Nutrition in Clinical Practice http://ncp.sagepub.com/
Assessing Copper Status in Pediatric Patients Receiving Parenteral Nutrition Mark MacKay, Cecilia W. Mulroy, Jennifer Street, Charisse Stewart, Jake Johnsen, Daniel Jackson and Irasema Paul Nutr Clin Pract published online 16 June 2014 DOI: 10.1177/0884533614538457 The online version of this article can be found at: http://ncp.sagepub.com/content/early/2014/06/11/0884533614538457
Published by: http://www.sagepublications.com
On behalf of:
The American Society for Parenteral & Enteral Nutrition
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538457
research-article2014
NCPXXX10.1177/0884533614538457Nutrition in Clinical PracticeMacKay et al
Clinical Research
Assessing Copper Status in Pediatric Patients Receiving Parenteral Nutrition
Nutrition in Clinical Practice Volume XX Number X Month 201X 1–5 © 2014 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0884533614538457 ncp.sagepub.com hosted at online.sagepub.com
Mark MacKay, BSPharm1; Cecilia W. Mulroy, RD1; Jennifer Street, RD1; Charisse Stewart, RN1; Jake Johnsen, PharmD1; Daniel Jackson, MD2; and Irasema Paul, PharmD1
Abstract Background: Copper is a trace mineral essential for numerous physiological processes. The purpose of this article is to provide data on copper levels in pediatric patients receiving parenteral nutrition (PN) that are useful to guide supplementation in PN formulation. Method: This is a retrospective review of hospitalized pediatric patients receiving PN supplemented and not supplemented with copper. In total, 751 supplemented pediatric patients and 90 pediatric patients not supplemented had serum copper levels measured. We assessed patient demographics, days on PN before copper level was drawn, serum copper levels, conjugated bilirubin levels, and C-reactive protein (CRP). Results: The mean serum copper level was 80 mcg/dL at 20 days for supplemented patients and 64 mcg/dL at 14 days for the 90 nonsupplemented patients (P = .0002). In the supplemented patients, 50% of the levels were low and 45% were within the normal range. The remaining 5% of patients had high levels. In nonsupplemented patients, 71% were low and 29% within the normal range. There was no correlation between copper levels and conjugated bilirubin 2 mg/dL (P = .3421). Copper levels correlated with CRP for CRP >4 mg/dL (P = .03). Conclusion: Pediatric patients receiving PN should be supplemented with copper to prevent deficiency. Serum copper levels should be assessed at 14 days. Assessment of copper status should not be determined by conjugated bilirubin levels. Serum copper levels may be elevated in patients with acute inflammation and may be falsely elevated when CRP is >4 mg/dL. (Nutr Clin Pract. XXXX;xx:xx-xx)
Keywords copper; micronutrients; trace elements; nutritional assessment; pediatrics; minerals/trace elements; parenteral nutrition
Background Copper is an essential part of several enzyme systems used in metabolism and has antioxidant properties.1 Copper is absorbed predominantly in the duodenum and is transported to the liver by carrier proteins through the vascular system.2 In the liver, copper is stored or bound to ceruloplasmin, which is the principal carrier for copper in the plasma.3 Copper is excreted by the hepatobiliary route, bound to bile salts, and excreted into the intestinal tract, preventing copper reabsorbtion.4 Copper deficiency is rare but has been reported in premature infants and children receiving parenteral nutrition (PN) without copper supplementation.5 Copper deficiency is increased in premature infants because most copper accumulates during the third trimester.6 Deficiency usually manifests as hypochromic microcytic anemia, leukopenia, neutropenia, and bone anomalies such as osteoporosis.7-9 Copper toxicity is also rare and is usually seen in Wilson disease; it is manifested by cirrhosis of the liver with high tissue copper levels and low copper serum levels. Ceruloplasmin and C-reactive proteins (CRPs) are acute-phase reactants and increase in inflammatory processes along with serum copper levels. In the presence of inflammatory processes, copper levels may be falsely normal or elevated in pediatric patients with suboptimal copper status.10,11
