Copper Deficiency Anemia Research Articles

Copper deficiency anemia and neutropenia secondary to total gastrectomy

Copper deficiency anemia and neutropenia secondary to total gastrectomy

Ferritin Is Not an Indicator of Available Hepatic Iron Stores in Anemia of Copper Deficiency in Rats,

Serum ferritin is a sensitive indicator of available iron stores (1), but in certain instances it cannot be used in diagnosis, e.g., in anemias of chronic disease, infections, inflammation, liver disease, and malignancies (2)(3)(4)(5)(6)(7). Iron stores may be normal or increased, though accompanied by increased serum ferritin, in anemias of chronic disorders, aplastic anemia, sideroblastic anemia, and chronic hemolytic anemia. Because ferritin is also a positive acute-phase reactant protein that is increased in inflammation (2), serum ferritin concentration is not a reliable index of available iron stores in individuals with chronic diseases. There is no information, however, on whether ferritin can be used as a marker of available iron stores in the anemia of copper deficiency. Unlike iron-deficiency anemia, in which body iron stores are usually depleted as evidenced by diminished serum ferritin concentrations, anemia of copper deficiency (8)(9)(10) results from increased hepatic iron stores and impaired mobilization and delivery of iron from storage to bone marrow for heme synthesis, leading to iron-deficient erythropoiesis (11). Can serum ferritin be utilized as a reliable tool to measure available iron stores in anemia of copper deficiency? We evaluated in experimental copper deficiency the potential usefulness of three different concentrations of dietary iron …

Evidence that dimethyl sulfoxide inhibits defects of copper deficiency by inhibition of glycation

Prior studies have indicated that dimethyl sulfoxide (DMSO), when fed to rats, can inhibit the cardiac enlargement and anemia of a concurrent dietary copper (Cu) deficiency. Because DMSO is capable of chemically destroying the hydroxyl radical, its inhibition of defects of Cu deficiency was taken as evidence that those defects resulted from oxidative stress. To examine this conclusion further, rats were fed Cu-adequate (6.4 μg/g) and -deficient (0.5 μg/g) diets and given water with or without 5% DMSO. Two additional groups of rats were pair-fed to test for the effects of reduced food intake caused by DMSO. To test for mechanism of action of DMSO, indices of lipid peroxidation and nonenzymatic glycosylation of protein (glycation) were measured. Compared to Cu-adequate rats, Cu-deficient rats were anemic and had enlarged hearts, increased serum malondialdehyde (MDA), increased heart thiobarbituric acid reactive substances (TBARS) and an enhanced percentage of glycated hemoglobin (Hb A 1). Both DMSO administration and pair feeding ameliorated the anemia of Cu deficiency; pair feeding reduced the cardiac enlargement of Cu deficiency. Neither DMSO nor pair feeding inhibited the rise in serum MDA or heart TBARS, but both caused a similar degree of inhibition of the rise in Hb A 1. Although dietary Cu deficiency is associated with an increase in products of peroxidation, the inhibition of defects by DMSO appears to be related to food restriction and inhibition of glycation.

Implication of nonenzymatic glycosylation as a mode of damage in dietary copper deficiency

The purpose of this study was to determine whether nonenzymatic glycosylation of proteins (glycation) could be implicated in the defects associated withdietary copper deficiency. Male, weanling Sprague-Dawley rats were fed for 5 weeks diets that were adequate (5 ppm) or deficient in Cu (∼0.5 ppm). Half of each group were given daily intraperitoneal injections of aminoguanidine, which inhibits glucation beyond formation of the Amadori product. Copper deficiency caused cardiac enlargement, anemia, enhanced production of thiobarbituric acid reactive substances (TBARS) in the heart and enhanced percentage of glycated hemoglobin (Hb A 1). Aminoguanidine ameliorated the cardiac enlargement and anemia but had no effect on TBARS production or hemoglobin glycation caused by copper deficiency. The enhanced percentage of Hb A 1 suggests that generalized protein glycation occurs in copper-deficient rats. The higher TBARS production in copper deficiency indicates that the peroxidation reported to be associated with glycation is occurring. The amelioration of cardiac enlargement and anemia of copper deficiency by aminoguanidine suggests that glucose-induced cross linking of proteins and their degradation into advanced glycosylation endproducts may contribute to those defects.

