Original Research
Serum Zinc and Copper Status in Hospitalized vs. Healthy Elderly Subjects Slimane Belbraouet, PhD, Hughes Biaudet, PhD, Ambroise Te´bi, PhD, Nearkasen Chau, PhD, Katherine Gray-Donald, PhD, and Ge´rard Debry, PhD, MD Centre de Nutrition Humaine, Nancy (A.T., G.D.), ISHA (H.B.), Inserm (N.C.), Paris, FRANCE, ESANEF, Universite´ de Moncton, New Brunswick (S.B.), School of Dietetic and Human Nutrition, McGill University, Montreal, Quebec (K.G.-D.), CANADA Key words: trace elements, zinc, copper, elderly, chronic diseases Objective: To assess serum zinc and copper concentrations of elderly hospitalized patients with a broad range of diseases and compare their levels to those of healthy community dwelling controls of similar age. Methods: This case-control study compared serum zinc and copper levels of 668 hospitalized subjects, aged 70 or over, with 104 healthy controls of the same age and from the same geographical area. The study protocol, conducted by one physician on the day after the admission to the hospital, included a questionnaire on sociodemographic characteristics, a medical examination, and serum zinc and copper measured with flame atomic absorption spectrophotometry. Data were analysed using analysis of covariance, controlling for age and sex. Results: The diseased subjects had markedly lower zinc concentrations than the control group. The frequency of low values (⬍0.70 mg/L) was high (20.2% vs. zero in controls, p ⬍ 0.001), and it differed among various disease categories: 35.7% for respiratory disease, 20%- 27% for cancer, infectious disease, trauma, blood diseases, and genitourinary diseases, and less than 20% for the other diseases. Low values for serum copper concentration (⬍0.80 mg/L) were rare in hospitalized subjects (1.4% vs. zero in controls). Whatever the disease category and number of diagnoses considered, the serum copper/zinc ratio was significantly (p ⬍ 0.001) higher in diseased than in healthy people. Conclusions: Elderly hospitalized patients are at elevated risk of low zinc but not copper values. The significantly lower values of serum zinc found in the hospitalized elderly compared to healthy elderly are likely to be related to disease rather than to aging per se. In addition to other classic anthropometric (BMI) and biological (serum proteins) nutritional parameters, copper/zinc ratio may be a useful marker of malnutrition.
INTRODUCTION
Serum zinc and copper have been studied in both healthy and ill elderly subjects with specific health conditions [9,10 – 12], and have been often used, with other parameters, in the assessment of their nutritional status. However, these studies have been done in small samples and have not been studied in a broad range of pathologies. The aim of this study was to assess serum zinc and copper concentrations of older hospitalized patients with different diseases and compare their levels to those of healthy community dwelling controls of similar age. Protein malnutrition is the dominant factor influencing weight loss and mortality, and zinc malnutrition is associated with reduced survival time and may contribute to global immunosuppression [13]. Therefore
With advancing age, there is a higher incidence of chronic diseases and many bear a nutritional component, either as a cause or result of that condition. The trace elements, such as zinc and copper, are constituent components of many metalloproteins and metalloenzymes and a deficiency of one of these elements could lead to a impairment of organ function [1]. Decreased plasma zinc concentration [2,3] and elevated plasma copper levels have been reported among the elderly [4 – 6]. In older people, it is difficult to distinguish whether the changes in trace element status are due to the aging process [7] or are mainly associated with chronic disease [8].
Address reprint requests to: S. Belbraouet, Ecole de Nutrition, Universite´ de Moncton, Moncton, New Brunswick E1A 3E9, CANADA. E-mail:
[email protected]
Journal of the American College of Nutrition, Vol. 26, No. 6, 650–654 (2007) Published by the American College of Nutrition 650
Elderly and Serum Zinc and Copper Concentrations knowledge of zinc status in the diseased elderly may be helpful information for health care professionals to correct possible nutritional deficiencies detected at hospital admission.
