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Latent Copper Deficiency in Patients Receiving Low-Copper Enteral Nutrition for a Prolonged Period

Posted on: Sunday, 4 September 2005, 03:00 CDT

ABSTRACT. Background: Copper deficiency has been reported in patients supported with long-term enteral nutrition. Occasionally, this leads to anemia and leukopenia. There is no detailed report relating to the onset time of copper deficiency and how the symptoms develop. This report describes the relation between copper deficiency symptoms and duration of enteral nutrition. Methods: The study included 55 patients, with 82 measurements, at the neurologic ward of Nagoya Daini Red Cross Hospital. The mean age was 71 11 years. The daily average dosage of energy was 938 kcal/d. A commercial nutrient for enteral administration that contains 0.13 mg/ 1000 mL copper was used. Baseline measures on individual patients were taken every month. Blood was collected at 8 AM before and after the start of enteral nutrition. Levels of copper, zinc, ceruloplasmin, hemoglobin, and white blood cells were measured. Results: The serum level of copper in the patients was 94.0-181.0 g/ dL before the start of enteral nutrition. The level of serum copper remained within the normal range for about 3 months. The level of serum copper in the patients decreased gradually and was less than the normal level after 3 months, with the exception of 1 patient. The serum level of copper in the patients was 3.0-123.0 g/dL 3 months after the start of enteral nutrition. The levels of serum copper were below normal in 25 cases out of 82 measurements. However, the number of patients with symptoms of copper deficiency was only 2. Copper deficiency symptoms appeared at 41 and 77 months, the average being 59 months. Conclusions: Almost all patients showed a latent copper deficiency about 3 months after the start of enteral nutrition. However, only a few patients developed overt symptoms of copper deficiency. (Journal of Parenteral and Enteral Nutrition 29:360-366, 2005)

Copper is an essential trace element in humans.1 It plays an important role in iron absorption and transport as a component of ceruloplasmin, which has a ferroxidase-like activity.1 Copper is also essential for normal development of the skeleton, for normal function and structure of the central nervous system,1 and for taste sensation.2

Copper deficiency in patients receiving parenteral nutrition (PN) have been associated with anemia, leukopenia, neutropenia,3-9 and skeletal abnormalities.3,4 Copper deficiency has been regarded as a rare complication of enterai nutrition. In 1988, Higuchi et al10 reported the first case of neutropenia due to copper deficiency in a patient receiving enteral nutrition. Since then, several reports of neutropenia and anemia in copper-deficient patients receiving enteral nutrition have been published.11,12 These later reports take into account that some defined-formula diets do not contain sufficient copper. It is postulated that the serum copper level should be closely monitored during long-term enteral nutrition. However, little is known about how the symptoms of copper deficiency develop due to enteral nutrition. This report describes the relation between copper deficiency and the period of enteral nutrition. It was recognized that a latent copper deficiency will develop in patients receiving long-term enteral nutrition.

MATERIALS AND METHODS

Patients

In the index case, anemia in the peripheral circulating blood was detected during an evaluation to rule out iron deficiency. Hypocupremia was recognized as a latent cause of the anemia when it became clear that the patient had been receiving low copper enteral nutrition (Lifelon-L, Nikken Co, Ltd.) for a long period. Then, in the study population of patients in the neurologic ward of Nagoya Daini Red Cross Hospital, a different enterai nutrition rich in copper (Lifelon-PZ, Nikken Co, Ltd.) was given as a new standard diet for patients (Table I). Serum copper levels were monitored in patients who had been fed the new standard enteral nutrition. The study then investigated the relation between copper deficiency and duration of enteral nutrition. The mean age of patients was 71 11 (range, 40-96) years. Patients receiving enterai tube feeding began receiving a standard tube-feeding protocol. The clinical details and indication for enterai nutrition are presented in Table II. The daily average dosage of energy was 938 kcal/d (400-1200 kcal/d). Patients with abnormalities of liver or kidney function were excluded.

TABLE I

Formulary of enteral nutrition in 100 mL

Composition of the Diet

A commercial nutrient for enteral administration was used. Lifelon-L and Lifelon-PZ contain 0.06 mg/1000 mL and 0.13 mg/1000 mL of copper, respectively. The formulation of the enteral nutrition is shown in Table I. No supplements of zinc or iron were administered during this experiment.

