Toxicological Diseases

Copper Poisoning

Primary copper poisoning has been reported in the goat, but is not common. It can produce a severe hemolytic ane­mia with hemoglobinuria and death, as occurs in the more commonly affected ruminants - sheep and young cattle.

Epidemiology

There is a marked difference in susceptibility between sheep and goats regarding chronic copper poisoning. The condition is harder to produce experimentally in goats than in sheep (S0li and Nafstad 1978; Solaiman et al. 2001), and published reports of naturally occurring caprine cop­per poisoning are few. In sheep, several naturally occurring forms of the disease are recognized, including acute copper poisoning, primary chronic copper poisoning, secondary phytogenous copper poisoning, and secondary hepatoge­nous copper poisoning. Until recently, only the acute and primary chronic forms of copper poisoning had been reported to occur naturally in goats. The acute form was reported from Israel (Shlosberg et al. 1978) and involved the oral administration of copper sulfate solution to goats as an anthelmintic. Primary chronic copper poisoning cases have been reported from New Zealand and the United Kingdom, involving young, hand-reared Angora goats exposed to a variety of copper-containing feeds and supple­ments (Belford and Raven 1986; Humphries et al. 1987). In the United States, primary chronic copper poisoning has been reported in dairy goats (Cornish et al. 2007) and in meat goats of the Boer breed. Some of these Boer goat cases were associated with excessive feeding of copper (Mongini 2011a), while in others the underlying cause was not clear (Bozynski et al. 2009; Cregar et al. 2012). Now, there is also a well-documented case of hepatogenous chronic copper poisoning in a goat associated with grazing Brachiaria decumbens in Brazil (Rosa et al. 2016).

Etiology and Pathogenesis

Acute copper poisoning is sporadic in occurrence and results from an accidental or unintentional ingestion of abnormally high doses of inorganic copper over a short period.

Acute copper poisoning can be induced in sheep and young calves with a single oral dose of copper in the range of 20-110 mg/kg bw. The dose is similar in goats, with acute copper toxicity observed after an oral dose of approxi­mately 60 mg/kg of copper sulfate (Shlosberg et al. 1978). Experimentally, acute toxicosis was produced in goats within three to four days by three daily IV injections of CuSO₄ ∙ 5H₂O at a total daily dose of 50 mg (Wasfi and Adam 1976).

Regarding the pathogenesis of primary chronic copper toxicity, it is generally believed that ingested copper accu­mulates in the liver over time until maximum hepatic lev­els are reached, at which point there is a sudden release of the accumulated copper into the blood, initiating an acute hemolytic crisis. However, there may be breed or species variation in this process, as a well-documented herd out­break of primary chronic copper toxicosis in a dairy goat herd did not involve hemolysis as part of the clinical pres­entation in affected goats (Cornish et al. 2007).

In primary chronic copper poisoning, copper is ingested continuously as part of the regular ration. The level of cop­per may be, but need not be, abnormally high, because the uptake of copper from the rumen and subsequent accumu­lation in the liver are conditioned by the concentrations of other minerals present in the ration. Low dietary levels of molybdenum, zinc, calcium, and sulfates can permit exces­sive uptake and accumulation of otherwise normal dietary levels of copper.

In secondary phytogenous chronic copper poisoning, grazing of specific pasture plants, notably subterranean clover (Trifolium subterraneum), promotes the accumula­tion of copper in the liver, although the plants themselves are relatively low in copper and do not produce any liver damage. The mechanism behind this phenomenon is not fully understood, but British breeds of sheep and Merino crosses seem more susceptible. This syndrome has not been reported in goats.

