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Copper in Parenteral Nutrition
GASTROENTEROLOGY 2009;137:S13–S17
Copper in Parenteral Nutrition MOSHE SHIKE Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York
Copper is an essential nutrient for humans. Copper is a component of numerous enzymes that affect a wide variety of metabolic processes. Copper deficiency can result in anemia, neutropenia, skeletal abnormalities, and other clinical manifestations. There is no wellestablished laboratory measurement of body copper status. Copper supplementation is essential in parenteral nutrition to prevent an adverse effect of deficiency. Balance studies indicate that copper requirements in total parenteral nutrition amount to 0.3 mg/day in the adult. For children and infants, the estimated requirement is 20 g/kg body wt/day. These amounts may have to be decreased in patients with cholestasis.
T
he copper content in the adult human body is estimated to range between 50 and 120 mg.1 Copper is found in high concentrations in liver, brain, and, to a lesser degree, in kidney, heart, and pancreas.2 The term neonate has significant hepatic copper stores that are gained during the third trimester of pregnancy. In the newborn, the liver has a high concentration of copper, about 6 –10 times that of an adult.2 However, it is important to note that circulating copper levels may be low during the first 3 postnatal months, mostly due to low synthesis of ceruloplasmin. More than 90% of copper in the blood is bound to ceruloplasmin. The rest is bound to albumin and amino acids. It is not present in blood in ionic form because of its poor solubility. Copper is absorbed mostly in the small intestines and to a lesser degree in the stomach. The average copper intake from the diet in the United States is 1–1.6 mg according to the Third National Health and Nutrition Survey,3 less than previous estimates of 3–5 mg.2 The estimated average requirements amount to 0.70 mg for an average adult and between 0.26 and 0.68 mg in different stages of childhood.1 Copper is found in high quantities in shellfish, nuts, liver, and legumes.1 The fractional absorption from the gastrointestinal tract is regulated to maintain homeostasis. Most copper excretion and loss is through the bile, but small amounts are also excreted through urine, sweat, and menstrual blood.2 Once absorbed through the enterocytes, copper is transported to the liver bound by albumin or transcuprein. In the liver, it is incorporated into ceruloplasmin. Copper is released from the liver into the blood bound to
ceruloplasmin and is delivered in this form to the peripheral tissues. Ceruloplasmin binds to its receptors on the cell surface; the copper is released from its binding protein and enters the cell.
Copper Biochemical and Physiologic Functions Copper is an essential nutrient in animal and human physiology. In biological systems, it is found most frequently as Cu2⫹. Copper is a part of numerous proteins with a wide range of activities. The following enzymes are among those that include copper as an essential constituent. 1. Ferroxidases (including ceruloplasmin), which catalyze the oxidation of ferrous iron in the process of transferring iron from storage sites to bone marrow for hemoglobin synthesis. Reduced activity results in anemia, which appears like iron deficiency. 2. Lysyl oxidase participates in cross-linking of collagen and elastin in connective tissues. Deficiency results in bone formation abnormalities and defects in connective tissues and blood vessels. 3. Dopamine -hydroxylase catalyzes the conversion of dopamine to norepinephrine in the brain. Deficiency causes neurologic abnormalities. 4. Copper/zinc superoxide dismutase functions as a free radicals scavenger; copper deficiency is associated with oxidative damage. 5. Monoamine oxidase is essential for serotonin synthesis. 6. Tyrosinase participates in melanin synthesis. Deficiency results in hypopigmentation.
Copper Deficiency and Toxicity in Humans Assessment of Copper Status In severe copper deficiency, serum copper and ceruloplasmin levels are low and reflect the copper status of the body. However, in marginal deficiency, these parameters are usually normal and do not reflect the copper status of the body. Furthermore, ceruloplasmin is an Abbreviation used in this paper: PN, parenteral nutrition. © 2009 by the AGA Institute 0016-5085/09/$36.00 doi:10.1053/j.gastro.2009.08.017
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acute phase reactant; in the presence of inflammatory processes, its levels as well as those of copper may be elevated, even in the presence of marginal copper deficiency.1,2 Copper levels in hair, nails, and saliva have been proposed as indices of copper status but were found to be unreliable. Cytochrome oxidase and superoxide dismutase in red blood cells have been considered as potential measures of copper adequacy, but they have not been studied vigorously.1
Manifestations of Copper Deficiency Copper deficiency is rare in humans. It has been reported in patients with prolonged severe malabsorption, premature infants, children recovering from severe malnutrition, and patients receiving parenteral nutrition (PN) without copper supplementation. Manifestations of copper deficiency include anemia (often hypochromic, microcytic), leukopenia, and a variety of bone abnormalities, including osteoporosis, new subperiosteal bone formation, and fibrosis of epiphysis. It has been suggested, but not well proven, that prolonged marginal copper deficiency can result in cardiac diseases, arthritis, loss of hair pigmentation,4 and neurologic abnormalities, mimicking vitamin B12 deficiency.5 Menkes disease is a rare fatal X-linked disorder in which copper accumulates in intestinal mucosa and is not transported to other sites. This leads to copper deficiency in the liver and other tissues. The serum copper and ceruloplasmin levels are low. The disease is manifested as defective arteries, degeneration of brain cells, severe mental retardation, and death. The anemia and neutropenia seen in nutritional copper deficiency do not occur in Menkes disease.2
Manifestations of Copper Toxicity Acute copper toxicity is rare in humans and occurs mostly from consumption of beverages stored in copper vessels or from consumption of contaminated water. Acute copper toxicity results in abdominal pain, liver and kidney failure, and death. Chronic copper toxicity is illustrated in Wilson’s disease, an inborn error of copper metabolism characterized by high levels of copper in liver, brain, kidney, and other organs. The serum copper levels are usually low, as are the ceruloplasmin levels. The disease is manifested as cirrhosis of the liver, a variety of neurologic disorders, and renal damage.2 In idiopathic copper toxicosis, which mostly manifests as cirrhosis of the liver, a high dietary copper level appears to play a role in addition to an inherited disposition.
