Chronic Copper Poisoning Research Articles

Wilson's disease or chronic copper poisoning?

The case history is given of a child who presented at 14 months with ascites and was found to have severe micronodular cirrhosis with biochemical evidence of Wilson9s disease, but in view of the severity of the pathology and early age of presentation, the possibility of chronic copper poisoning was investigated. It was found that the child9s drinking water was obtained from a bore via new copper pipes. The bore water had a <i>p</i>H of 4·4 and after passage through copper pipes had a very high copper level of 675 μg/100 ml. He subsequently died from liver failure and at necropsy very high copper levels were found in his liver. The final diagnosis remains uncertain.

Effect of copper on red cell glutathione and enzyme levels in high and low glutathione sheep.

SummaryEffects of copper on red cell glutathione and enzyme levels were investigated in sheep of high- and low-glutathione types. No significant differences were observed in copper induced inhibition of glutathione regeneration or erythrocyte enzyme activities in the two groups of sheep. These results, together with those showing the effect of copper on GSH oxidation suggest that low-glutathione sheep should not be more sensitive to small doses of copper, commonly encountered in chronic copper poisoning in sheep than are high-glutathione sheep.

Copper, molybdenum and sulphur contents of oats and barley in relation to chronic copper poisoning in housed sheep

SUMMARYThe copper, molybdenum, and total sulphur contents were estimated in 124 samples of oats and 67 samples of barley obtained from various parts of Northern Ireland. Copper contents were in the low-normal range, the average of all oat samples being 3–9 ppm and of barley samples 4–9 ppm, and the range 1–5 to 8–4 ppm covering all samples analysed. The corresponding averages for molybdenum were 0–25 ppm and 0–30 ppm, about 10% of the samples in each case containing less than 0–02 ppm. Sulphur contents (expressed as sulphate) ranged from 0–23 to 0–46 %. The low molybdenum contents are considered to be of significance in the copper metabolism of housed sheep.

Experimental Chronic Copper Toxicity in Sheep: Biochemical and Haematological Studies during the Development of Lesions in the Liver

Summary Eight sheep were dosed repeatedly with copper sulphate in order to induce chronic copper poisoning. This object was achieved in 7 animals and several had repeated haemolytic episodes. Raised blood copper levels were found only immediately before or during haemolysis and both plasma copper and red cell copper fractious were increased at this time. An increase in the concentration of sorbitol dehydrogenase, arqinase andglutamate-oxaloacetate transaminase was detected in the serum one week after the start of dosing and by 2 weeks 5 animals also showed an increased serum glutamate dehydrogenase concentration. Subsequently the enzyme levels fluctuated and in some instancesfell to near the pre-dosing range. A marked increase in serum enzyme activity occurred immediately prior to the haemolytic crisis. Serum bilirubin leveb followed a similar trend and the highest values were recorded during haemolytic episodes. Reduced bromsulphthalein clearance occurred several weeks before haemolysis and particularly low rates of clearance were recorded in the 2 weeks prior to haemolytic crises. Haemolysis was associated with neutrophilia, Heinz body formation and high blood urea levels. Post mortem markedly elevated copper levels were found in the liver and kidneys and slightly elevated copper levels were found in the spinal cord. Liver zinc levels were raised, kidney iron levels were markedly increased but spinal cord iron levels were decreased.

Potential Hepatotoxicity of Copper in Recurrent Hemodialysis

Tap water acting on copper plumbing contributes up to 1 ppm of copper to dialysis fluid in Australian hemodialysis units. Patients dialyzed against 0.4 ppm of copper show uptake of copper by both plasma and red blood cells during hemodialysis. In experimental dialysis of dogs against 0.4 and 1 ppm of copper, the initial uptake is mainly by the plasma, but copper concentration occurs in the red blood cells and in the liver. The possibility that, in patients on longterm hemodialysis, copper accumulation in the liver might eventually lead to hepatitis and hemolysis is discussed in relation to chronic copper poisoning of sheep and to Wilson's disease.