In hepatogenous chronic copper poisoning, hepatotoxic plants are ingested and produce liver damage that increases hepatocyte affinity for copper accumulation. This can accelerate the development of hemolytic crisis, even when dietary levels of copper are within normal limits. Plants most often involved are Heliotropium europaeum and other pyrrolizidine alkaloid-containing species, including Senecio spp. and Echium plantagineum. This syndrome has not been reported in goats. In fact, goats are relatively resistant to the effects of Senecio, and the use of goats has been proposed to clear rangelands of the plant to make them suitable for grazing by cattle (Dollahite 1972). The single reported case of hepatogenous chronic copper poi­soning was associated with the consumption of Br. decum- bens or signal grass, which does not contain pyrrolizidine alkaloids and is usually associated with hepatic photosen­sitization in grazing animals (Rosa et al. 2016).

Primary chronic copper poisoning can be induced in sheep with daily oral doses as low as 3.5 mg/kg bw, but goats require more aggressive challenge. In one study, oral administration of CuSO₄ ∙ 5H₂O twice daily at a dose of 20 mg/kg bw for 56 days produced hemolytic crisis in only one of three Norwegian breed goats.

In another study with Nubian goats, neither of two goats given CuSO₄ ∙ 5H₂O daily at 20 mg/kg/bw developed hemo­lytic anemia, while one of two given 40 mg/kg/day and one of two given 80 mg/kg/day did (Adam et al. 1977). In a more recent experimental study, Nubian goats were fed supplemental copper at increasing levels from 100 mg/ head/day up to 1200 mg/head/day for up to 35 weeks. Only individuals receiving 600 mg/head/day or higher showed a clinical effect, with signs of thirst, diarrhea, dehydration, lethargy, and weight loss. However, none experienced hemolytic anemia. The authors report that daily doses of copper of 100 mg/head/day are sufficient to produce clini­cal toxicity in sheep, and conclude that goats are more resistant to copper toxicity than are sheep (Solaiman et al. 2001). It has been postulated that the difference in susceptibility of sheep and goats to copper poisoning is a function of differences in the distribution of copper- and zinc-binding soluble hepatic proteins (Mjor-Grimsrud et al. 1979).

In goats, as in sheep, development of copper toxicosis may be conditioned by influences of other elements. Goats pretreated with vitamin E and selenium injections devel­oped hemolytic crisis after 50 days of oral dosing with 15 mg/kg of copper as copper sulfate, while animals receiv­ing the same copper dose with no vitamin E or selenium pretreatment showed no clinical signs after the same period. Goats with evidence of hemolytic crisis had decreased liver levels of reduced glutathione and higher glutathione disulfide levels (Hussein et al.

Clinical Signs

Acute copper poisoning in goats resulting from oral inges­tion of copper produces signs of gastrointestinal irritation, including evidence of abdominal pain, grinding of the teeth, frothing at the mouth, vomiting, and diarrhea. Additional signs include labored breathing, muscle fascic- ulation, tachycardia, and increased amplitude of heart sounds. Within six hours, severely affected animals may collapse and die. Morbidity and mortality rates are dose dependent. Mortality rates as high as 53% have been reported in goats given oral copper sulfate at a dose of 60 mg/kg.

In cases of chronic copper toxicosis and acute toxicosis associated with parenteral administration of copper, dull­ness, anorexia, thirst, dehydration, and elevated heart and respiratory rates are early signs. Diarrhea may also be pre­sent. If hemolytic anemia is part of the clinical syndrome, then icterus will be noted on mucous membranes, serum will be pink, and the urine red-brown. Dyspnea may develop as a result of severe anemia, and death may occur in 24-48 hours after the onset of signs. In untreated ani­mals surviving longer, anuria and uremia may develop as a result of hemoglobinuric nephrosis.

However, in the report of chronic copper toxicosis in a dairy goat herd (Cornish et al. 2007), none of the affected animals showed indications of hemolytic anemia. Only lactating does were clinically affected, though young goats had laboratory evidence of copper levels consistent with intoxication. Clinical signs in lactating does included ano­rexia, agalactia, dullness, dehydration, teeth grinding, and drooling. Affected does progressed to recumbency and showed neurologic abnormalities such as paddling and vocalization, followed by death. Signs associated with hemolytic anemia such as icterus or hemolyzed plasma were absent (Cornish et al. 2007).