Sample Analysis for Copper

Baseline measures on individual patients were taken every month. Blood was collected at 8 AM. The concentration of copper was measured by nameless atomic absorption spectrophotometry. Other laboratory tests were made using routine methods and protocols. Tests were conducted at the Nagoya Daini Red Cross Hospital. Copper deficiency was diagnosed according to the Shaw criteria.13 The Shaw criteria are anemia, neutropenia, plasma copper level usually <12 g/ dL, and serum ceruloplasmin <10 g/dL.

Latent Copper Deficiency

The copper levels were lower than normal range, but not anemia and neutropenia.

Overt Copper Deficiency

The Shaw criteria were applied.13 Overt copper deficiency shows physiologic dysfunctions such as anemia and neutropenia.

RESULTS

Index case

A 57-year-old man with a 4-year history of amyotrophic lateral sclerosis, who had been taking enteral nutrition Lifelon-L (900 kcal/ d formulas with 0.054 mg of copper/d) for 4 years, developed anemia and leukopenia.

His low serum copper (4 μg/dL; normal, 64-156 g/dL) and ceruloplasmin (3 mg/dL; normal, 18-37 mg/dL) levels indicated copper deficiency (Figure 1, day 0), and so 12.8 mg of elemental copper (CuSO^sub 4^.SH^sub 2^O: 50 mg/d) was added daily to the enterai nutrition. Over the next 3 weeks, serum copper levels rose, and the patient's neutropenia and anemia improved rapidly. After 6 weeks of copper supplementation, his anemia improved. Thereafter, the patient did not require red cell transfusion support. Over the next month, serum copper levels rose to 54 g/dL (Figure 1, day 38). After 6 months, the copper supplementation was decreased to 2.56 mg of elemental copper (CuSO^sub 4^.5H^sub 2^O: 10 mg/d). His serum copper levels rose to 60 g/dL. After 8 months, the copper supplementation was decreased to 2.56 mg of elemental copper (CuSO^sub 4^.5H^sub 2^O: 10 mg/week) once a week. Two months after the copper supplementation was decreased to once a week, his serum copper levels rose to 72 g/dL. After 1 year of copper supplementation was begun, the amount was decreased to 1.28 mg of elemental copper (CuSO^sub 4^.5H^sub 2^O: 5 mg/week) once a week. Three months after the copper supplementation was decreased to 1.28 mg once a week, his serum copper levels rose to 85 g/dL (Figure 1).

TABLE II

Clinical data on patients

FIGURE 1. Clinical course of the index case. Evolution of red blood cell (RBC), hemoglobin (Hb), or white blood cell (WBC) counts during recovery from pancytopenia on a low-copper diet. The administration of copper sulfate led to a rapid improvement in the anemia and neutropenia.

Monitoring Serum Copper Levels

After the index case, a different enteral nutrition with a greater amount of copper (0.13 mg/1000 mL) was given as a new standard diet for patients. Serum copper levels were monitored in enteral nutrition patients who had been fed the new diet.

The study included 55 patients and 82 measurements. The range of serum copper levels in the patients before the start of enteral nutrition was 94.0-181.0 g/dL (normal: 64-156 g/dL). Three months after the start of enteral nutrition, the range was 3.0-123.0 g/dL. The level of serum copper was kept within the normal range for about 3 months. However, it was decreased gradually to drop below normal levels after 3 months, with the exception of 1 patient (Figure 2A, R^sup 2^ = 0.916).

Monitoring Ceruloplasmin Levels

Ceruloplasmin levels were monitored because ceruloplasmin has the capacity to form copper complexes and is a multifunctional protein involved not only in the mobilization of plasma iron but also in copper transport and in the regulation of biogenic amines. This phase of the study included 43 patients and 66 measurements. The range of ceruloplasmin levels in the patients before the start of enteral nutrition was 23.0-46.0 mg/dL (normal: 25-35 mg/dL). The range 3 months after the start of enteral nutrition was 2.0-124.0 mg/ dL. The level of ceruloplasmin was not correlated with the period of enterai nutrition (Figure 2B, R^sup 2^ = 0.406). However, there was a correlation between the serum copper level and ceruloplasmin level (Figure 3A, R^sup 2^ = 0.884).

Symptoms of Copper Deficiency

According to the definition of copper deficiency provided by Shaw, only 2 patients (3 measurements) out of 55 patients were deficient in copper (3.6%). Symptoms appeared at 41 and 77 (average, 59) months (Table III).