Observations on Serum Adenosine Deaminase Activity in Experimentally Produced Liver Diseases of Cattle and Sheep: Yellow-Wood, Lantana, Carbon Tetrachloride and Chronic Copper Poisoning

Serum adenosine deaminase activity was studied in four cases of yellow-wood poisoning and five cases of lantana poisoning in cattle and also four cases of both carbon tetrachloride and chronic copper poisoning in sheep. In each of these liver diseases marked elevations of SAD activity were observed. The levels observed in cases of yellow-wood poisoning were considerably greater than those in the other liver conditions, this difference was discussed in relation to lesions in other organs in yellow-wood poisoning. L’activité de la désaminase adénosive dans le sérum a été étudiée dans 4 cas d’empoisonnement par le santal et 5 cas d’empoisonnement par le lantanier chez le bétail, et aussi 4 cas d’empoisonnement par le tétrachlorure de carbone et par le cuivre (chronique) chez les moutons. Dans chacune de ces maladies du foie on a observé une augmentation marquée de l’activité de la désaminase adénosive dans le sérum. Les niveaux observés dans les cas d’empoisonnement par le santal étaient considérablement plus élevés que ceux correspondant aux autres conditions hépatiques, cette différence fit l’objet d’une étude au sujet de lésions d’autres organes lors de l’empoisonnement par le santal. Die Serumadenosindeaminasetätigkeit wurde bei vier Rindern mit Visetholzvergiftung und fünf Rindern mit Lantanavergiftung sowie bei vier Schafen mit Tetrachlorkohlenstoff- und chronischer Kupfervergiftung untersucht. Die SAD-Tätigkeit war bei allen diesen Leberstörungen beträchtlich erhöht. Bei den Fällen mit Visetholzvergiftung wurden bedeutend höhere Spiegel beobachtet als bei den anderen Leberstörungen, und dieser Unterschied wird im Zusammenhang mit der Schädigung anderer Organe durch eine Viset olzvergiftung diskutiert. La actividad de la adenosina desaminasa sérica fue estudiada en cuatro casos de envenenamiento con fustete y en cinco casos con lantana en ganado vacuno y también caatro casos en ovejas que fueron envenenadas con tetracloruro de carbono y con cobre-. En cad: una de estas enfermedades hepáticas se encontró marcada elevación de la adenosina desaminasa sérica. Los niveles encontrados en los casos debidos a envenenamiento con fustete fueron considerablemente mayores que en los otros. Se discute esta diferencia en relación a las lesiones en otros órganos encontrados en los casos debido a envenenamiento con fustete.

Chronic copper toxicity of ruminants.

There has been an active interest in the toxicology of copper since the middle of the 19th century and a review by Davenport (1953) covers the early work on the hazard to man and animals of both the acute and chronic forms. Review material specific to chronic copper poisoning in farm livestock has also been published by Broughton &amp; Hardy (1934), Eden (1940), Todd (1962) and Bull (1964).The first description of true chronic copper poisoning in farm animals would seem to be that of Mallory (1925) who produced the condition experimentally in sheep. Beijers (1932) described similar symptoms in sheep grazing orchards which had been sprayed with a copper fungicide, and 2 years later Broughton &amp; Hardy (1934) published their detailed experimental investigations showing the dangers of excessive copper intakes to sheep. The similarity between the symptoms described in these reports and those of ‘yellows’ or ‘toxaemic jaundice’ in Australia was recognized (Bull, 1964) and the experiments of Albiston, Bull, Dick &amp; Keast (1940) confirmed that this naturally-occurring condition was of similar origin. The importance of chronic copper poisoning as a nutritional hazard was, therefore, fully established.

Chronic copper toxicity of ruminants

There has been an active interest in the toxicology of copper since the middle of the 19th century and a review by Davenport (1953) covers the early work on the hazard to man and animals of both the acute and chronic forms. Review material specific to chronic copper poisoning in farm livestock has also been published by Broughton &amp;amp; Hardy (1934), Eden (1940), Todd (1962) and Bull (1964).The first description of true chronic copper poisoning in farm animals would seem to be that of Mallory (1925) who produced the condition experimentally in sheep. Beijers (1932) described similar symptoms in sheep grazing orchards which had been sprayed with a copper fungicide, and 2 years later Broughton &amp;amp; Hardy (1934) published their detailed experimental investigations showing the dangers of excessive copper intakes to sheep. The similarity between the symptoms described in these reports and those of ‘yellows’ or ‘toxaemic jaundice’ in Australia was recognized (Bull, 1964) and the experiments of Albiston, Bull, Dick &amp;amp; Keast (1940) confirmed that this naturally-occurring condition was of similar origin. The importance of chronic copper poisoning as a nutritional hazard was, therefore, fully established.

