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Copper Deficiency in Humans
This is not a brief review, I suggest that you read it completely for all the details. Here are some interesting parts from it:
This is not a brief review, I suggest that you read it completely for all the details. Here are some interesting parts from it:
- "The importance of reductions in the activity of cytochrome oxidase in causing the manifestations of Cu deficiency has probably been underestimated. Many authors have suggested that the reduction to 50% of normal activity seen in Cu deficiency is unlikely to cause disease (e.g. 85)."
- "Maintaining a steady level of copper in the body of a healthy subject depends primarily upon a balance between intestinal absorption and biliary excretion, with small additional losses in sweat and by the desquamation of skin. Biliary excretion is capable of increasing substantially when there is copper overload."
- "Metallothionein is involved in the important mechanism by which excessive zinc (Zn) intake can block Cu absorption (32). Zinc is a stronger inducer of metallothionein production than Cu, yet Cu can displace Zn from metallothionein (5). Large doses of Zn can trap Cu in the intestinal mucosal cells bound to metallothionein until the mucosal cells are shed."
- "The conventional view has been that Cu is taken up by the liver, incorporated into ceruloplasmin, and carried by it to other tissues. However, this process cannot explain the high proportion of orally administered 64Cu found in nonhepatic tissues in the first hours after oral administration (52)."
- "Ceruloplasmin is an important Cu protein. It is a large glycoprotein containing six atoms of Cu per molecule, has an oxidase activity against many substrates (10, 13, 31), and contributes approximately 90% of the Cu present in plasma. Consequently, measurement of plasma Cu is effectively measurement of ceruloplasmin."
- "Anemia and neutropenia are seen in all animal species and in nutritional Cu deficiency in humans. Lack of the ferroxidase activity of ceruloplasmin and consequent failure of release of iron from tissue stores has been blamed for the anemia (28), but this is unlikely to be the complete explanation (70, 71). Patients with Wilson disease or Menkes disease may have very little ceruloplasmin, yet they do not develop anemia or neutropenia (16) nor do brindled mice (7, 71). Severe reduction of cytochrome oxidase and superoxide dismutase has been shown in bone marrow of Cu-deficient mice, but not in brindled mice (71). This might explain both the anemia and the neutropenia. Reduction of erythropoietin has been described in rats (105)."
- "Osteoporosis is another feature seen in all species. It is probably the consequence of inadequate cross-linking of collagen caused by lysyl oxidase deficiency. Lysyl oxidase deficiency also leaves elastin inadequately crosslinked (and therefore more soluble than normal when tissues are studied in the laboratory), a defect that is responsible for the aortic rupture and emphysema seen in several species (8, 35, 62)."
- "Myocardial disease due to Cu deficiency was first noted as a cause of sudden death ("falling disease") in cattle in Western Australia in the late 1930s and has also been seen in sheep (96). Myocardium is generally hypertrophied, but may become dilated and thin, and may even rupture. Fibrosis is found diffusely through the hypertrophied muscle with a distribution quite different from that seen in ischemic heart disease seen in humans."
- "The type of myocardial disease seen in these various animals seems to have much more in common with the cardiomyopathy seen in cytochrome oxidase deficiency in humans (21) than with human ischemic heart disease. Lysyl oxidase deficiency and dopamine-f3-hydroxylase deficiency may also be playing a part."
- "Neuronal loss is marked in the cerebellum and spinal tracts with extensive demyelination (84, 85, 96)."
- "Claims of a specific role of copper in myelination have become entrenched in articles on copper, but there is little evidence of a specific role (72). This claim began because myelin deficiency is so marked in swayback, but this condition has the features of demyelination, not defective synthesis, and the distribution of lesions corresponds with the distribution of neuronal loss (72, 83-85)."
- "Interference with cross-linking of elastin and collagen can be blamed for many of the features of the [Menkes] disease (16)--premature rupture of the membranes leading to premature birth, lax skin and joints, elongation and dilatation of major arteries leading to rupture and hemorrhage, subintimal thickening with partial occlusion of major arteries, hernias, and diverticulae of bladder and ureters causing recurrent infection or rupture. Osteoporosis, flaring of metaphyses, fractures of metaphyseal edges, and Wormian bones in cranial sutures may all be secondary to collagen abnormalities."
- "Lack of pigmentation of skin and hair and abnormal spiral twisting (pili torti) and fragility of the hair add to the characteristic appearance of the affected babies (19). Disulfide bonding of keratin is defective as in Cudeficient sheep (20)."
- "The fine hair and depigmentation observed in Peruvian children with Cu deficiency (30) is difficult to interpret because these features are also described in kwashiorkor and the children were grossly malnourished. One cannot tell whether protein-caloric deficiency was causing these effects in the Peruvian children or whether Cu deficiency could be involved in causing these features in many cases of severe malnutrition."
- "Chronic diarrhea may have been important in the Cu deficiency observed in Peruvian children (10, 30)."