Copper in Total PN Copper Deficiency in Recipients of Total PN Copper deficiency in patients receiving PN is rare and has been reported only after prolonged dependence on PN without copper supplementation. These features
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of copper deficiency may be due to a number of factors, including availability of copper body stores before beginning PN, contamination of various PN components with copper, and absorption from oral intake of copper-containing food. PN-associated copper deficiency reports are limited to single patients, primarily because of the rarity of this problem, and include the following. 1. An infant with short-bowel syndrome developed anemia, neutropenia, and bone abnormalities after 8.5 months on PN without copper. The abnormalities were corrected with copper supplementation.6 2. An adult with long-standing scleroderma with severe malabsorption developed neutropenia and hypocellular bone marrow after 6 months of PN without copper supplementation. This was corrected by the addition of copper to the PN solutions.7 3. A female patient with short-bowel syndrome developed cholestasis after 6 months of PN with copper supplementation. Copper was discontinued, and 15 months later the patient developed anemia, neutropenia, and thrombocytopenia with a low serum copper level. Two months of copper supplementation in PN resulted in normalization of the serum copper level and correction of all the hematologic abnormalities.8 Hurowitz et al reported on 4 pediatric patients who had their PN copper omitted after developing cholestasis.9 Manifestations of copper deficiency were seen in these patients, including low serum copper level, anemia, neutropenia, and hypopigmentation. Bone abnormalities were reported in 2 infants receiving PN without copper for a few months.10 The abnormalities were similar to those seen in scurvy and included fibrosis of the epiphyses, subperiosteal new bone formation, and osteoporosis. It appears from these case reports that the time of onset of copper deficiency in recipients of PN without copper varies but is not immediate. It is also clear that copper supplementation is essential. PN solutions may contain various amounts of copper present inadvertently11,12; however, the occurrence of copper deficiency indicates that these amounts are inadequate and cannot be relied on to provide the needed quantities. Although copper losses in patients with cholestasis may be decreased because of decline in excretion through the biliary tract, it does not necessarily follow that all copper supplementation should be stopped. These cases show that even in the presence of cholestasis, copper deficiency can develop in patients maintained on home PN without copper supplementation.
Copper Supplementation in PN The first guidelines for copper supplementation in PN were formulated by an American Medical Association expert committee.13 The recommendations were based on oral intake, gastrointestinal absorption, and
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general physiologic considerations because at the time there were no specific data on appropriate copper doses for patients receiving PN. A wide range of supplementation between 0.5 and 1.5 mg/day was suggested for adults and 20 g/kg/day was suggested for pediatric patients.13 Subsequently, detailed balance studies in adults receiving PN in the hospital and kept “nothing by mouth” indicated that the average optimal daily copper supplementation in PN solutions amounted to 0.3 mg/day.11 These studies were performed over a 3-week period, and during each week patients received PN solutions supplemented with copper with one of 3 doses: 0.25, 1.05, and 1.85 mg/day. It was found that patients with cholestasis (defined as elevation of the alkaline phosphatase level) had decreased copper excretion through the gastrointestinal tract and tended to retain copper excessively. In these patients, a smaller amount of infused copper averaging 0.15 mg/day appeared to be the right dose. Patients with diarrhea had increased copper losses and required on average 0.4 – 0.5 mg/day to maintain balance. The serum copper level did not correlate with copper balance and thus does not appear to be a reliable marker of needs for copper supplementation. Excess copper supplementation in PN solutions may accumulate in the liver and other tissues and can potentially cause damage. A recent autopsy study of 8 patients who received home PN for an average duration of 14 years with a copper supplementation amounting to 1.4 mg/day14 showed that the copper content of liver and kidney tissues was very high compared with healthy controls. The levels were particularly high in those with liver failure. The role of cholestasis in inducing copper retention in the liver was underscored in a study by Blaszyk et al, who found that PN recipients with significant cholestasis tended to have high liver copper content, often exceeding the threshold of Wilson’s disease.15 The amount of liver copper did not correlate with the serum copper levels. Subsequent guidelines for copper supplementation in adult PN solutions adopted the findings of the balance studies mentioned previously.11 The expert committee of the American Society for Parenteral and Enteral Nutrition recommended a daily dose of 0.3– 0.5 mg/day for adults.16 There have not been specific balance studies in the pediatric group. The expert committee of the American Society for Clinical Nutrition recommended 20 g/kg/day for preterm and term infants.17 Based on the available literature, copper supplementation should be prescribed for patients receiving PN at a dosage of 0.3 mg/day, with a smaller dosage in patients with liver disease and a larger dosage in those with excessive prolonged gastrointestinal fluid losses. For infants and children, a weight-based dose should be prescribed (20 g/kg/day).
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Clinical Recommendations ●
Copper should be routinely prescribed to patients receiving PN.
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The usual dosage of copper in PN is 0.3 mg/day for adults and 20 g/kg/day for pediatric patients (not to exceed 0.3 mg/day).
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Patients with liver disease should receive a reduced dosage of 0.15 mg/day.
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Patients with persistent diarrhea or gastrointestinal fluid losses should receive between 0.4 and 0.5 mg/ day.