Copper Deficiency Anemia and Prolonged Enteral Feeding

Letters1 September 1994Copper Deficiency Anemia and Prolonged Enteral FeedingJiro Masugi, MD, Masahiko Amano, MD, and Tsuneo Fukuda, MDJiro Masugi, MDSearch for more papers by this author, Masahiko Amano, MDSearch for more papers by this author, and Tsuneo Fukuda, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-121-5-199409010-00021 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Copper deficiency is a rare disease because of the ubiquitous distribution of copper and low daily requirements. Copper deficiency has been reported in patients who receive total parenteral nutrition [1], who have the short-bowel syndrome [2], and who receive oral zinc therapy [3] and in premature infants [4]. We describe a patient who developed copper deficiency anemia after long-term enteral feeding.A 77-year-old woman was hospitalized in July 1993 because of severe macrocytic anemia. She had an erythrocyte count of 110 × 104/µL, a hemoglobin level of 4.4 g/dL, a hematocrit of 12.8%, and a mean corpuscular ...

Cystine feeding enhances defects of dietary copper deficiency by a mechanism not involving oxidative stress

Dietary cystine supplementation exacerbates the effects of dietary copper deficiency. We examined the possibilities that this exacerbation is caused by an oxidative mechanism or by an effect on copper status. Male Sprague-Dawley rats (∼ 120 g) were fed copper-adequate or copper-deficient diets (0.5 or 16 mg/kg diet) that were supplemented with combinations of l-cystine (20 g/kg diet), vitamin E (37 mg/kg diet), and sodium tungstate (360 mg/L in drinking water). Dietary copper deficiency depressed serum and organ copper concentrations; increased heart size; caused anemia; reduced heart and liver superoxide dismutase and cytochrome c oxidase activities; and increased serum, heart, and liver thiobarbituric acid reactive substances. Cystine feeding exacerbated the cardiac enlargement and anemia of copper deficiency and reduced liver cytochrome oxidase and superoxide dismutase activities, but had no effect on organ copper content. Cystine feeding had no effect on serum or heart thiobarbituric acid reactive substances but depressed liver thiobarbituric acid reactive substances production. Neither vitamin E nor tungsten, which was used to inhibit sulfite oxidase and its potential production of free radicals, had an effect on the copper- or cystine-dependent changes in heart size, hematocrit, or hemoglobin. Dietary vitamin E and tungsten had variable beneficial effects on copper- and cystine-dependent changes in variables related to red blood cell size, but these effects could not be consistently related to the inhibition of TBARS production caused by vitamin E and tungsten. We conclude that, while cystine feeding enhanced signs of copper deficiency, it did not do so by an oxidative mechanism or by altering copper status.

Anemia plays a major role in myocardial hypertrophy of copper deficiency

The present study was undertaken to establish whether anemia plays a role in the cardiomegaly and myocardial pathology of copper deficiency. Fifteen weanling male rats were fed a copper-deficient (0.6 μg Cu/g) diet for 5 weeks. Six rats were intraperitoneally injected once a week with packed red blood cells (RBC) that were obtained from copper-deficient rats fed starch. The remainder (n = 9) served as controls. The administration of RBC to copper-deficient rats fed fructose prevented the anemia. As a result, none of the injected rats exhibited heart hypertrophy or gross pathology and they all survived. In contrast, all other control, nontreated copper-deficient rats that were fed fructose were anemic and all exhibited severe signs of copper deficiency, which included heart hypertrophy with gross pathology, and four died of the deficiency. The data suggest that the anemia of copper deficiency contributes to heart pathology. Once the anemia is prevented, the copper-deficient rats should be protected against heart pathology and mortality.

Copper deficiency anemia: altered red blood cell lipids and viscosity in rats

To investigate membrane lipid abnormalities and their possible role in copper deficiency anemia, we studied lipids, osmotic fragility, and viscosity of red blood cells (RBCs) of rats fed diets containing 1.1 mg Cu/kg (deficient, Cu-) and 6.0 mg Cu/kg (supplemented, Cu+) at age 3 wk for 9 wk. Data show an increase in cholesterol of 43% and in phospholipids of 38% per cell in Cu- compared with Cu+ rats. Thin-layer chromatography of RBC lipids showed an increased amount of phospholipid-malonyldialdehyde adduct in Cu- (0.70 +/- 0.35% [means +/- SD] of total phospholipids) compared with Cu+ (0.29 +/- 0.19%) rats, suggesting increased membrane lipid peroxidation in Cu- RBC. Osmotic fragility of RBCs from Cu- rats was lower. RBC viscosity was significantly higher in Cu- than in Cu+ rats at shear rates of 23, 11.5, and 5.75 shear/s and was similar at shear rates 115 and 46 shear/s. Increased cell viscosity caused by lipid loading and crosslinking of membrane components caused by lipid peroxidation may have a role in the reduced RBC survival and anemia in Cu deficiency.