Monitoring Hemoglobin (Hb) Levels

A deficiency of copper usually presents as anemia and leukopenia. Hb levels had \been checked every month. The effect of low copper enteral nutrition on the level of Hb was investigated. This phase of the study included 49 patients and 77 measurements. The range of Hb levels in the patients before the start of enteral nutrition was 6.2- 15.1 g/dL (normal: 12.0-16.0 g/dL). The range 3 months after the start of enteral nutrition was 4.0-15.5 g/dL. The levels of Hb were not correlated with the period of enterai nutrition (Figure 4A).

FIGURE 2. Correlation between the period of enteral nutrition and serum copper (A) and ceruloplasmin (B) levels. Studies A and B included 55 and 43 patients, with 82 and 66 measurements, respectively. The levels of copper were measured by nameless atomic absorption spectrophotometry. One dot represents 1 time point of sample. We draw a line through the sample for given patients to show that all these are from 1 person. The thick line represents the mean of data in all patients.

Monitoring White Blood Cell (WBC) Counts

WBC counts were checked every month. Therefore, the effect of low copper enteral nutrition on numbers of WBC was investigated. The study included 49 and 77 measurements. The range of WBC count in the patients before the start of enteral nutrition was 4.2-9.4 10^sup 3^/L (normal: 4.5-8.5 10^sup 3^/L). The range of 3 months after the start of enteral nutrition was 2.1-18.0 103/L. The WBC counts were not correlated with the period of enteral nutrition (Figure 4B).

FIGURE 3. Correlation between the serum copper and the serum ceruloplasmin (A) or the serum zinc (B) level. One dot represents 1 time point of sample. The lines show the correlation among copper, ceruloplasmin, and zinc. A, Patient with copper deficiency.

TABLE III

Copper deficiency symptoms in 2 patients and 3 measurements

Monitoring Zinc Levels

Zinc levels were monitored because zinc interferes with copper use by inducing intestinal metallothionein. This phase of the study included 30 patients and 52 measurements. The range of serum zinc concentrations in the patients before the start of enteral nutrition was 95.0-139.0 g/dL (normal: 64.0-111.0 g/dL). The range 3 months after the start of enteral nutrition was 55.0-152.0 g/dL. The levels of zinc were not correlated with the period of enteral nutrition (Figure 4C). There was no correlation between the serum copper level and serum zinc level (Figure 3B, R^sup 2^ = .097).

FIGURE 4. Relation between the period of enterai nutrition and Hb (A), WBC (B), and serum zinc (C) levels. The study included 49 patients, with 77 measurements (A, B). The study included 30 patients and 52 measurements (C). One dot represents 1 time point of the sample.

DISCUSSION

A wide variety of enteral feeding solutions are available in Japan. Most commercial enteral feeding solutions contain adequate amounts of copper between 0.5 and 3.0 mg/1000 mL.14 In Japan, solutions used for enteral feeding have been classified prescription or nonprescription enteral nutrition by the government to control medical cost. The price of the nonprescription one is much cheaper than that of the prescription one. Therefore, many hospitals use the nonprescription one instead of the prescription one. However, nonprescription enteral nutrition solutions are prepared from a limited number of food items, and sometimes the amount of items is not sufficient. In addition, we cannot change the amount of trace elements of commercially available nonprescription enteral feeding solutions, because Japanese food hygiene law prohibits adding trace elements to the nonprescription one. Therefore, if medical staff would not care about this point, the patients would be deficient of trace elements.

Cordano et al14 first reported a deficiency of copper in infants and young children in 1964. Symptoms of copper deficiency have been reported in patients treated with a high-calorie infusion solution long term.3-9 Copper deficiency has been reported less frequently after the development of trace element preparations for addition to parenteral nutrition. However, copper deficiency symptoms have recently been reported in patients treated with enterai nutrition.10- 12

Copper deficiency has been found in a number of patients classified according to the following criteria: (a) insufficient intake of copper, prolonged intake of copper diets by oral and parenteral routes3-9,15-17; (b) malabsorption of copper, chronic diarrhea,15,17-18 intestinal malabsorption syndrome,3,15 short- bowel syndrome,18 alkaline therapy for renal tubular acidosis19; (c) excess loss of copper, prolonged use of chelating agents,2 and chronic ambulatory peritoneal dialysis20; (d) poor liver stores of copper, premature infants.4,15,17 Patients were observed receiving an insufficient intake of copper belonging to the first category. Some defined-formula diets do not contain sufficient copper.