Patients receiving only PN can become deficient or toxic depending on the administration and monitoring of copper. The recommended pediatric daily dose for copper in PN is 20 mcg/ kg/d.12,13 Assessment of copper status is determined by serum copper concentration, although it does not reflect copper in hepatic storage.14 The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) nutrition support curriculum states that assessment of copper is determined by considering both ceruloplasmin and serum copper levels.15 The clinical practice of some institutions is to reduce or eliminate copper from the PN when the patient is cholestatic or when the conjugated bilirubin is >2 mg/dL.16-18 Others have indicated that there is no correlation between conjugated bilirubin and serum copper levels.19 Because ceruloplasmin is an acute-phase reactant affecting copper levels, institutions may not monitor serum copper levels, increasing the risk of deficiency or toxicity. From 1Primary Children’s Hospital, Salt Lake City, Utah, and 2Primary Children’s Medical Center, Salt Lake City, Utah. Financial disclosure: None declared. Corresponding Author: Mark MacKay, BSPharm, Primary Children’s Hospital, 100 N Mario Capecchi Dr, Salt Lake City, UT 84123, USA. Email: [email protected]
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2
Nutrition in Clinical Practice XX(X)
Table 1. Patient Demographics for Copper-Supplemented Patients. Disease Abdominal wall defect Biliary atresia Bone marrow transplant Cardiac Congenital hernia Liver transplants Necrotizing enterocolitis Oncology Other Prematurity Respiratory Small bowel obstruction Sepsis Small bowel atresia Tracheal esophageal atresia
No. of Patients
Mean ± Weight, kg
Age, y
67 14 15 77 23 26 114 91 80 51 20 52 79 24 18
2.64 ± 0.9 8.04 ± 6.6 42.6 ± 27.3 5.75 ± 11.2 31.5 ± 1.2 18.96 ± 19.4 4.06 ± 4.5 28.1 ± 20.3 15.32 ± 18.5 1.82 ± 1.1 8.6 ± 14.6 15.76 ± 17.2 16.4 ± 18 2.36 ± 1.77 2.44 ± 6.6
0–1 0–14 1–24 0–15 0–1 1–16 0–11 1–18 1–17 0–1 0–14 1–18 1–23 0–1 0–1
The purposes of this study were to describe the number of patients with normal, low, or high serum copper levels while receiving 20 mcg/kg/d as the standard dose; determine if there is a correlation between conjugated bilirubin >2 mg/dL and 4 mg/dL. Therefore, we conclude that reliable serum copper levels can be obtained at CRP levels ≤4 mg/dL. The data presented for the CRP indicate more research is needed to determine if there is an exact point at which CRP affects the serum copper level. This retrospective review of copper indicates that patients who are not supplemented with copper may have low levels within 2 weeks and should have a serum copper level measured. Patients in the supplemented group may also have low levels and require serum copper evaluation. Using conjugated bilirubin to determine copper dose adjustments is unreliable, and removal of copper from PN should be based on measured serum copper level. CRP is an inflammatory marker and does
affect serum copper levels, although more research is needed to assess when copper levels should be drawn. Past research has been directed at identifying deficiencies in copper and the need for copper supplementation. The data from this review may guide copper supplementation in PN for the hospitalized pediatric patient.
Conclusion In this study, we have presented our data and experience in the assessment of serum copper levels for monitoring copper supplementation in our pediatric patients receiving PN. Patients receiving long-term PN should obtain copper as a daily additive in the PN. Patients not supplemented with copper may develop low copper levels within 14 days and should be assessed for supplementation. Low copper levels may also be observed in a significant proportion of supplemented patients, requiring dosage adjustment. Increasing conjugated bilirubin does not
Downloaded from ncp.sagepub.com at The University of Auckland Library on October 15, 2014
MacKay et al
5
correlate with serum copper levels. Copper levels may increase with increasing CRP levels, especially for CRP >4 mg/dL.
References 1. Linder MC, Hazegh-Azam M. Copper biochemistry and molecular biology. Am J Clin Nutr. 1996;63:797S-811S. 2. Van Campen DR, Mitchell EA. Absorption of Cu64, Zn65, Mo99, and Fe59 from ligated segments of the rat gastrointestinal tract. J Nutr. 1965;86: 120-124. 3. Van den Berghe PVE, Klomp LWJ. New developments in the regulation of intestinal copper absorption. Nutr Rev. 2009;67:870-878. 4. Lewis KO. The nature of copper complexes in bile and their relationship to the absorption and excretion of copper in normal subjects and in Wilson’s disease. Gut. 1973;14:221-232. 5. Marquardt M, Done S, Sandrock M, Berdon W, Feldman K, Copper deficiency presenting as metabolic bone disease in extremely low birth weight, short-gut infants. Pediatrics. 2012;130:e695. 6. Hurowitz M, Garcia MG, Poole RL, et al. Copper deficiency during parenteral nutrition: a report of four pediatric cases. Nutr Clin Pract. 2004;19: 205-308. 7. Karpel JT, Peden VH. Copper deficiency in long-term parenteral nutrition. J Pediatr. 1972;80:32-36. 8. 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. 9. Mason KE. A conspectus of research of copper metabolism and requirements of man. J Nutr. 1979;109:1979-2066.