Dietary copper deficiency and autoimmunity in the NZB mouse

NZB mice were exposed from birth to a diet either adequate or deficient in copper. By age 6 wk the mice exposed to the copper-deficient diet showed symptoms characteristic of copper deficiency (anemia, hypoceruloplasminemia, and achromatrichia). The splenic lymphocytes from the copper-deficient group had reduced numbers of cells expressing the following surface markers: Ly-5, Ly-1, B-220, and sIg. Less than 10% of the splenic lymphocytes in this group were cycling, as determined by flow cytometry analysis. The spontaneous 96-h anti-ss-DNA levels in the copper-deficient group were lower than those in the control group. The exogenous colony-forming units (CFUs) were significantly enhanced in the copper-deficient mice. The decreased splenic lymphoid populations, decreased anti-ss-DNA titers, and increased exogenous CFUs in the copper-deficient mice appear to be due to an increase in erythropoiesis at the expense of lymphopoiesis.

Effects of Varying Dietary Iron on the Expression of Copper Deficiency in the Growing Rat: Anemia, Ferroxidase I and II, Tissue Trace Elements, Ascorbic Acid, and Xanthine Dehydrogenase

The effect of dietary iron on the development of copper-deficiency anemia in the growing rat was investigated. For up to 80 d, female rats (75 g) were fed purified diets containing adequate, marginal or low levels of iron, and either 0.7 or 10 ppm copper. Hemoglobin levels and factors postulated to affect liver iron mobilization, including ferroxidase (Fox) I and II, ascorbate and liver xanthine dehydrogenase (XDH) were assayed. By d 7, Fox I activity in the copper-deficient groups was 10% that of the copper-sufficient groups; thereafter, Fox I activity remained low, and was not affected by dietary iron. Fox II activity in the copper-deficient groups after d 28 was 50–75% of values from rats adequate in copper. On d 49, hemoglobin levels in the copper-deficient groups were lower than in the copper-sufficient groups fed low and marginal levels of iron, but were similar to those fed adequate iron. Liver iron was similar in both groups fed adequate iron, but was higher in the copper-deficient than in the copper-sufficient rats fed low or marginal levels of iron. Copper deficiency tended to result in slightly lower ascorbate levels on d 80 at all levels of iron. Liver XDH activity tended to be lower in the copper-deficient groups than in the copper-sufficient groups on d 28 and 49. These results show that copper deficiency may impair liver iron mobilization in the growing rat if dietary iron is low. Possible mechanisms include decreased Fox activity and/or decreased iron reduction by ascorbate or XDH.

A patient with copper deficiency anemia while on prolonged intravenous feeding: G. Joffe, A. Etzioni, J. Levy, et al. Clin Pediatr 20:226–228, (March), 1981

A patient with copper deficiency anemia while on prolonged intravenous feeding: G. Joffe, A. Etzioni, J. Levy, et al. Clin Pediatr 20:226–228, (March), 1981

Anemia of Lead Intoxication: A Role for Copper

Lead-induced anemia in rats, which is of a microcytic, hypochromic type, has been shown to be a result of an interference with the metabolism of copper and iron. In this complex interaction, copper may be the target upon which ingested lead has its antagonistic effect on hematopoiesis. The depressions in hematocrit and hemoglobin levels resulting from exposure to lead may occur secondarily to the effects of a lead-induced copper deficiency on iron mobilization and utilization. The metabolic fault induced by lead is seen in a reduction of serum iron, elevation of serum iron binding capacity, and increase in liver iron, all manifestations of systemic effects related to an interference with copper metabolism. These results relate many of the characteristics of the lead-induced anemia to those found in the copper-deficiency anemia.

Observations on the anemia and neutropenia of human copper deficiency

Following extensive bowel resection, a young woman experienced severe malnutrition; subsequent administration of parenteral nutrition precipitated the copper deficiency syndrome. This consisted of hypocupremia, subnormal ceruloplasmin levels, anemia, and severe neutropenia. The bone marrow was megaloblastic, vacuolated, and sideroblastic; granulocytic maturation was not observed beyond the myelocyte stage. Copper sulfate therapy was followed by a marked reticulocytosis, increase in hematocrit, and recovery of neutrophils. Additional studies indicated that both serum and urinary erythropoietin values were low; serum activity increased after copper supplementation. Abnormal granulopoiesis was demonstrated using the in vitro granulocyte colony assay. The patient's granulcoytic stem cells were normal on two occasions; however, mixing studies showed that culture of the patient's copper-deficient marrow with her copper-deficient serum yielded significantly reduced numbers of granulocyte colonies. Thus, copper appears to be a necessary element for normal hematopoiesis; lack of this trace element may result in ineffective erythropoiesis and granulopoiesis.