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Copper requirements (as those of other nutrients) should be periodically reassessed and corrections made as needed.
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Serum copper and ceruloplasmin levels should not be used as the sole indicators of copper requirements (the clinical circumstances should be a part of the assessment).
Research Priorities ●
Indices of assessment copper status, preferably in blood or plasma.
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A better understanding of the relationship between liver disease and copper requirements.
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Determination of the amount of copper contamination present in components of PN solutions.
Question and Answer Session DR KELLY: I would like to clarify some of the information on the Mayo study. These are people who had liver biopsies because they had evidence of liver disease, and I believe the level of intake was about 800 g/day of copper. DR PIRONI: In patients on long-term PN, is assessment of trace metals in hair a useful technique? DR SHIKE: Hair copper is not a reliable marker of copper nutriture. First of all, everybody uses hair shampoos and hair shampoos contain a lot of copper. There have been numerous studies that have shown that hair copper is not a good marker. For instance, in anorexia nervosa, there can be very high copper levels in hair, and there are single reports in the literature of patients with copper deficiency with a normal hair copper level. I do not think it is a reliable marker or easy to perform. DR FORBES: This is a continuation of the same question. I enjoyed the talk and the presentation, and I agree with your final discussion point, but what are you suggesting we use other than serum copper and ceruloplasmin for the assessment of copper? DR SHIKE: As Dr Jeejeebhoy indicated, I think we should look at the patient as a whole using the modest
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knowledge that we have. If the patient does not have excessive gastrointestinal losses, I think a 0.3-mg daily dose of copper based on the balance studies that we have conducted is a reasonable amount, knowing that we may be somewhat off because of what Dr Howard mentioned earlier: the amount of copper that is absorbed from the diet and the amount of copper that is present as a contaminant in the PN solution. Of course we must follow the liver function tests of the patient and the blood count. If liver function is deteriorating, we recommend reducing the PN copper level by 50%. If there is an indication of leukopenia and microcytic hypochromic anemia, it should make you scratch your head and rethink whether the amount of copper being given is adequate. However, we really don’t have one single laboratory measure to make our lives easy. DR SHULMAN: The recommendation for the pediatric patient, I think, is reasonable. We did some balance studies for copper several years ago, and the numbers you gave are pretty close to what we found. A basic issue is patients with liver disease; you recommend reduction of daily copper by 50%, and I have heard many different recommendations in that regard. Our concern is for small preterm babies, who have a greater risk of liver disease and a greater likelihood of copper deficiency. Are there any data about what the actual reduction should be rather than just people’s gestalt of what it should be? DR SHIKE: No. I found in the literature, and you know these data far better than I do, that newborns have quite a high content of copper in the liver, higher than the adult per gram of dry liver tissue. If the newborn develops rapid onset of liver disease, I would be reluctant to give generous amounts of copper. Of course, more research is needed. DR SHENKIN: Thank you for a very interesting talk, and I agree by and large with the conclusions that you have made. I would like to comment on the level of copper intake and the question of how toxic is copper in overdosage. I am thinking of our European experience, where the trace elements preparations most available for supplementation provide about 1.1 mg/day of copper, and these have been used widely for the best part of 20 years. In addition, there are the autopsy tissue studies, giving 1.4 mg/day of copper, in which 4 of the 8 patients who had been fed intravenously for between 2 and 20 years had liver copper levels comfortably within the normal range. The patients with extremely high levels were, of course, those with liver disease. I am just wondering if we need to be so concerned about a small amount of extra copper. These higher doses seem to be managed perfectly well as long as liver function is okay. DR SHIKE: I would say that based on our current knowledge, modest as it is, 1.1 mg of copper is an excessive amount given over a long period, particularly because a lot of patients on home PN have some degree of cholestasis, with elevation of alkaline phosphatase and
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hepatic transaminase levels. I think, based on our current knowledge, that we should go down to 0.3 mg/day. I think 1.1 mg/day is excessive. DR SHENKIN: I’m not saying it’s not excessive. I’m just wondering what are the side effects of having chronic marginal excess copper levels. We don’t appear to have case reports in the literature of copper toxicity during PN over a long period inducing the neurologic and psychiatric manifestations seen in Wilson’s disease. DR SHIKE: One could infer from patients with Wilson’s disease that as copper accumulates in the liver it precipitates cirrhosis. Based on the study from the Mayo Clinic, in which a good number of patients had high levels of hepatic copper in the range of that seen in Wilson’s disease, it is only plausible to conclude that the presence of a very high copper level in the liver can indeed damage the liver. Based on all of this, I think we should be careful. If PN is given for only a few weeks in the hospital, I don’t sweat it. However, in the long-term patient, because they are already prone to develop liver disease from numerous other causes, it is imperative to be very careful and very thoughtful about the amount of copper we give. DR BORUM: I would like to turn the attention back to the neonate and particularly to the very preterm neonate: the 24- to 26-week-old neonate who is in the neonatal intensive care unit. A subset will have necrotizing enterocolitis or something else that will send them home on PN. What kind of data do we have to guide us in giving copper to these small individuals? DR SHIKE: I am really not aware of any more data than I provided. As I said, earlier newborns have a good amount of copper in the liver. If it is foreseen that the newborn is going to be on