In Boer goats with chronic copper toxicity, it has been observed that after the initial signs of weakness, inappe­tence, and tachypnea, two different clinical presentations may occur in the subsequent 12-24 hours.

In the case of chronic hepatogenous copper poisoning associated with the grazing of Br. decumbens, the affected 4-year-old female mixed-breed goat presented with chronic weight loss, dehydration, mild icterus, and apathy and then, two days before its death, developed acute severe icterus and hemoglobinuria (Rosa et al. 2016).

Clinical Pathology and Necropsy

During the acute hemolytic crisis, PCV may fall below 10%, and RBC and Hb levels drop correspondingly. Heinz bodies can be seen in RBCs and there may also be methemo­globinemia. Serum bilirubin is markedly elevated and the urine is strongly positive for hemoglobin. Alterations in clinical chemistry are consistent with liver damage, and elevations of aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), sorbitol dehydrogenase (SDH), and blood ammonia are reported in the goat, though the magnitude of increase is highly variable. Elevation in liver enzymes may precede the acute hemolytic crisis by several weeks, and this may be helpful for screening animals in a herd not yet showing clinical disease. None of these changes is diagnostic for copper poisoning and it is impor­tant to establish the presence of abnormally elevated cop­per levels in blood, liver, kidney, or other tissues to confirm the diagnosis.

In a recent report of field cases of primary chronic cop­per toxicosis, it was noted that in clinically affected goats there was no clear association between the magnitude of increase of serum hepatic enzymes and the concentrations of copper in the serum or liver. In clinically unaffected, younger does in the same herd, there was no consistent relationship between serum hepatic enzyme activities, serum copper concentration, and liver copper concentra­tion. It was concluded that serum liver enzymes and serum copper levels are insensitive markers of liver copper con­centration, and the definitive method for diagnosis ante mortem is to measure copper concentrations in liver sam­ples obtained by biopsy (Cornish et al. 2007). Another study confirmed the reliability of liver as the optimal sam­ple for establishing copper toxicosis, and pointed out that hair samples did not reflect the copper status of animals (Solaiman et al. 2001).

Normal goat liver copper levels are reported in the range of 0.188-1.805 μmol∕g (12-115 ppm) (Mjor-Grimsrud et al. 1979), but goats seem to be able to tolerate liver concentra­tions up to 200 ppm without evidence of toxicity (Mongini 2011b). The normal kidney copper level in goats has been reported as 0.1 μmol∕g (6.4 ppm). Normal serum copper levels in goats are reported to be in the range of 9.4-23.6 μmol∕L (60-150 μg∕dL or 0.6-1.5 ppm) (Underwood 1981).

In field cases of chronic copper toxicity in goats in New Zealand, plasma copper levels of 34.6 μmol∕L (219.8 μg∕dL or 2.2 ppm) and RBC copper levels of 95.8 μmol∕L (608.6 μg∕ dL or 6.1 ppm) were observed during acute hemolytic cri­sis. Liver copper levels were as high as 21.4 μmol∕g dry mat­ter (1359 ppm), and kidney levels as high as 6.4 μmol∕g dry matter (406 ppm) (Humphries et al. 1987).

In experimental chronic copper intoxication in goats, animals with hemolytic crises had liver copper levels more than 900 ppm and kidney copper levels more than 170 ppm. Goats that were fed excessive copper but did not develop hemoglobinuria had liver copper levels between 300 and 1100 ppm and kidney levels between 3 and 150 ppm, while a control goat not fed copper had liver copper levels of 18.5 ppm and kidney levels of 6.7 ppm (Adam et al. 1977; Soli and Nafstad 1978).

