations of copper (i.e. pig rations), feeding ammonium molybdate and sodium sulfate will help reduce the absorption of copper.

            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.

1. Rapid removal of poison from the stomach by stomach tube.

2. Giving pencillamine and BAL to combine with copper and convert it into non-toxic substances.

3. Adding of molybdenum to the animal food to prevent reserving within the liver.

4. Dietary supplementation with zinc acetate may be useful to reduced the absorption of copper.   

            Chronic poisoning In general, death occurs within a few hours of presentation of these symptoms. Once jaundice is evident, treatment is unlikely to be effective. Before jaundice, dimercaprol (BAL), 2-4 mg/kg, by intramuscular route, twice in the first 24 hours, then two to four times in the next 48 hours should be administered. Another treatment includes EDTA (sodium calcium edentate 25% w/v), 40-50 mg/kg by intravenous route, given in one to two doses daily for 2-3 days. Ammonium molybdenate (50-500 mg/day per animal) and sodium thiosulphate (0.3-1 g/day per animal) may be administrated orally in the diet for 10 to 15 days. Laboratory investigations show accumulation in liver, kidney, feeds, and hay.

            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.

            Prevention of copper poisoning is simple. Owners of sheep and goats must remain aware that premixed complete feeds, salts, and nutritional supplements designed for other species may contain concentrations of copper that are dangerous to sheep and goats. Because poultry manure (litter) and swine manure contain potentially dangerous concentrations of copper, sheep and goats should not be allowed to graze pastures where these have been applied as fertilizer.