- "Oral administration of Zn has also caused Cu deficiency in humans. The mechanism was discussed above. In some patients, the Zn was given for specific reasons in sickle cell anemia (68) or in delayed wound healing. A current vogue of liberally prescribing Zn supplements (with or without multivitamin preparations) by some practitioners of alternative forms of medicine is a serious concern. The practice often follows analysis of trace element levels in hair and/or fingernails of patients with various symptoms and sufficient money to pay for the procedures. The interpretation of these results is difficult and generally of dubious validity (see below). Some people buy vitamins and Zn across the counter of "health food" shops and consume large quantities in the belief that they are harmless and good for health. This practice should be discouraged."
- "[In severe deficiency,] Serum Cu and ceruloplasmin levels are reduced to a degree that leaves no doubt, e.g. to 30% of the normal level."
- The authors suggest that everything that happens in severe deficiency, can help diagnose mild chronic deficiency when those symptoms still occur (but in a milder form) and are not responsive to other (more direct) treatments.
- "If ceruloplasmin does really transport Cu to connective tissues, then the estrogen/Cu interaction may be relevant since serum ceruloplasmin levels are partly determined by estrogen levels (31)."
- "Arthritis is another common condition in which Cu status may be relevant. Collagen and elastin are important in cartilage so Cu must be necessary. One might anticipate a role in osteoarthritis rather than in rheumatoid arthritis or other joint disorders of early onset. Copper has been used in arthritis for many years without any scientific basis. Many arthritis sufferers wear Cu bracelets. Advocates of the copper/arthritis connection have pointed out that Cu is absorbed transdermally from metallic Cu and some have advocated dermal application of organic Cu complexes such as Cu aspirinate for the treatment of arthritis (87). The same workers have argued that the beneficial effects of penicillamine in rheumatoid arthritis might be the result of a redistribution of Cu between tissues."
- "The exaggerated claims of these proponents should not deter others from taking seriously the possibility of a causative association. Careful studies are needed in a large group of patients once good methods' of assessing Cu status have been developed."
- "The principal abnormality in the arterial walls in Cu deficiency is in elastin, with great increases in soluble elastin and reduction in cross-linked mature fibrils (8, 62). Consequently one might expect the impact of the disorder to be maximal in the aorta and large arteries, with less effect on smaller vessels, which have more smooth muscle in their walls."
- "Myocardial disease has not been firmly related to Cu deficiency in humans, although it clearly does occur in animals (see above). The myocardial changes observed in Cu-deficient animals are quite different from those of ischemic heart disease in humans. This has not deterred Klevay (45) from promoting very strongly his "zinc-copper hypothesis" of ischemic heart disease ever since 1973."
- "Mere avoidance of deficiency does not guarantee good nutrition. This may require the supply of enough plus a little to spare."
- "The liver plays a special role in Cu homeostasis as the organ through which most Cu is excreted from the body and the organ taking up the largest part of Cu after its absorption from the intestine. Liver Cu levels fall more rapidly than the levels of Cu in other organs during Cu deficiency, which suggests that part of the Cu in the liver is available as a store for other organs."
- "Ceruloplasmin is an acute-phase responsive protein. Consequently, levels are altered by a variety of intercurrent factors. Its production is stimulated by estrogens (31). Levels are higher in adult females than males, vary during the menstrual cycle, and are greatly elevated during pregnancy (31)."
- "Poorly cross-linked collagen is broken down more rapidly than normal collagen. Some of the breakdown products of collagen are unique (e.g. hydroxylysine) and can be measured in urine. Quantitation of these compounds may provide a useful indicator of Cu deficiency."
- "Information available about adult human Cu requirements has been reviewed repeatedly (58, 78, 102). Many balance studies in healthy adults have shown losses of 1.5-2.0 mg per day, mostly in the stools. Therefore intakes of at least 2.0 mg per day have been recommended. A number of nutritional surveys have shown intakes of less than 1.0 mg, which suggests that mild Cu deficiency is very common, or else the requirement stated is overly generous for most people (78)."
- "Foods with high copper content include animal livers and shellfish, but the principal contributors in an average diet are potatoes, fruit, bread, meats, fish, and legumes (78). Cow's milk and dairy products contain little Cu and that present is poorly absorbable, apparently because it is bound to casein (11). Although the Cu content in human milk is only a little higher than that of cow's milk, the Cu present is well absorbed, most of it being found in the whey (11)."
- "There is clearly a complex interrelationship between the intake of Cu, of Zn, and the growth rate: a high growth rate or high Zn intake increased the requirement for Cu."
- "Protein and dietary fiber content appear to diminish the availability of Cu (78). High dietary intake of ascorbic acid has also been shown to lower serum ceruloplasmin and Cu levels (27). A number of studies have examined the interrelationship between fructose and Cu status. The consensus is that fructose increases the requirement for Cu, rather than interfering with its absorption. Red cell superoxide dismutase activity was significantly reduced by the high fructose intake, whereas ceruloplasmin levels and serum Cu were not decreased (76)."
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