In acute copper poisoning of goats, animals dying shortly after ingestion had normal liver and kidney levels of cop­per, but the copper contents of rumen ingesta and feces were elevated to 225 ppm and 1060 ppm, respectively. At least in sheep, some fatal cases have elevated kidney cop­per, while liver copper is in the normal range. It is impor­tant to take samples from both organs and to submit kidney if the liver value is normal but copper toxicosis is still suspected.

Findings at necropsy may include thin, watery blood and general icterus. The liver is enlarged, friable, and yellow. The kidneys are swollen, dark brown to black, metallic, and softened. Hemorrhages on the epicardium and endo­cardium and congestion of the lungs and spleen may be noted. In acute oral intoxication, marked inflammation of the abomasal and intestinal mucosae is evident. Histologically, the liver lesion is characterized by hemosid­erin deposits, centrilobular necrosis and fatty degenera­tion, and biliary hyperplasia. The kidney exhibits lesions of nephrosis, with casts present in tubules. One experimental study of chronic copper poisoning in the goat resulted in liver lesions atypical for the disease, and it was suggested that the pathogenesis of chronic copper poisoning in the goat may differ from that in the sheep (Soli and Nafstad 1978). Others have consistently described lesions found in the goat to be similar to those found in the sheep.

Diagnosis

When signs of abdominal pain are prominent - as in acute copper toxicosis - intestinal accidents, urethral obstruc­tion, and early infectious enteritis must be considered. When hemolytic anemia is present, the differential diagno­sis for chronic copper toxicosis in the goat includes the hemoparasites babesiosis and trypanosomosis, where they occur, and several plant poisonings that could lead to hemolytic anemia, particularly kale, which also can pro­duce Heinz bodies. Other intoxications must be ruled out in acute copper toxicity, including arsenic ingestion, organ­ophosphate toxicosis, cyanide poisoning, and nitrate poi­soning. The recent report of goats with chronic copper toxicosis that had no evidence of hemolytic anemia but did have elevated liver enzymes and neurologic signs suggests that various causes of hepatic encephalopathy may have to be considered in the differential diagnosis of chronic cop­per toxicity.

Treatment

Treatment is directed at the clearance and elimination of copper from the blood and tissues through the use of chelat­ing agents. For a long time, the only treatment reported spe­cifically in goats was ammonium tetrathiomolybdate, administered at a dose of 1.7 mg∕kg bw IV for three treat­ments on alternate days (Humphries et al. 1987). In lambs, a daily oral total dose of 100 mg of ammonium molybdate in combination with 1 g of sodium sulfate given for as long as three weeks has been effective in reducing tissue copper concentrations and may prevent or ameliorate hemolytic crisis. Other chelating agents also have been used, includ­ing oral D-penicillamine at a dose of 52 mg/kg bw daily for six days. More recently, the successful use of penicillamine, ammonium molybdate, and sodium thiosulfate in the treat­ment of adult goats with primary chronic copper toxicosis was described (Cornish et al. 2007). Penicillamine was given orally at a dose of 50 mg/kg bw every 24 hours for 7 days, ammonium molybdenate orally at a total dose of 300 mg every 24 hours for 3 weeks, and sodium thiosulfate orally at a total dose of 300 mg every 24 hours for 3 weeks. Vitamin E was also given orally at a total dose of 2000U every 24 hours for 3 weeks as an antioxidant.

Penicillamine is expensive and, though effective, its use may be limited in commercial herds by cost considerations. Where such therapy is cost prohibitive, a demonstrably effective approach to therapeutic management has been to identify and remove all excess copper from the ration and allow accumulated copper to leach slowly back out of the liver. Appropriate levels of copper can be re-introduced into the ration three to nine months later, based on herd monitoring of copper levels in livers collected at slaughter or by biopsy (Mongini 2011b). Therapeutic consideration should also be given to management of anemia when pre­sent, as well as management of potential nephrosis in severely affected individuals. Blood transfusion might be indicated in exceptional cases when PCV is perilously decreased. Continuous IV administration of balanced elec­trolyte solutions helps maintain urine outflow and reduce the potential for irreversible hemoglobinuric nephrosis.