Heme biosynthesis in copper deficient swine.

SummaryThe steps in the heme biosynthetic pathway were evaluated in normal and in copper deficient swine. As anemia developed, the activity of heme biosynthetic enzymes increased. These data suggest that the anemia of copper deficiency is not the result of defective heme biosynthesis and, therefore, that copper is not a cofactor in any of the reactions studied. Since the morphologic characteristics of the anemia of copper deficiency suggest defective hemoglobin synthesis, it is concluded that copper is essential either for the normal metabolism of iron or for the synthesis of globin.

Studies on the Requirements and Interaction of Copper and Iron in Broad Breasted Bronze Turkeys to 4 Weeks of Age ,

Abstract IRON and copper have been recognized as essential trace elements for poultry for a number of years. Many important functions which these elements perform in metabolism have been determined. However, we have been unable to find published data concerning the turkey’s requirements for copper and iron. Hart et al. (1925, 1928) and Elvehjem and Hart (1929) reported that copper acts as a cofactor or supplement to iron in hemoglobin synthesis in chicks and rats. Gallapher (1957) was unable to produce a pure copper-deficiency anemia in chicks. Hill and Matrone (1961), on the other hand, conducted studies in which copper deficiency and/or iron deficiency anemias were produced in the chick. With a copper deficiency they observed a decrease in the number of erythrocytes, decreased feather pigmentation and reduced heart cytochrome oxidase activity. A deficiency of iron decreased the hemoglobin content of erythrocytes and decreased feather pigmentation only slightly. Hill and Matrone…

Studies on copper metabolism. XIX. The kinetics of iron metabolism and erythrocyte life-span in copper-deficient swine.

Ferrokinetic studies were performed in three copper-deficient swine and the results have been compared with similar studies in 18 normal pigs. The mean value for the plasma iron turnover rate in the deficient swine was 1.76 mg./kg. day; for the red cell iron incorporation rate, 1.24 mg./kg. day; for the red cell iron turnover rate, 1.18 mg./kg. day; for the red cell life span, 13 days. Corresponding figures in the normal swine were 1.11 mg./kg. day, 1.01 mg./kg. day, 0.59 mg./kg. day and 63 days, respectively. The red cell life span was measured by the use of radioactive chromium in a total of 26 pigs. The mean erythrocyte half-life of normal cells transfused into normal pigs was 17 days. The mean half-life of erythrocytes from copperdeficient swine transfused into copper-deficient swine was 9 days. The mean half-life of red cells from control animals transfused into copper-deficient swine was 16 days while that of erythrocytes from copper-deficient swine transfused into normal pigs, was 13 days. The mean half-life of cells from iron-deficient pigs transfused into iron-deficient pigs was 19 days. It is concluded that copper deficiency anemia results from both a shortened erythrocyte survival time and limited capacity of the bone marrow to produce red cells. It is suggested that copper is an essential component of erythrocytes in swine.

Studies on Copper Metabolism XVII. Further Observations on the Anemia of Copper Deficiency in Swine

Abstract 1. The morphology of the erythrocytes has been studied in 22 normal swine, 65 swine deficient in copper, and 16 swine deficient in iron. The mean values (± the standard deviation) for the volumes of packed red cells in the three groups were 42 ± 2.5, 21 ± 6.6, and 21 ± 6.1 ml/100 ml., respectively. The mean values for the mean corpuscular volumes were 55 ± 3.1, 43 ± 7.1, and 36 ± 5.3, respectively. The mean values for the mean corpuscular hemoglobin concentrations were 33 ± 1.1, 29 ± 2.3, and 28 ± 3.0, respectively. 2. The addition of 11 water-soluble B vitamins, 4 fat-soluble vitamins, ascorbic acid, and minerals (with the exception of copper) to the copper-deficient milk diet did not prevent or delay the development of anemia, modify the morphology of the red cells or alter the degree of hypoferremia. 3. The normoblasts in the marrow of a copper-deficient pig were similar morphologically to those in the marrow of a pig deficient in iron. 4. The intravenous administration of one Gm. of iron, given prior to the development of copper-deficiency, did not delay or prevent the development of anemia. 5. It is concluded that the anemia of copper-deficiency in swine is morphologically similar to the anemia due to iron deficiency in swine.