home PN for the next 2 years, based on the few case reports available in the literature, I think it is reasonable to give small amounts of copper using the guideline of 20 g/kg/day. If there is liver disease, I think it should be half of that amount, but that is kind of a guess. DR BERGER: Thanks for a great presentation. There is one point I would like to make about acute deficiencies. There is one condition that has been associated with severe copper deficiency, and that is major burns. There are papers published in the 1970s from Zurich describing children with acute copper deficiency with major burns. In some of these case reports, copper deficiency in major burns appeared to contribute to death. Conducting balance studies, we were able to show that burn patients with 30% body surface affected were losing 30 to 40 mg of copper in 1 week. We have conducted prospective randomized supplementation trials showing that by giving 4 mg of copper intravenously per day for the period when the wounds were open, we were able to restore both copper and ceruloplasmin levels. Here is a condition with proven high losses, not on PN because burn patients are enterally fed most of the time, but receiving intravenous
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supplements in the range of 4 mg/day of copper that appears not only safe but is associated with restored neutrophil activity and improved wound healing. You showed that elastin and collagen synthesis are highly dependent on copper. So again, there are different types of patients and what you have been recommending for home PN individuals clearly applies, but there are conditions with much higher requirements. DR SHIKE: I think these are fascinating numbers that you are giving because 30 mg/wk is a huge amount. I assume you measured it in secretions from wounds? DR BERGER: In exudates, yes. It is a balance study, which was conducted in many patients and repeated many times. All the data were analyzed in triplicate along with zinc and selenium losses. DR SHIKE: Just a word of caution about giving large doses of copper intravenously; as you know, in Wilson’s disease there are sometimes crises provoked by excessive release of copper into the bloodstream that induce severe hemolytic anemias. I don’t know if the amount you gave could cause such a crises, but just a word of caution. DR BERGER: We have been delivering the copper as copper gluconate and not copper sulfate. We have been giving these intravenous supplements since 1988 in all our burn patients. Another point I want to raise briefly: shouldn’t we ask industry to address the quantities delivered in the PN solution components as contaminants? Shouldn’t this information be provided on PN bags? ANONYMOUS: I think for people taking care of patients at home, what we would like to know is what dose of trace elements is recommended and what modifications are appropriate if liver dysfunction develops. DR SHIKE: I believe the task of this session is to make some recommendations for the infusion industry. In my mind, it is clear that we should have available the separate trace elements so we can modify what we give when metabolic changes develop. The various trace elements have completely different functions in human metabolism, and we need to have the ability to adjust the amount we are giving to each patient without having the burden of altering the other trace elements. I personally favor a separate solution for each trace element. References 1. Turnland JR. Copper. In: Shils M, Shike M, Ross AC, et al, eds. Modern nutrition in health and disease. 10th ed. Philadelphia, PA: Lippincott, Williams & Wilkins, 2005:286 –299. 2. Mason KE. A conspectus of research on copper metabolism and requirements of man. J Nutr 1979;109:1979 –2066. 3. Institute of Medicine. Copper. In: Food and Nutrition Board, ed. Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum,
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4. 5.
6. 7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
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nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press, 2002;224 –257. Danks DM. Copper deficiency in humans. Ann Rev Nutr 1988;8: 235–257. Kumar N, Gross JB, Ahlskog JE. Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology 2004;63:33–39. Karpel JT, Peden VH. Copper deficiency in long-term parenteral nutrition. J Pediatr 1972;80:32–36. Vilter RW, Bozian RC, Hess EV, et al. Manifestations of copper deficiency in a patient with systemic sclerosis on intravenous hyperalimentation. N Engl J Med 1974;291:188 –191. Fuhrman MP, Herrmann V, Masidonski P, et al. Pancytopenia after removal of copper from total parenteral nutrition. JPEN J Parenter Enteral Nutr 2000;24:361–366. Hurowitz M, Garcia MG, Poole RL, et al. Copper deficiency during parenteral nutrition: a report of four pediatric cases. Nutr Clin Pract 2004;19:305–308. Heller RM, Kirchner SA, O’Neill J, et al. Skeletal changes of copper deficiency in infants receiving prolonged PN. J Pediatr 1978;92:947–949. Shike M, Roulet M, Kurian R, et al. Copper metabolism and requirements in total parenteral nutrition. Gastroenterology 1981; 81:290 –297. Pluhator-Murton MM, Fedorak RN, Audette RJ, et al. Extent of trace-element contamination from simulated compounding of total parenteral nutrient solutions. Am J Health-Syst Pharm 1996; 53:2299 –2303. Expert Panel for Nutrition Advisory Group, AMA Department of Foods and Nutrition. Guidelines for essential trace element preparations for parenteral use. JAMA 1979;241:2051–2054. Howard L, Ashley C, Lyon D, et al. Autopsy tissue trace elements in 8 long-term parenteral nutrition patients who received the current U.S. food and drug administration formations. JPEN J Parenter Enteral Nutr 2007;31:388 –396. Blaszyk H, Wild PJ, Oliveira A, et al. Hepatic copper in patients receiving long-term total parenteral nutrition. J Clin Gastroenterol 2005;39:318 –320. A.S.P.E.N. guidelines: normal requirements—Adults A.S.P.E.N. Board of Directors and the Clinical Guidelines Task Force. Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. J Parenter Enteral Nutr 2002;26S:22SA– 24SA. Greene HL, Hambidge KM, Schanler R, et al. Guidelines for the use of vitamins, trace elements, calcium, magnesium, and phosphorus in infants and children receiving total parenteral nutrition: report of the subcommittee on pediatric parenteral nutrient requirements from the committee on clinical practice issues of the American Society for Clinical Nutrition. Am J Clin Nutr 1988;48: 1324 –1342.
Received May 22, 2009. Accepted August 7, 2009. Reprint requests Address requests for reprints to: Moshe Shike, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065. e-mail: [email protected]. Conflicts of interest The author discloses no conflicts.