Control

Control of acute copper poisoning in the goat depends on conscientious management and good common sense, to avoid accidental exposure to and ingestion of high doses of copper. Because chronic copper poisoning in goats is rare, aggressive control methods such as fertilization of crop and grazing lands with molybdenum and molybdenum supple­mentation of feed are probably unnecessary. However, some caution should be exercised in using feedstuffs for­mulated for cattle, like mineral mixes and especially calf milk replacers used in kids. Nutritional requirements for copper in goats are discussed in Chapter 19.

Kale Anemia (Brassica Poisoning)

The use of kale (Brassica oleracea) as a feedstuff for rumi­nants may lead to the development of Heinz body anemia, with possible mortality. Cattle are most susceptible and sheep least susceptible. Goats have an intermediate position.

Epidemiology

Clinical outbreaks of Heinz body anemia can occur in ruminants when kale has a predominant role in feeding programs. This has been a notable problem in Great Britain and Germany. Consumption of large amounts for extended periods increases the likelihood of disease, and anemia rarely develops until animals have been consuming kale for one to three weeks. Mature plants and plants with second­ary growth are more toxic. The consumption of plants that have been frosted or frozen also increases the likelihood of disease. Certain varieties of kale are more toxic than others, but heating or ensilage destroys the toxic principle.

The condition is reproducible experimentally in goats (Greenlagh et al. 1969, 1970; Smith 1980). It has been reported as a cause of mortality in Angora goats in New Zealand (Anonymous 1988). Affected goats had been graz­ing the kale for less than two weeks, while lambs that had preceded kids in grazing were unaffected. It was suspected that kids, already anemic from haemonchosis, were more severely affected by kale toxicity.

Etiology and Pathogenesis

Kale contains high levels of S-methyl cysteine sulfoxide that is converted by rumen bacteria to dimethyl disulfide. This is then absorbed from the rumen and induces Heinz body anemia via the oxidation of hemoglobin in circulating RBCs. Mature RBCs are more susceptible to oxidation than young cells so that the anemia may become temporarily self-limiting, as the regenerative response increases the relative proportion of young cells to old. As these cells mature, the anemia may worsen again if kale continues to be fed. This phenomenon is associated with higher levels of glutathione reductase in young cells that are protective against oxidation of hemoglobin (Smith 1980).

Clinical Findings

After one to three weeks of kale ingestion, goats develop a marked anemia. Sudden death may be the first reported sign in an affected herd or flock. Closer inspection may identify additional animals that hang back from the flock, appear weak, and have pale mucous membranes. Additional signs include inappetence, tachypnea, and tachycardia. Red-brown urine may be noted because of hemoglobinuria.

Clinical Pathology and Necropsy

Anemia may be pronounced, as hemoglobin levels can decrease below 6 g/dL and sometimes as low as 3 g/dL, with a concomitant decline in RBC counts and PCV. The appearance of Heinz bodies in RBCs in the peripheral blood, detectable in smears stained with new methylene blue stain, may precede the decrease in Hb by as much as a week. Methemoglobinemia, sometimes observed in cattle, is rare in goats. The anemia is regenerative, and reticulo­cytes and an increase in MCV can be noted.

Necropsy findings specific for the goat have not been reported. In other species, postmortem lesions include pal­lor, hemoglobinuria, thin watery blood, dark kidneys, and congestion of the liver with moderate hepatic necrosis. Icterus, especially of the subcutaneous fat, is pronounced.

Diagnosis

Diagnosis is presumptive based on the presence of Heinz body anemia in conjunction with a history of kale feeding. In other ruminants, rape (Brassica napus), wild onion (Allium validum), cultivated onion, and stubble turnip consumption also produce Heinz body anemia. When widespread icterus is noted at necropsy, chronic copper toxicosis and Ieptospiro- sis must be considered in the differential diagnosis.