10. Turnlund JR. Copper. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern Nutrition in Health and Disease. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006: 286-299. 11. Shike M. Copper in parenteral nutrition. Gastroenterology. 2009;137: S13-S17. 12. Frem J, Sarson Y, Stemberg T, Cole C. Copper supplementation in parenteral nutrition in cholestatic infants. J Pediatr Gastroenterol. 2010;50: 650-654. 13. Zlotkin SH, Atkinson S, Lockitch G. Trace minerals in nutrition for premature infants. Clin Perinatol. 1995;22:223-240. 14. McDonald CM. Copper nutrition and cholestasis: dosing issues in pediatric parenteral nutrition. Support Line. 2003;25:13-19. 15. Gottschlich M, DeLegge M, Mattox T, et al. The A.S.P.E.N. Nutrition Support Core Curriculum. Silver Spring, MD: American Society for Parenteral and Enteral Nutrition; 2007. 16. Mirtallo J, Canada T, Johnson D, et al. Task force for the revision of safe practices for parenteral nutrition. JPEN J Parenter Enteral Nutr. 2004;28:S39-S70. 17. Blackmer A, Bailey E. Management of copper deficiency in cholestatic infants: review of the literature and a case series. Nutr Clin Pract. 2013;28:75-86. 18. McMillian N, Mulroy C, MacKay M, McDonald C, Jackson D. Correlation of cholestasis with serum copper and whole-blood manganese levels in pediatric patients. Nutr Clin Pract. 2008;23:161-165. 19. Mysler E, Psioni C, Tate P, Tate G. Influence of corticosteroids on C-reactive protein in patients with rheumatoid arthritis. Arthritis Res Ther. 2004;6(suppl 3):57.
Downloaded from ncp.sagepub.com at The University of Auckland Library on October 15, 2014
Assessing Copper Status in Pediatric Patients Receiving Parenteral Nutrition Mark MacKay, Cecilia W. Mulroy, Jennifer Street, Charisse Stewart, Jake Johnsen, Daniel Jackson and Irasema Paul Nutr Clin Pract published online 16 June 2014 DOI: 10.1177/0884533614538457 The online version of this article can be found at: http://ncp.sagepub.com/content/early/2014/06/11/0884533614538457
Published by: http://www.sagepublications.com
On behalf of:
The American Society for Parenteral & Enteral Nutrition
Additional services and information for Nutrition in Clinical Practice can be found at: Email Alerts: http://ncp.sagepub.com/cgi/alerts Subscriptions: http://ncp.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> OnlineFirst Version of Record - Jun 16, 2014 What is This?
Downloaded from ncp.sagepub.com at The University of Auckland Library on October 15, 2014
538457
research-article2014
NCPXXX10.1177/0884533614538457Nutrition in Clinical PracticeMacKay et al
Clinical Research
Assessing Copper Status in Pediatric Patients Receiving Parenteral Nutrition
Nutrition in Clinical Practice Volume XX Number X Month 201X 1–5 © 2014 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0884533614538457 ncp.sagepub.com hosted at online.sagepub.com
Mark MacKay, BSPharm1; Cecilia W. Mulroy, RD1; Jennifer Street, RD1; Charisse Stewart, RN1; Jake Johnsen, PharmD1; Daniel Jackson, MD2; and Irasema Paul, PharmD1
Abstract Background: Copper is a trace mineral essential for numerous physiological processes. The purpose of this article is to provide data on copper levels in pediatric patients receiving parenteral nutrition (PN) that are useful to guide supplementation in PN formulation. Method: This is a retrospective review of hospitalized pediatric patients receiving PN supplemented and not supplemented with copper. In total, 751 supplemented pediatric patients and 90 pediatric patients not supplemented had serum copper levels measured. We assessed patient demographics, days on PN before copper level was drawn, serum copper levels, conjugated bilirubin levels, and C-reactive protein (CRP). Results: The mean serum copper level was 80 mcg/dL at 20 days for supplemented patients and 64 mcg/dL at 14 days for the 90 nonsupplemented patients (P = .0002). In the supplemented patients, 50% of the levels were low and 45% were within the normal range. The remaining 5% of patients had high levels. In nonsupplemented patients, 71% were low and 29% within the normal range. There was no correlation between copper levels and conjugated bilirubin 2 mg/dL (P = .3421). Copper levels correlated with CRP for CRP >4 mg/dL (P = .03). Conclusion: Pediatric patients receiving PN should be supplemented with copper to prevent deficiency. Serum copper levels should be assessed at 14 days. Assessment of copper status should not be determined by conjugated bilirubin levels. Serum copper levels may be elevated in patients with acute inflammation and may be falsely elevated when CRP is >4 mg/dL. (Nutr Clin Pract. XXXX;xx:xx-xx)
Keywords copper; micronutrients; trace elements; nutritional assessment; pediatrics; minerals/trace elements; parenteral nutrition