In most studies, the amount of nutrition that patients received by enteral nutrition set the calorie intake at 1000-2000 kcal/d. In this study, patients were fed 900 mL of Liferon-PZ per day, which yielded 900 kcal. Because the patients enrolled in this study are aged and confined to bed, their energy metabolism is assumed to be low.21 In addition, their body weight is lower (44.8 7.9 kg on average) than that of subjects in other studies. This prompted the administration of 900 mL of Liferon-PZ per day. Giving smaller amounts of enterai nutrition raises the concern that it may cause a deficiency of some micronutrient or vitamin, potentially complicating the analysis of data. However, according to the guidelines for the dietary allowance disclosed by the Ministry of Health, Labor and Welfare of Japan, 900 mL of Liferon-PZ can provide sufficient micronutrients and vitamin for Japanese aged 70 or higher,22 which supports and rationalizes our research design. There is so little copper that the addition of a trace element is necessary for intestinal administration.

In our index case, the hematologic abnormalities showed a dramatic response to copper deficiency because the neutropenia and anemia were improved by addition of copper as shown in Figure 1. Turnlund et al22 demonstrated that copper absorption is dependent on dietary copper intake. The percent absorption will be decreased when dietary copper is increased. The amount of absorption (in mg) is increased when dietary copper is increased but not in proportion to the amount fed. When the amount of copper in the high-copper diet is nearly 10 times more than that in the low-copper diet, the amount of absorption is only doubled.22 In our index case, when the dietary copper level was decreased, the serum copper level increased. Copper deficiency has been regarded as a rare complication of enterai nutrition. In 1988, Higuchi et al10 reported the first case of neutropenia due to copper deficiency in a patient receiving enteral nutrition. Since then, another report of neutropenia and anemia in copper-deficient patients receiving enteral nutrition has been published in 1994.11 All the reported cases mentioned the onset of symptoms of copper deficiency. However, there is no detailed report on how symptoms develop.

Many copper deficiency symptoms are overlooked. The initial levels of serum copper in our patients were normal, except for one severely malnourished patient, whose level was low. Higuchi at al10 reported a significant correlation between copper intake and the serum copper level, indicating that the amount of dietary copper required to maintain normal serum levels is ~20 g/kg/d. Adult dietary recommendations have been estimated at between 1.5 and 3.0 mg of copper per day.24 Although some of the study patients had a negative copper balance during the weeks when their daily intake of copper was 0.25 mg, they did not have low plasma copper levels. Copper body stores in normal adults have been reported to be 50-120 mg.1 This copper is distributed predominantly in the liver. It is likely that the release of copper from the liver continues to maintain normal plasma levels in a state of negative balance. Only when the copper stores are depleted do the plasma levels decline as a result of a total body deficiency.

Despite increased interest in the role of copper deficiency in clinical problems and an increased understanding of the physiologic roles of copper, a diagnosis for marginal deficiency has not been established. There is only 1 report about copper deficiency symptoms in infants.13 Only 2 of our cases applied to the definition of Shaw. However, our data show that almost all the study patients had latent copper deficiency about 3 months after the start of enteral nutrition. Latent copper deficiency represents an early stage of copper deficiency in which copper stores are depleted but Hb levels remain unaffected. Dietary copper deficiency progresses in a sequence of 3 overlapping stages with the same progress as iron deficiency.25 In the first 2 stages, copper stores and the copper in blood are depleted, and the last stage occurs with diminished production of copper proteins that have known physiologic functions. The early stage of copper deficiency is defined as latent copper deficiency, and the manifest or last stage appears as anemia, leukopenia, neutropenia, and skeletal abnormalities.

Latent copper deficiency represents an early stage of copper deficiency in which stores are depleted but Hb levels remain unaffected. This stage is characterized by copper depletion concomitant with a low serum copper concentration and undersaturation of the serum copper concentration and undersaturation of ceruloplasmin. It should be noted that there is latent copper deficiency during low copper diet intake and that hypocupremia is not always associated with anemia and neutropenia. Copper deficiency associated with hematologic abnormalities should be supplemented during long-term nutrition for long-term bed-ridden elderly patients. It is evident from our data that the feeding o\f a marginally copper-deficient diet maintained Hb levels in the normal range for some time, but thereafter a slight decrease occurred.