Treatment and Control

Therapy is limited to supportive care and the possibility of blood transfusion. Removal of kale from the diet results in a return of normal Hb levels within two to three weeks. Affected goats should not be subjected to stress or vigorous exercise during the recovery.

Other Plant-Related Anemias

Several reports identify plants toxic to goats with anemia as a clinical manifestation. Acanthospermum hispidum, a weed of the Compositae family, has been associated with livestock poisoning in the Sudan, and its toxicity for goats has been confirmed experimentally. Animals fed the plant at a dose of 5 g/kg bw daily showed anorexia, jaundice, and diarrhea within one week, followed by dullness, dyspnea, weakness of the hind end, and terminal neurologic signs, probably because of hepatoencephalopathy. Clinical pathology indicated acute liver dysfunction and develop­ment of a marked hemolytic anemia during the course of disease (Ali and Adam 1978).

Ipomoea carnea, in the family Convolvulacae, is a tropical plant with strong drought-resistant properties; it may be an abundant source of browse for goats during adverse climatic periods. Toxicity in goats because of Ipomoea spp. has been presumed or documented in India, Brazil, and the Sudan (Damir et al. 1987; Dobereiner et al. 1987; Tirkey et al. 1987). Experimentally, daily repeated doses of fresh leaves of I. carnea as low as 5g∕kg bw can produce a clinical syn­drome of inappetence, depression, pallor, weakness of the hindquarters, dyspnea, weight loss, and death within three weeks, although there is individual variation in response, and some goats survived for longer than three months. A moderate, normocytic, normochromic, occasionally hypochromic anemia is observed in severely affected goats. PCVs as low as 15% occur, with Hb as low as 5g∕dL. In acute cases the anemia is non-regenerative, but in animals that survived for longer periods a macrocytic response was observed. Serum chemistry analysis suggested liver dysfunc­tion with elevated AST and ammonia and hypoproteinemia (Tartour et al. 1974; Damir et al. 1987). Toxicity from I. carnea is dose dependent. In an Indian study, no clinical signs or laboratory abnormalities occurred in goats fed an aqueous extract of the plant at a dose of 160mg∕kg, consid­ered to be one-fifth the LD₅₀ dose (Tirkey et al. 1987).

Anemia also has been reported as an incidental finding in several plant poisonings in the Sudan, including Capparis tomentosa (Ahmed and Adam 1980), Tephrosia apollinea (Suliman et al. 1982), and, experimentally, Solanum dubium. The latter plant is not routinely eaten by goats, but may be consumed during periods of drought (Barri et al. 1983).

Bracken fern (P. aquilinum) ingestion has been associated with a number of clinical syndromes in cattle and sheep, including depression of bone marrow activity leading to aplastic anemia, leukopenia with secondary bacterial infec­tions, and ecchymoses secondary to thrombocytopenia, as well as ruminal papillomatosis, progressive retinal degen­eration, and enzootic hematuria. There is only one clinical report associating exposure to bracken fern with disease in goats (Tomlinson 1983). Affected goats showed a marked anemia and high fevers that responded to antibiotic ther­apy, suggestive of secondary bacterial infections. Leukocyte counts and bone marrow evaluations were not performed. The goats concurrently experienced severe gastrointestinal helminthiasis and the contribution of bracken fern inges­tion to the anemia and infections was not well established. Currently goats should be considered potentially suscepti­ble to bracken fern toxicity. A report from Venezuela states that bracken fern can cause permanent blindness in goats (Alonso-Amelot 1999).

A number of plants have been associated with hemoglo­binuria in sheep, including privet (Ligustrum spp.), broom (Cytisus spp.), hellebore (Helleborus spp.), Ranunculus spp., Colchicum spp., and frosted turnips (Kimberling and Arnold 1983). Currently, there are no reports of poisoning with these plants in goats, but it is reasonable to assume that a toxic potential exists.