Histochemigal Detection of Copper in the Liver from Sheep Chronically Poisoned by Copper

Continued ingestion of copper in excess of the nutritional requirement leads in all animals to its passive accumulation within the tissues, especially the liver. Up to certain levels varying greatly with the species high concentrations of copper in the liver appear to impose no physiological hardship on the animal. Above these levels there may occur a catastrophic liberation of a high proportion of the copper into the blood stream resulting in extensive hemolysis and jaundice usually followed by death. Sheep are more prone to the hemolytic crisis of chronic copper poisoning than other animal species. The hemolytic crisis of chronic copper poisoning is associated with centrolobular necrosis of the liver. The copper concentration in the liver is usually 300 p.p.m. or more (wet tissue) compared with about 50 p.p.m. in normal sheep (Simesen & Møller 1969).

The copper-molybdenum complex in ruminant nutrition

The significance of molybdenum in the metabolism of higher animals and its association with copper were demonstrated in 1938. Since then much has been learnt about the interaction between copper and molybdenum in both ruminants and non-ruminants. This knowledge has contributed greatly to our ability to prevent or to treat ‘teart’ and ‘peat scours’ in ruminants. The copper-molybdenum interaction may also be involved in chronic copper poisoning and copper deficiency.

The Relative Merit of Various Blood Analyses and Liver Function Tests in Giving an Early Diagnosis of Chronic Copper Poisoning in Sheep

SUMMARY Six different biochemical determinations were made to assess blood copper status and liver function at intervals on sheep which were dosed regularly with copper sulphate to induce chronic copper toxicity. SGOT concentration was the only test found to give abnormal values consistently in advance of the terminal stages of chronic copper poisoning. Elevated SGOT concentrations were found some 1—6 weeks in advance of obvious clinical symptoms for all but one sheep. In this case an abnormal SGOT concentration was not found until 3 days before the onset of the haemolytic crisis.

Observations on Blood Copper in the Sheep : II.—Chronic Copper Poisoning

SUMMARY A detailed study of blood copper in 4 cases of induced chronic copper poisoning in sheep was made. The development of chronic copper poisoning followed a pattern of 3 stages, according to the level of whole blood copper attained. Apart from transient elevation of the RBC Cu level no marked changes occurred during Stage I which lasted from 62 to 104 days. During Stage II an increase in whole blood copper to about twice normal levels was accompanied by a change in plasma colour due to bilirubin, a decrease in liver function and changes in the level of haematocrit. The blood copper levels were a result of changes in both RBC Cu and DR Cu. The excess copper (up to 19 µg./ml.) present in the blood during the crisis of Stage III was seen first in the plasma, as DR Cu, and later in the red blood cells. These changes are comparable in nature, though not in duration, with those which arc observed after a single massive dose of copper. It would appear that the inability of the red blood cell to release its extra copper is responsible, in part, for the level of whole blood copper and the time for which this level persists. The immediate cause of death in 2 of these sheep would appear to have been the acute general toxic effect of copper, while in the other 2, anaemia and uraemia may well have played an additional part.

Chronic dialysis and copper poisoning.

Chronic dialysis and copper poisoning.

Studies on Chronic Copper Poisoning IV: Biochemistry of the Toxic Syndrome in the Calf

SUMMARY (1) Chronic copper poisoning was produced in two calves by feeding up to 500 p.p.m. copper as copper sulphate in the ration, death taking place after 20 and 21 weeks. (2) Clinical symptoms were those of a haemolytic crisis and included jaundice, methaemoglobinaemia, and haemoglobinuria. Post-mortem appearance was of a generalized icterus. (3) Estimations of the following blood constituents were made before and during the haemolytic crisis: copper, haemoglobin, methaemoglobin, reduced glutathione, oxidized glutathione, transaminase and lactic dehydrogenase enzymes. (4) Plasma glutamic-oxalacetic transaminase and lactic dehydrogenase activities were found to be increased one week before the haemolytic crisis and also during the clinical phase. (5) Blood copper concentrations remained normal until the haemolytic crisis when five to ten-fold increases were recorded. (6) The concentration of reduced glutathione in the red cells was very low during the haemolysis and the concentration of oxidized glutathione was also lowered. (7) The significance of these results is discussed in relation to the development of the toxic syndrome.