Copper in Parenteral Nutrition MOSHE SHIKE Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York
Copper is an essential nutrient for humans. Copper is a component of numerous enzymes that affect a wide variety of metabolic processes. Copper deficiency can result in anemia, neutropenia, skeletal abnormalities, and other clinical manifestations. There is no wellestablished laboratory measurement of body copper status. Copper supplementation is essential in parenteral nutrition to prevent an adverse effect of deficiency. Balance studies indicate that copper requirements in total parenteral nutrition amount to 0.3 mg/day in the adult. For children and infants, the estimated requirement is 20 g/kg body wt/day. These amounts may have to be decreased in patients with cholestasis.
T
he copper content in the adult human body is estimated to range between 50 and 120 mg.1 Copper is found in high concentrations in liver, brain, and, to a lesser degree, in kidney, heart, and pancreas.2 The term neonate has significant hepatic copper stores that are gained during the third trimester of pregnancy. In the newborn, the liver has a high concentration of copper, about 6 –10 times that of an adult.2 However, it is important to note that circulating copper levels may be low during the first 3 postnatal months, mostly due to low synthesis of ceruloplasmin. More than 90% of copper in the blood is bound to ceruloplasmin. The rest is bound to albumin and amino acids. It is not present in blood in ionic form because of its poor solubility. Copper is absorbed mostly in the small intestines and to a lesser degree in the stomach. The average copper intake from the diet in the United States is 1–1.6 mg according to the Third National Health and Nutrition Survey,3 less than previous estimates of 3–5 mg.2 The estimated average requirements amount to 0.70 mg for an average adult and between 0.26 and 0.68 mg in different stages of childhood.1 Copper is found in high quantities in shellfish, nuts, liver, and legumes.1 The fractional absorption from the gastrointestinal tract is regulated to maintain homeostasis. Most copper excretion and loss is through the bile, but small amounts are also excreted through urine, sweat, and menstrual blood.2 Once absorbed through the enterocytes, copper is transported to the liver bound by albumin or transcuprein. In the liver, it is incorporated into ceruloplasmin. Copper is released from the liver into the blood bound to
ceruloplasmin and is delivered in this form to the peripheral tissues. Ceruloplasmin binds to its receptors on the cell surface; the copper is released from its binding protein and enters the cell.
Copper Biochemical and Physiologic Functions Copper is an essential nutrient in animal and human physiology. In biological systems, it is found most frequently as Cu2⫹. Copper is a part of numerous proteins with a wide range of activities. The following enzymes are among those that include copper as an essential constituent. 1. Ferroxidases (including ceruloplasmin), which catalyze the oxidation of ferrous iron in the process of transferring iron from storage sites to bone marrow for hemoglobin synthesis. Reduced activity results in anemia, which appears like iron deficiency. 2. Lysyl oxidase participates in cross-linking of collagen and elastin in connective tissues. Deficiency results in bone formation abnormalities and defects in connective tissues and blood vessels. 3. Dopamine -hydroxylase catalyzes the conversion of dopamine to norepinephrine in the brain. Deficiency causes neurologic abnormalities. 4. Copper/zinc superoxide dismutase functions as a free radicals scavenger; copper deficiency is associated with oxidative damage. 5. Monoamine oxidase is essential for serotonin synthesis. 6. Tyrosinase participates in melanin synthesis. Deficiency results in hypopigmentation.
Copper Deficiency and Toxicity in Humans Assessment of Copper Status In severe copper deficiency, serum copper and ceruloplasmin levels are low and reflect the copper status of the body. However, in marginal deficiency, these parameters are usually normal and do not reflect the copper status of the body. Furthermore, ceruloplasmin is an Abbreviation used in this paper: PN, parenteral nutrition. © 2009 by the AGA Institute 0016-5085/09/$36.00 doi:10.1053/j.gastro.2009.08.017
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acute phase reactant; in the presence of inflammatory processes, its levels as well as those of copper may be elevated, even in the presence of marginal copper deficiency.1,2 Copper levels in hair, nails, and saliva have been proposed as indices of copper status but were found to be unreliable. Cytochrome oxidase and superoxide dismutase in red blood cells have been considered as potential measures of copper adequacy, but they have not been studied vigorously.1
Manifestations of Copper Deficiency Copper deficiency is rare in humans. It has been reported in patients with prolonged severe malabsorption, premature infants, children recovering from severe malnutrition, and patients receiving parenteral nutrition (PN) without copper supplementation. Manifestations of copper deficiency include anemia (often hypochromic, microcytic), leukopenia, and a variety of bone abnormalities, including osteoporosis, new subperiosteal bone formation, and fibrosis of epiphysis. It has been suggested, but not well proven, that prolonged marginal copper deficiency can result in cardiac diseases, arthritis, loss of hair pigmentation,4 and neurologic abnormalities, mimicking vitamin B12 deficiency.5 Menkes disease is a rare fatal X-linked disorder in which copper accumulates in intestinal mucosa and is not transported to other sites. This leads to copper deficiency in the liver and other tissues. The serum copper and ceruloplasmin levels are low. The disease is manifested as defective arteries, degeneration of brain cells, severe mental retardation, and death. The anemia and neutropenia seen in nutritional copper deficiency do not occur in Menkes disease.2
Manifestations of Copper Toxicity Acute copper toxicity is rare in humans and occurs mostly from consumption of beverages stored in copper vessels or from consumption of contaminated water. Acute copper toxicity results in abdominal pain, liver and kidney failure, and death. Chronic copper toxicity is illustrated in Wilson’s disease, an inborn error of copper metabolism characterized by high levels of copper in liver, brain, kidney, and other organs. The serum copper levels are usually low, as are the ceruloplasmin levels. The disease is manifested as cirrhosis of the liver, a variety of neurologic disorders, and renal damage.2 In idiopathic copper toxicosis, which mostly manifests as cirrhosis of the liver, a high dietary copper level appears to play a role in addition to an inherited disposition.