In our results, there was a significant correlation between copper levels and ceruloplasmin levels. The synthesis of ceruloplasmin still proceeds in a copper-deficient state, but copper is necessary to provide the molecule with its ferroxidase activity, which appears to be beneficial in scavenging free oxygen radicals generated from neutrophils and macrophages. A further benefit of the ceruloplasmin changes is that they may have a role in the transport of Fe as a result of the ferroxidase activity. At least 3 mechanisms have been proposed for the anemia due to copper deficiency11: (1) a reduction in ceruloplasmin impairs iron transfer from macrophages and hepatocytes to plasma, resulting in hypoferremia in the presence of normal iron stores; (2) iron cannot be incorporated into heme because of a diminished mitochondrial uptake of iron, and as a result, iron accumulates within the cytoplasm, forming sideroblasts; or (3) erythrocyte survival is shortened by a membrane defect secondary to the decreased activity of superoxide dismutase. Hirase et al26 have measured copper/zinc superoxide dismutase (Cu/Zn-SOD) activity in erythrocytes because of the dependency on copper for activity. They found that the Cu/Zn-SOD activity in copper- deficient subjects is 20% of the normal erythrocyte Cu/Zn-SOD value. They concluded that the shortened life span of erythrocytes is due to a decrease of Cu/Zn-SOD, an antioxidant. Erythrocyte and extracellular SOD is reduced with more severe copper restriction but confers no advantage over plasma copper, because of a lack of adequate sensitivity and specificity.27

The leukocytes in peripheral blood are known to be a sensitive indicator of copper deficiency.16 The mechanism by which copper deficiency results in neutropenia is not known. Copper deficiency may damage the cell from either within the bone marrow or within the circulation. Copper deficiency might impair the rate of cell synthesis or differentiation or might cause a more rapid rate of cellular destruction and clearance. There are several possibilities by which copper deficiency results in neutropenia.28 The mechanisms for the neutropenia during copper deficiency may include a decrease in neutrophil life span a defect in maturation15 and antineutrophil antibody.29 Infection may produce a transient neutrophilic response despite the presence of copper deficiency. In our study, the infectious disease was not recognized. In our results, even with the low copper value, WBC counts may not have always been low. More research in this area is needed.

Copper deficiency also commonly occurs in people who consume high levels of zinc.30,31 Zinc interferes with copper use by inducing intestinal metallothionein that subsequently blocks the transport of copper across the enterocyte.30 The morphological findings in zinc- induced neutropenia are identical to those found in copper deficiency.31 However, the serum copper level did not always relate to the zinc level in our case.

In conclusion, this is the first report on latent copper deficiency in patients receiving enteral nutrition long-term. We suggest that the serum copper level be monitored closely during long- term enteral nutrition and that a defined-formula diet that does not contain sufficient copper not be used unless enteral feeding is used for only a short period.

REFERENCES

1. Turnlund JR. Copper. In: Shils ME, Oison JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. Philadelphia, PA: Lippincott Williams & Wilkins; 1998:241-252.

2. Henkin RI, Reiser HR, Jafee IA, Sternlieb I, Scheinberg IH. Decreased taste sensitivity after D-penicillamine reversed by copper administration. Lancet. 1967;2:1268-1271.

3. Shike M, Roulet M, Kurian R, Whitwell J, Stewart S, Jeejeebhoy KN. Copper metabolism and requirements in total parenteral nutrition. Gastroenterology. 1981;81:290-297.

4. Suita S, Masumoto K, Yamanouchi T, Nagano M, Nakamura M. Complications in neonates with short bowel syndrome and long-term parenteral nutrition. JPEN J Parenter Enteral Nutr. 1999; 23(suppl):S106-S109.

5. Spiegel JE, Willenbuncher RF. Rapid development of severe copper deficiency in a patient with Crohn's disease receiving parental nutrition. JPEN JParenter Enteral Nutr. 1999;23:169-172.

6. Wasa M, Satani M, Tanano H, Nezu R, Takagi Y, Okada A. Copper deficiency with pancytopenia during total parenteral nutrition. JPEN J Parenter Enteral Nutr. 1994;18:190-192.

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8. Sriram K, O'Gara JA, Strunk JR, Peterson JK. Neutropenia due to copper deficiency in total parenteral nutrition. JPEN J Parenter Enteral Nutr. 1986;10:530-532.

9. Fuhrman MP, Herrmann V, Masidonski P, Eby C. Pancytopenia after removal of copper from total parenteral nutrition. JPBN J Parenter Enteral Nutr. 2000;24:361-366.