Background Copper is an essential part of several enzyme systems used in metabolism and has antioxidant properties.1 Copper is absorbed predominantly in the duodenum and is transported to the liver by carrier proteins through the vascular system.2 In the liver, copper is stored or bound to ceruloplasmin, which is the principal carrier for copper in the plasma.3 Copper is excreted by the hepatobiliary route, bound to bile salts, and excreted into the intestinal tract, preventing copper reabsorbtion.4 Copper deficiency is rare but has been reported in premature infants and children receiving parenteral nutrition (PN) without copper supplementation.5 Copper deficiency is increased in premature infants because most copper accumulates during the third trimester.6 Deficiency usually manifests as hypochromic microcytic anemia, leukopenia, neutropenia, and bone anomalies such as osteoporosis.7-9 Copper toxicity is also rare and is usually seen in Wilson disease; it is manifested by cirrhosis of the liver with high tissue copper levels and low copper serum levels. Ceruloplasmin and C-reactive proteins (CRPs) are acute-phase reactants and increase in inflammatory processes along with serum copper levels. In the presence of inflammatory processes, copper levels may be falsely normal or elevated in pediatric patients with suboptimal copper status.10,11
Patients receiving only PN can become deficient or toxic depending on the administration and monitoring of copper. The recommended pediatric daily dose for copper in PN is 20 mcg/ kg/d.12,13 Assessment of copper status is determined by serum copper concentration, although it does not reflect copper in hepatic storage.14 The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) nutrition support curriculum states that assessment of copper is determined by considering both ceruloplasmin and serum copper levels.15 The clinical practice of some institutions is to reduce or eliminate copper from the PN when the patient is cholestatic or when the conjugated bilirubin is >2 mg/dL.16-18 Others have indicated that there is no correlation between conjugated bilirubin and serum copper levels.19 Because ceruloplasmin is an acute-phase reactant affecting copper levels, institutions may not monitor serum copper levels, increasing the risk of deficiency or toxicity. From 1Primary Children’s Hospital, Salt Lake City, Utah, and 2Primary Children’s Medical Center, Salt Lake City, Utah. Financial disclosure: None declared. Corresponding Author: Mark MacKay, BSPharm, Primary Children’s Hospital, 100 N Mario Capecchi Dr, Salt Lake City, UT 84123, USA. Email: [email protected]
Downloaded from ncp.sagepub.com at The University of Auckland Library on October 15, 2014
2
Nutrition in Clinical Practice XX(X)
Table 1. Patient Demographics for Copper-Supplemented Patients. Disease Abdominal wall defect Biliary atresia Bone marrow transplant Cardiac Congenital hernia Liver transplants Necrotizing enterocolitis Oncology Other Prematurity Respiratory Small bowel obstruction Sepsis Small bowel atresia Tracheal esophageal atresia
No. of Patients
Mean ± Weight, kg
Age, y
67 14 15 77 23 26 114 91 80 51 20 52 79 24 18
2.64 ± 0.9 8.04 ± 6.6 42.6 ± 27.3 5.75 ± 11.2 31.5 ± 1.2 18.96 ± 19.4 4.06 ± 4.5 28.1 ± 20.3 15.32 ± 18.5 1.82 ± 1.1 8.6 ± 14.6 15.76 ± 17.2 16.4 ± 18 2.36 ± 1.77 2.44 ± 6.6
0–1 0–14 1–24 0–15 0–1 1–16 0–11 1–18 1–17 0–1 0–14 1–18 1–23 0–1 0–1
The purposes of this study were to describe the number of patients with normal, low, or high serum copper levels while receiving 20 mcg/kg/d as the standard dose; determine if there is a correlation between conjugated bilirubin >2 mg/dL and 4 mg/dL. Therefore, we conclude that reliable serum copper levels can be obtained at CRP levels ≤4 mg/dL. The data presented for the CRP indicate more research is needed to determine if there is an exact point at which CRP affects the serum copper level. This retrospective review of copper indicates that patients who are not supplemented with copper may have low levels within 2 weeks and should have a serum copper level measured. Patients in the supplemented group may also have low levels and require serum copper evaluation. Using conjugated bilirubin to determine copper dose adjustments is unreliable, and removal of copper from PN should be based on measured serum copper level. CRP is an inflammatory marker and does
affect serum copper levels, although more research is needed to assess when copper levels should be drawn. Past research has been directed at identifying deficiencies in copper and the need for copper supplementation. The data from this review may guide copper supplementation in PN for the hospitalized pediatric patient.