Copper in Total PN Copper Deficiency in Recipients of Total PN Copper deficiency in patients receiving PN is rare and has been reported only after prolonged dependence on PN without copper supplementation. These features
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of copper deficiency may be due to a number of factors, including availability of copper body stores before beginning PN, contamination of various PN components with copper, and absorption from oral intake of copper-containing food. PN-associated copper deficiency reports are limited to single patients, primarily because of the rarity of this problem, and include the following. 1. An infant with short-bowel syndrome developed anemia, neutropenia, and bone abnormalities after 8.5 months on PN without copper. The abnormalities were corrected with copper supplementation.6 2. An adult with long-standing scleroderma with severe malabsorption developed neutropenia and hypocellular bone marrow after 6 months of PN without copper supplementation. This was corrected by the addition of copper to the PN solutions.7 3. A female patient with short-bowel syndrome developed cholestasis after 6 months of PN with copper supplementation. Copper was discontinued, and 15 months later the patient developed anemia, neutropenia, and thrombocytopenia with a low serum copper level. Two months of copper supplementation in PN resulted in normalization of the serum copper level and correction of all the hematologic abnormalities.8 Hurowitz et al reported on 4 pediatric patients who had their PN copper omitted after developing cholestasis.9 Manifestations of copper deficiency were seen in these patients, including low serum copper level, anemia, neutropenia, and hypopigmentation. Bone abnormalities were reported in 2 infants receiving PN without copper for a few months.10 The abnormalities were similar to those seen in scurvy and included fibrosis of the epiphyses, subperiosteal new bone formation, and osteoporosis. It appears from these case reports that the time of onset of copper deficiency in recipients of PN without copper varies but is not immediate. It is also clear that copper supplementation is essential. PN solutions may contain various amounts of copper present inadvertently11,12; however, the occurrence of copper deficiency indicates that these amounts are inadequate and cannot be relied on to provide the needed quantities. Although copper losses in patients with cholestasis may be decreased because of decline in excretion through the biliary tract, it does not necessarily follow that all copper supplementation should be stopped. These cases show that even in the presence of cholestasis, copper deficiency can develop in patients maintained on home PN without copper supplementation.
Copper Supplementation in PN The first guidelines for copper supplementation in PN were formulated by an American Medical Association expert committee.13 The recommendations were based on oral intake, gastrointestinal absorption, and
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general physiologic considerations because at the time there were no specific data on appropriate copper doses for patients receiving PN. A wide range of supplementation between 0.5 and 1.5 mg/day was suggested for adults and 20 g/kg/day was suggested for pediatric patients.13 Subsequently, detailed balance studies in adults receiving PN in the hospital and kept “nothing by mouth” indicated that the average optimal daily copper supplementation in PN solutions amounted to 0.3 mg/day.11 These studies were performed over a 3-week period, and during each week patients received PN solutions supplemented with copper with one of 3 doses: 0.25, 1.05, and 1.85 mg/day. It was found that patients with cholestasis (defined as elevation of the alkaline phosphatase level) had decreased copper excretion through the gastrointestinal tract and tended to retain copper excessively. In these patients, a smaller amount of infused copper averaging 0.15 mg/day appeared to be the right dose. Patients with diarrhea had increased copper losses and required on average 0.4 – 0.5 mg/day to maintain balance. The serum copper level did not correlate with copper balance and thus does not appear to be a reliable marker of needs for copper supplementation. Excess copper supplementation in PN solutions may accumulate in the liver and other tissues and can potentially cause damage. A recent autopsy study of 8 patients who received home PN for an average duration of 14 years with a copper supplementation amounting to 1.4 mg/day14 showed that the copper content of liver and kidney tissues was very high compared with healthy controls. The levels were particularly high in those with liver failure. The role of cholestasis in inducing copper retention in the liver was underscored in a study by Blaszyk et al, who found that PN recipients with significant cholestasis tended to have high liver copper content, often exceeding the threshold of Wilson’s disease.15 The amount of liver copper did not correlate with the serum copper levels. Subsequent guidelines for copper supplementation in adult PN solutions adopted the findings of the balance studies mentioned previously.11 The expert committee of the American Society for Parenteral and Enteral Nutrition recommended a daily dose of 0.3– 0.5 mg/day for adults.16 There have not been specific balance studies in the pediatric group. The expert committee of the American Society for Clinical Nutrition recommended 20 g/kg/day for preterm and term infants.17 Based on the available literature, copper supplementation should be prescribed for patients receiving PN at a dosage of 0.3 mg/day, with a smaller dosage in patients with liver disease and a larger dosage in those with excessive prolonged gastrointestinal fluid losses. For infants and children, a weight-based dose should be prescribed (20 g/kg/day).
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Clinical Recommendations ●
Copper should be routinely prescribed to patients receiving PN.
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The usual dosage of copper in PN is 0.3 mg/day for adults and 20 g/kg/day for pediatric patients (not to exceed 0.3 mg/day).
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Patients with liver disease should receive a reduced dosage of 0.15 mg/day.
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Patients with persistent diarrhea or gastrointestinal fluid losses should receive between 0.4 and 0.5 mg/ day.