10. Higuchi S, Higashi A, Nakamura T, Matsuda I. Nutritional copper deficiency in severely handicapped patients on a low copper enterai diet for a prolonged period: estimation of the required dose of dietary copper. J Pediatr Gastroenterol Nutr. 1988;7:583-587.

11. Tamura H, Hirose S, Watanabe O, et al. Anemia and neutropenia due to copper deficiency in enterai nutrition. JPEN J Parenter Enteral Nutr. 1994;18:185-189.

12. Masugi J, Amano M, Fukuda T. Copper deficiency anemia and prolonged enteral feeding. Ann Intern Med. 1994;121:386.

13. Shaw JC. Trace elements in the fetus and young infant, II: copper, manganese, selenium, and chromium. Am J Dis Child. 1980;134:74-81.

14. Shike M. Enteral feeding. In: Shils ME, Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. Philadelphia, PA: Lippincott Williams & Wilkins; 1998:1643-1656.

15. Cordano A, Placko RP, Graham GG. Copper deficiency in infancy. Pediatrics. 1964;34:324-336.

16. Cordano A, Placko RP, Graham GG. Hypocupremia and neutropenia in copper deficiency. Blood. 1966;28:280-283.

17. Graham GG, Cordano A. Copper depletion and deficiency in the malnourished infant. Johns Hopkins Med J. 1969;124:139-150.

18. Cordano A, Grahma GG. Copper deficiency complicating severe chronic intestinal malabsorption. Pediatrics. 1966;38:596-604.

19. Nishi Y, Kittaka E, Fukuda K, Hamano S, Usui T. Copper deficiency associated with alkali therapy in a patient with renal tubular acidosis. J Pediatr. 1981;98:81-83.

20. Becton DL, Schultz WH, Kinney TR. Severe neutropenia caused by copper deficiency in a child receiving continuous ambulatory peritoneal dialysis. J Pediatr. 1986;108:735-737.

21. Yamanaka C. Nutritional assessment for patients with neurosurgical diseases. Neurol Surg. 1993;21:703-709.

22. Health and Nutrition Division. Recommended Dietary Allowances for the Japanese, 5th ed. Tokyo, Japan: Dai-Ichi Shuppan Publishing Co; 1996.

23. Turnlund JR, Keyes RW, Anderson LH, Acord LL. Copper absorption and retention in young men at three levels of dietary copper by use of the stable isotope ^sup 65^Cu1-4. Am J Clin Nutr. 1989;49:870-878.

24. Food and Nutrition Board. Recommended Dietary Allowances. 10th ed. Washington, DC: National Academy Press; 1989:224-230.

25. Dallman PR. Manifestations of iron deficiency. Semin Hematol. 1982;19:19-30.

26. Hirase N, Abe Y, Sadamura S, et al. Anemia and neutropenia in a case of copper deficiency: Role of copper in normal hematopoiesis. Acta Haematol. 1992;87:195.

27. Hambidge M. Biomarkers of trace mineral intake and status. J Nutr. 2003;133(suppl 3):948S-955S.

28. Susan SP. Neutropenia cause by copper deficiency: possible mechanism of action. Nutr Rev. 1995;53:59-66.

29. Higuchi S, Higashi A, Nakamura T, Yanabe Y, Matsuda I. Antineutrophil antibodies in patients with nutritional copper deficiency. Eur J Pediatr. 1991;150:327-330.

30. Prasad AS, Brewer GJ, Schoomaker EB, Rabbani P. Hypocupremia induced by zinc therapy in adults. JAMA. 1978;240:2166-2168.

31. Botash AS, Nasca J, Dubowy R, Weinberger HL, Oliphant M. Zinc- induced copper deficiency in an infant. Am J Dis Child. 1992;146:709- 711.

Yuki Ito, MS*; Tetsuo Ando, MD[dagger]; and Toshitaka Nabeshima, PhD[double dagger]

From the * Department of Pharmacy, Nagoya Daini Red Cross Hospital, Nagoya, Japan, [dagger] Department of Neurology, Anjo Kosei Hospital, Anjo, Japan, and [double dagger] Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan

Received for publication January 28, 2004.

Accepted for publication April 15, 2005.

Correspondence: Yuki Ito, Nagoya Daini Red Cross Hospital, 2-9 Myoken-cho Showa-ku, Nagoya, Aichi 466-8650, Japan. Electronic mail may be sent to yuki@yakujien.com.

Copyright American Society for Parenteral and Enteral Nutrition Sep/ Oct 2005

Source: JPEN, Journal of Parenteral and Enteral Nutrition

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