MATERIALS AND METHODS A total of 668 patients (217 men and 451 women), aged 70 or older, admitted over a 1-year period to the Nancy University Hospital Geriatric Department, accepted to participate in this study. This geriatric unit serves patients from throughout Lorraine (2.3 million inhabitants, in north-eastern France). The only inclusion criterion was age. These patients were compared to a sample of 104 healthy randomly chosen subjects (27 men and 77 women) aged 70 or over, living autonomously in residential flats for seniors which serve the same geographical area. The healthy elderly group had good health status and no chronic diseases at the time. The health status was assessed in healthy and hospitalized patients by a medical examination (blood pressure, electrocardiogram, pulmonary radiography). None of the hospitalized or the healthy subjects reported taking vitamin/mineral supplements, but it is likely that some of the patients forgot to report them or were confused about the pills they were taking. The study protocol, conducted by one physician on the day after admission to the geriatric unit, included a questionnaire on sociodemographic characteristics and a medical examination where the main diagnosis and up to five secondary diagnoses were noted. The diagnoses were coded according to the WHO classification system [14]. Informed consent was obtained from each subject. Height was measured with a “microtoise”, and the weight with an electronic balance (accuracy 200 grams). The body mass index (BMI) was defined as weight/height2 (kg/m2). Venous blood was drawn from subjects in the morning after a 12h overnight fast at the beginning of their hospitalization. For serum zinc and copper concentrations, the samples were collected in trace metal-free tubes to avoid contamination and analyzed on the day the blood was collected. All the measurements were carried out by the same team at the Chemical Laboratory of Nancy Hospital. Serum zinc and copper were analyzed by flame atomic absorption spectrophotometry (Perkin-Elmer AA300). Recovery was 96.5% and 99.8% for serum zinc and copper respectively. All values reported in the study were the mean of three consecutive determinations. Values under 10.7 mol/L (0.70 mg/L) [15] and 12.7 mol/L (0.80 mg/L) [16] for zinc and copper plasma concentrations respectively, are considered as the cut-off values commonly used to determine risk of deficiency. Albumin was evaluated with radial immunodiffusion using Norpartigen plates from Behring Diagnostics [17]. The comparison of the serum concentration values between the patients with each category of disease and the healthy subjects was made using analysis of covariance adjusting for age and sex. The frequency of low values was compared using
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
the Fisher’s exact probability test. In order to detect a difference of 0.5 sd, between means of the two groups for copper and zinc, with a type 1 error of 0.05 and power of 0.95, a sample size of approximately 105 was required. A correlation between serum albumin and serum zinc was run in order to identify factors known or suspected to affect serum zinc concentrations. The analyses were performed via using Stata program (Stata Corporation: Stata Statistical Software: release 5.0. 702 University Drive Est, College Station, Texas: Stata Corporation, 1997).
RESULTS The healthy and the diseased samples were of similar age (80.4 ⫾ 5.3 vs. 80.9 ⫾ 6.0 yr) and each had a similar percentage of men (26% vs. 32%). The most common diagnoses among the hospitalized subjects were cardiovascular disease, psychiatric illness, and respiratory disease. Among the diseased subjects, 54.3% had one diagnosis, 31.4% two, and 14.2% three or more. Table 1 shows that all the healthy subjects had zinc and copper concentrations above the threshold values (0.70 and 0.80 mg/L respectively). Overall 20% of hospitalised subjects had zinc concentrations lower than the threshold value. The proportion of subjects with low zinc