862. Copper poisoning in calves: Todd, J. R. & Thompson, R. H. (1965). Studies on chronic copper poisoning. IV: Biochemistry of the toxic syndrome in the calf. Br. vet. J.121, 90

Red cell glycolysis, glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase and methaemoglobin reductase activities, reduced glutathione and the production of methaemoglobin under oxidative stress have been determined in 6 patients with burns ranging from 12 to 50 per cent. None developed methaemoglobinaemia. Periods of increased glycolysis, decreased response to ascorbate stimulation, lowered activity of glucose-6-phosphate dehydrogenase and increased activity of methaemoglobin reductase were found in 5 out of 6 patients. Additionally, reduced glutathione was low.Timing and magnitude of these findings suggest that individuals whose pre-injury glycolytic enzyme activities are in the upper normal range develop only a subclinical state. Oxidative stresses do not lead to acute haemolysis. The theoretical significance of the findings is discussed.

Studies on Chronic Copper Poisoning: III. Effects of Copper Acetate Injected into the Blood Stream of Sheep

Studies on Chronic Copper Poisoning: III. Effects of Copper Acetate Injected into the Blood Stream of Sheep

Studies on Chronic Copper Poisoning:: II. Biochemical Studies on the Blood of Sheep during the Haemolytic Crisis

Studies on Chronic Copper Poisoning:: II. Biochemical Studies on the Blood of Sheep during the Haemolytic Crisis

Studies on Chronic Copper Poisoning: I. Toxicity of Copper Sulphate and Copper Acetate in Sheep

Studies on Chronic Copper Poisoning: I. Toxicity of Copper Sulphate and Copper Acetate in Sheep

Methaemoglobin in chronic copper poisoning of sheep.

AFTER protracted periods of high copper-intake some species of farm animals accumulate large excesses of copper in the liver, and in certain circumstances this copper can be suddenly released into the blood and the clinical entity known as chronic copper poisoning develops1–4. Sheep are particularly susceptible, and the sequence of clinical symptoms is generally : anorexia, haemolysis of red cells, haemoglobinuria, anaemia, jaundice and death. Although the build-up of copper in the liver may take place over a period of weeks or months, the ‘haemolytic crisis’ is an acute illness and death usually occurs within 2–3 days.

An experimental investigation of the hepatotoxic and other effects on sheep of consumption of Heliotropium europaeum L. : Heliotrope poisoning of sheep

Experiments were conducted in which two flocks of breeding ewes were grazed on natural pastures containing H. europaeum L. A third flock was grazed on an area on which irrigation water was used to favour germination and early growth of the plant. After the sheep had grazed the plant for the first period, a small proportion, from 1 to 7 per cent., died with damaged livers. After they had again grazed the plant during the following year, the death rate from liver disease rose to 50 per cent. in the exploratory experiment, to 38 per cent. in the first controlled flock experiment, and to 70 per cent. in the second controlled flock experiment. Haematogenous jaundice was present in approximately half the sheep that died. Haemoglobinaemia with haemoglobinuria was present, usually in a mild form, in 31 per cent. of the deaths during the second year of the first controlled experiment, and in 5 per cent. during the second year of the second controlled experiment. In the autumn and spring when the pastures were lush, many of the sheep while in good bodily condition died suddenly without being seen to be sick. Later, most of the deaths were in sheep that had lost condition. Clinical pathological examinations showed that the affected sheep commonly exhibited a fall in haemoglobin and a rise in bilirubin in the blood. Tests showed a fall in prothrombin values. There were indications of a fall in plasma albumen, and also a fall in ability to store glucose. Chemical analyses of livers collected from sheep that died showed the copper concentration to be above normal values, approximately 80 per cent. being over 1000 p.p.m. Histopathological examinations of livers showed that the pathognomonic change was an increase in size of the liver cells associated with their increased death rate and loss of regenerative powers. The changes resulted in an atrophic hepatosis with little replacement fibrosis. There was an accumulation of ceroid in the livers, and a terminal occurrence of inclusion globules in the liver cells. Related field investigations confirmed the findings of the experiments, and showed that the liver damage produced by the consumption of H. europaeum predisposed sheep to the haemolytic crisis of chronic copper poisoning.