Conclusion In this study, we have presented our data and experience in the assessment of serum copper levels for monitoring copper supplementation in our pediatric patients receiving PN. Patients receiving long-term PN should obtain copper as a daily additive in the PN. Patients not supplemented with copper may develop low copper levels within 14 days and should be assessed for supplementation. Low copper levels may also be observed in a significant proportion of supplemented patients, requiring dosage adjustment. Increasing conjugated bilirubin does not
Downloaded from ncp.sagepub.com at The University of Auckland Library on October 15, 2014
MacKay et al
5
correlate with serum copper levels. Copper levels may increase with increasing CRP levels, especially for CRP >4 mg/dL.
References 1. Linder MC, Hazegh-Azam M. Copper biochemistry and molecular biology. Am J Clin Nutr. 1996;63:797S-811S. 2. Van Campen DR, Mitchell EA. Absorption of Cu64, Zn65, Mo99, and Fe59 from ligated segments of the rat gastrointestinal tract. J Nutr. 1965;86: 120-124. 3. Van den Berghe PVE, Klomp LWJ. New developments in the regulation of intestinal copper absorption. Nutr Rev. 2009;67:870-878. 4. Lewis KO. The nature of copper complexes in bile and their relationship to the absorption and excretion of copper in normal subjects and in Wilson’s disease. Gut. 1973;14:221-232. 5. Marquardt M, Done S, Sandrock M, Berdon W, Feldman K, Copper deficiency presenting as metabolic bone disease in extremely low birth weight, short-gut infants. Pediatrics. 2012;130:e695. 6. Hurowitz M, Garcia MG, Poole RL, et al. Copper deficiency during parenteral nutrition: a report of four pediatric cases. Nutr Clin Pract. 2004;19: 205-308. 7. Karpel JT, Peden VH. Copper deficiency in long-term parenteral nutrition. J Pediatr. 1972;80:32-36. 8. 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. 9. Mason KE. A conspectus of research of copper metabolism and requirements of man. J Nutr. 1979;109:1979-2066.
10. Turnlund JR. Copper. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern Nutrition in Health and Disease. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006: 286-299. 11. Shike M. Copper in parenteral nutrition. Gastroenterology. 2009;137: S13-S17. 12. Frem J, Sarson Y, Stemberg T, Cole C. Copper supplementation in parenteral nutrition in cholestatic infants. J Pediatr Gastroenterol. 2010;50: 650-654. 13. Zlotkin SH, Atkinson S, Lockitch G. Trace minerals in nutrition for premature infants. Clin Perinatol. 1995;22:223-240. 14. McDonald CM. Copper nutrition and cholestasis: dosing issues in pediatric parenteral nutrition. Support Line. 2003;25:13-19. 15. Gottschlich M, DeLegge M, Mattox T, et al. The A.S.P.E.N. Nutrition Support Core Curriculum. Silver Spring, MD: American Society for Parenteral and Enteral Nutrition; 2007. 16. Mirtallo J, Canada T, Johnson D, et al. Task force for the revision of safe practices for parenteral nutrition. JPEN J Parenter Enteral Nutr. 2004;28:S39-S70. 17. Blackmer A, Bailey E. Management of copper deficiency in cholestatic infants: review of the literature and a case series. Nutr Clin Pract. 2013;28:75-86. 18. McMillian N, Mulroy C, MacKay M, McDonald C, Jackson D. Correlation of cholestasis with serum copper and whole-blood manganese levels in pediatric patients. Nutr Clin Pract. 2008;23:161-165. 19. Mysler E, Psioni C, Tate P, Tate G. Influence of corticosteroids on C-reactive protein in patients with rheumatoid arthritis. Arthritis Res Ther. 2004;6(suppl 3):57.
Downloaded from ncp.sagepub.com at The University of Auckland Library on October 15, 2014