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Copper requirements (as those of other nutrients) should be periodically reassessed and corrections made as needed.
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Serum copper and ceruloplasmin levels should not be used as the sole indicators of copper requirements (the clinical circumstances should be a part of the assessment).
Research Priorities ●
Indices of assessment copper status, preferably in blood or plasma.
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A better understanding of the relationship between liver disease and copper requirements.
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Determination of the amount of copper contamination present in components of PN solutions.
Question and Answer Session DR KELLY: I would like to clarify some of the information on the Mayo study. These are people who had liver biopsies because they had evidence of liver disease, and I believe the level of intake was about 800 g/day of copper. DR PIRONI: In patients on long-term PN, is assessment of trace metals in hair a useful technique? DR SHIKE: Hair copper is not a reliable marker of copper nutriture. First of all, everybody uses hair shampoos and hair shampoos contain a lot of copper. There have been numerous studies that have shown that hair copper is not a good marker. For instance, in anorexia nervosa, there can be very high copper levels in hair, and there are single reports in the literature of patients with copper deficiency with a normal hair copper level. I do not think it is a reliable marker or easy to perform. DR FORBES: This is a continuation of the same question. I enjoyed the talk and the presentation, and I agree with your final discussion point, but what are you suggesting we use other than serum copper and ceruloplasmin for the assessment of copper? DR SHIKE: As Dr Jeejeebhoy indicated, I think we should look at the patient as a whole using the modest
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knowledge that we have. If the patient does not have excessive gastrointestinal losses, I think a 0.3-mg daily dose of copper based on the balance studies that we have conducted is a reasonable amount, knowing that we may be somewhat off because of what Dr Howard mentioned earlier: the amount of copper that is absorbed from the diet and the amount of copper that is present as a contaminant in the PN solution. Of course we must follow the liver function tests of the patient and the blood count. If liver function is deteriorating, we recommend reducing the PN copper level by 50%. If there is an indication of leukopenia and microcytic hypochromic anemia, it should make you scratch your head and rethink whether the amount of copper being given is adequate. However, we really don’t have one single laboratory measure to make our lives easy. DR SHULMAN: The recommendation for the pediatric patient, I think, is reasonable. We did some balance studies for copper several years ago, and the numbers you gave are pretty close to what we found. A basic issue is patients with liver disease; you recommend reduction of daily copper by 50%, and I have heard many different recommendations in that regard. Our concern is for small preterm babies, who have a greater risk of liver disease and a greater likelihood of copper deficiency. Are there any data about what the actual reduction should be rather than just people’s gestalt of what it should be? DR SHIKE: No. I found in the literature, and you know these data far better than I do, that newborns have quite a high content of copper in the liver, higher than the adult per gram of dry liver tissue. If the newborn develops rapid onset of liver disease, I would be reluctant to give generous amounts of copper. Of course, more research is needed. DR SHENKIN: Thank you for a very interesting talk, and I agree by and large with the conclusions that you have made. I would like to comment on the level of copper intake and the question of how toxic is copper in overdosage. I am thinking of our European experience, where the trace elements preparations most available for supplementation provide about 1.1 mg/day of copper, and these have been used widely for the best part of 20 years. In addition, there are the autopsy tissue studies, giving 1.4 mg/day of copper, in which 4 of the 8 patients who had been fed intravenously for between 2 and 20 years had liver copper levels comfortably within the normal range. The patients with extremely high levels were, of course, those with liver disease. I am just wondering if we need to be so concerned about a small amount of extra copper. These higher doses seem to be managed perfectly well as long as liver function is okay. DR SHIKE: I would say that based on our current knowledge, modest as it is, 1.1 mg of copper is an excessive amount given over a long period, particularly because a lot of patients on home PN have some degree of cholestasis, with elevation of alkaline phosphatase and
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hepatic transaminase levels. I think, based on our current knowledge, that we should go down to 0.3 mg/day. I think 1.1 mg/day is excessive. DR SHENKIN: I’m not saying it’s not excessive. I’m just wondering what are the side effects of having chronic marginal excess copper levels. We don’t appear to have case reports in the literature of copper toxicity during PN over a long period inducing the neurologic and psychiatric manifestations seen in Wilson’s disease. DR SHIKE: One could infer from patients with Wilson’s disease that as copper accumulates in the liver it precipitates cirrhosis. Based on the study from the Mayo Clinic, in which a good number of patients had high levels of hepatic copper in the range of that seen in Wilson’s disease, it is only plausible to conclude that the presence of a very high copper level in the liver can indeed damage the liver. Based on all of this, I think we should be careful. If PN is given for only a few weeks in the hospital, I don’t sweat it. However, in the long-term patient, because they are already prone to develop liver disease from numerous other causes, it is imperative to be very careful and very thoughtful about the amount of copper we give. DR BORUM: I would like to turn the attention back to the neonate and particularly to the very preterm neonate: the 24- to 26-week-old neonate who is in the neonatal intensive care unit. A subset will have necrotizing enterocolitis or something else that will send them home on PN. What kind of data do we have to guide us in giving copper to these small individuals? DR SHIKE: I am really not aware of any more data than I provided. As I said, earlier newborns have a good amount of copper in the liver. If it is foreseen that the newborn is going to be on home PN for the next 2 years, based on the few case reports available in the literature, I think it is reasonable to give small amounts of copper using the guideline of 20 g/kg/day. If there is liver disease, I think it should be half of that amount, but that is kind of a guess. DR BERGER: Thanks for a great presentation. There is one point I would like to make about acute deficiencies. There is one condition that has been associated with severe copper deficiency, and that is major burns. There are papers published in the 1970s from Zurich describing children with acute copper deficiency with major burns. In some of these case reports, copper deficiency in major burns appeared to contribute to death. Conducting balance studies, we were able to show that burn patients with 30% body surface affected were losing 30 to 40 mg of copper in 1 week. We have conducted prospective randomized supplementation trials showing that by giving 4 mg of copper intravenously per day for the period when the wounds were open, we were able to restore both copper and ceruloplasmin levels. Here is a condition with proven high losses, not on PN because burn patients are enterally fed most of the time, but receiving intravenous
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supplements in the range of 4 mg/day of copper that appears not only safe but is associated with restored neutrophil activity and improved wound healing. You showed that elastin and collagen synthesis are highly dependent on copper. So again, there are different types of patients and what you have been recommending for home PN individuals clearly applies, but there are conditions with much higher requirements. DR SHIKE: I think these are fascinating numbers that you are giving because 30 mg/wk is a huge amount. I assume you measured it in secretions from wounds? DR BERGER: In exudates, yes. It is a balance study, which was conducted in many patients and repeated many times. All the data were analyzed in triplicate along with zinc and selenium losses. DR SHIKE: Just a word of caution about giving large doses of copper intravenously; as you know, in Wilson’s disease there are sometimes crises provoked by excessive release of copper into the bloodstream that induce severe hemolytic anemias. I don’t know if the amount you gave could cause such a crises, but just a word of caution. DR BERGER: We have been delivering the copper as copper gluconate and not copper sulfate. We have been giving these intravenous supplements since 1988 in all our burn patients. Another point I want to raise briefly: shouldn’t we ask industry to address the quantities delivered in the PN solution components as contaminants? Shouldn’t this information be provided on PN bags? ANONYMOUS: I think for people taking care of patients at home, what we would like to know is what dose of trace elements is recommended and what modifications are appropriate if liver dysfunction develops. DR SHIKE: I believe the task of this session is to make some recommendations for the infusion industry. In my mind, it is clear that we should have available the separate trace elements so we can modify what we give when metabolic changes develop. The various trace elements have completely different functions in human metabolism, and we need to have the ability to adjust the amount we are giving to each patient without having the burden of altering the other trace elements. I personally favor a separate solution for each trace element. References 1. Turnland JR. Copper. In: Shils M, Shike M, Ross AC, et al, eds. Modern nutrition in health and disease. 10th ed. Philadelphia, PA: Lippincott, Williams & Wilkins, 2005:286 –299. 2. Mason KE. A conspectus of research on copper metabolism and requirements of man. J Nutr 1979;109:1979 –2066. 3. Institute of Medicine. Copper. In: Food and Nutrition Board, ed. Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum,
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nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press, 2002;224 –257. Danks DM. Copper deficiency in humans. Ann Rev Nutr 1988;8: 235–257. Kumar N, Gross JB, Ahlskog JE. Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology 2004;63:33–39. Karpel JT, Peden VH. Copper deficiency in long-term parenteral nutrition. J Pediatr 1972;80:32–36. Vilter RW, Bozian RC, Hess EV, et al. Manifestations of copper deficiency in a patient with systemic sclerosis on intravenous hyperalimentation. N Engl J Med 1974;291:188 –191. Fuhrman MP, Herrmann V, Masidonski P, et al. Pancytopenia after removal of copper from total parenteral nutrition. JPEN J Parenter Enteral Nutr 2000;24:361–366. Hurowitz M, Garcia MG, Poole RL, et al. Copper deficiency during parenteral nutrition: a report of four pediatric cases. Nutr Clin Pract 2004;19:305–308. Heller RM, Kirchner SA, O’Neill J, et al. Skeletal changes of copper deficiency in infants receiving prolonged PN. J Pediatr 1978;92:947–949. Shike M, Roulet M, Kurian R, et al. Copper metabolism and requirements in total parenteral nutrition. Gastroenterology 1981; 81:290 –297. Pluhator-Murton MM, Fedorak RN, Audette RJ, et al. Extent of trace-element contamination from simulated compounding of total parenteral nutrient solutions. Am J Health-Syst Pharm 1996; 53:2299 –2303. Expert Panel for Nutrition Advisory Group, AMA Department of Foods and Nutrition. Guidelines for essential trace element preparations for parenteral use. JAMA 1979;241:2051–2054. Howard L, Ashley C, Lyon D, et al. Autopsy tissue trace elements in 8 long-term parenteral nutrition patients who received the current U.S. food and drug administration formations. JPEN J Parenter Enteral Nutr 2007;31:388 –396. Blaszyk H, Wild PJ, Oliveira A, et al. Hepatic copper in patients receiving long-term total parenteral nutrition. J Clin Gastroenterol 2005;39:318 –320. A.S.P.E.N. guidelines: normal requirements—Adults A.S.P.E.N. Board of Directors and the Clinical Guidelines Task Force. Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. J Parenter Enteral Nutr 2002;26S:22SA– 24SA. Greene HL, Hambidge KM, Schanler R, et al. Guidelines for the use of vitamins, trace elements, calcium, magnesium, and phosphorus in infants and children receiving total parenteral nutrition: report of the subcommittee on pediatric parenteral nutrient requirements from the committee on clinical practice issues of the American Society for Clinical Nutrition. Am J Clin Nutr 1988;48: 1324 –1342.
Received May 22, 2009. Accepted August 7, 2009. Reprint requests Address requests for reprints to: Moshe Shike, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065. e-mail: [email protected]. Conflicts of interest The author discloses no conflicts.