values increased markedly with age. The percentage of hospitalized subjects with zinc concentrations below the threshold value varied by diagnostic category. Indeed, the frequency of low values was particularly high in patients with respiratory disease (35.7%); between 20% and 27% for cancer, infectious disease, trauma, blood diseases, and genitourinary diseases, and lower than 20% for the other diseases. The healthy subjects had significantly higher (1.10 ⫾ 0.12 mg/L) serum zinc levels than the diseased subjects in all disease categories (0.87 ⫾ 0.19 mg/L). In contrast, for serum copper the percentage of diseased subjects with concentrations lower than the threshold value (0.80 mg/L) was low (1.4%). In fact, mean serum copper levels for some disease groups appeared to be higher than among the healthy controls. The serum copper/zinc ratio was significantly (p ⬍ 0.001) higher in diseased than in healthy people whatever the disease category. In addition, serum albumin concentration was positively correlated with zinc serum level both in healthy (r ⫽ 0.39; p ⬍ 0.0001) and diseased (r ⫽ 0.39; p ⬍ 0.0001) elderly subjects. Finally, it should be noted that the BMI varied considerably and was significantly higher in healthy than in diseased persons. In the patient group a significative positive correlation with BMI and serum zinc value was observed (r ⫽ 0.12, p ⫽ 0.007) but no such association was observed among the healthy elderly group
DISCUSSION The present study assessed the serum zinc and copper status of 668 elderly patients with a wide range of diagnoses and
651
652 27.0 ⫾ 4.0 23.9† ⫾ 4.7 24.1† ⫾ 4.7 23.7† ⫾ 4.5 23.5† ⫾ 5.1 24.8‡ ⫾ 5.4 24.7‡ ⫾ 5.3 23.6† ⫾ 4.5 23.0† ⫾ 4.0 24.0† ⫾ 4.5 24.5* ⫾ 5.5 24.1‡ ⫾ 5.4 23.3† ⫾ 5.3 24.3* ⫾ 4.6 24.6† ⫾ 4.1 23.8† ⫾ 4.5 23.6† ⫾ 4.9 25.0‡ ⫾ 5.0
Age (ys) 80.4 ⫾ 5.3 80.9 ⫾ 6.0 81.3 ⫾ 6.0 79.6 ⫾ 5.6 82.3 ⫾ 6.4 81.4 ⫾ 5.7 81.1 ⫾ 6.4 81.9 ⫾ 5.4 79.7 ⫾ 5.2 78.4 ⫾ 6.0 80.5 ⫾ 6.1 82.2 ⫾ 5.7 82.5 ⫾ 5.9 81.4 ⫾ 6.4 80.0 ⫾ 6.1 80.9 ⫾ 6.1 80.7 ⫾ 6.1 81.1 ⫾ 5.8
104 668
276 192 109
73
51 44 39
36 35 35 31 20 84
363 210 95
337 194 88
33 33 34 29 19 80
50 42 35
69
252 180 98
104 619
No of Values
0.88† ⫾ 0.21 0.86† ⫾ 0.18 0.87† ⫾ 0.18
0.94 ⫾ 0.16 0.87† ⫾ 0.23 0.81† ⫾ 0.19 0.87† ⫾ 0.21 0.84† ⫾ 0.15 0.88† ⫾ 0.17
0.87† ⫾ 0.15 0.88† ⫾ 0.19 0.89* ⫾ 0.30
0.87† ⫾ 0.19
0.86† ⫾ 0.18 0.90† ⫾ 0.18 0.80† ⫾ 0.20
1.10 ⫾ 0.12 0.87† ⫾ 0.19
Mean ⫾ SDb
Zinc (mg/L)
20.8† 20.1† 18.2†
6.1 21.2† 26.5† 24.1† 21.0† 15.0†
14.0† 19.0† 25.7†
18.8†
19.4† 13.3† 35.7†
0 20.2†
⬍0.70 mg/L (%c)
346 201 92
36 35 34 29 19 80
50 42 36
71
263 186 103
104 639
No of values
1.45 ⫾ 0.35 1.47 ⫾ 0.36 1.41 ⫾ 0.30
1.31 ⫾ 0.32 1.42 ⫾ 0.30 1.42 ⫾ 0.27 1.38 ⫾ 0.44 1.45 ⫾ 0.37 1.49* ⫾ 0.41
1.43 ⫾ 0.28 1.41 ⫾ 0.42 1.46* ⫾ 0.34
1.50* ⫾ 0.33
1.49* ⫾ 0.34 1.39 ⫾ 0.35 1.52‡ ⫾ 0.34
1.41 ⫾ 0.21 1.45 ⫾ 0.35
Mean ⫾ SDb
Copper (mg/L)
1.2 2.1 3.4
5.6 2.9 0 6.9 0 1.2
2.0 0 2.8
0
0.8 2.1 0
0 1.4
⬍0.80 mg/L (%c)
* p ⬍ 0.05, ‡ p ⬍ 0.01, † p ⬍ 0.001. The sum of the numbers of subjects with different diseases was higher than 668 as some subjects had more than one disease. Each group of patients with a category of diseases was compared with the healthy subjects using aanalysis of covariance controlling for age and sex, and bthe Fisher exact test.
Healthy sample Hospitalized sample Cardio-vascular diseases Mental disturbance Respiratory diseases Endocrine and metabolic diseases Osteo-muscular diseases Digestive diseases Cancers Nervous system diseases Infectious diseases Trauma Blood diseases Genitourinary diseases Undefined symptoms Number of diagnoses 1 2 ⱖ3
Body mass index (kg/m2)
No of Subjects
1.77† ⫾ 0.66 1.82† ⫾ 0.68 1.71† ⫾ 0.57
1.45* ⫾ 0.55 1.80† ⫾ 0.81 1.80† ⫾ 0.39 1.64† ⫾ 0.56 1.77† ⫾ 0.47 1.80† ⫾ 0.70
1.73† ⫾ 0.60 1.70† ⫾ 0.73 1.80† ⫾ 0.73
1.83† ⫾ 0.68
1.82† ⫾ 0.60 1.63† ⫾ 0.64 2.03† ⫾ 0.73
1.30 ⫾ 0.23 1.77† ⫾ 0.65
Mean ⫾ SDb
87.7† 90.2† 87.5‡
72.7 87.9* 100.0† 79.3 89.5 92.3†
84.0 85.7 85.7
89.9‡
91.2† 83.2* 100.0†
70.9 88.5†
⬎ 1.15 (%c)
Ratio Copper/Zinc
Table 1. Values and Frequency of Low Values of Serum Zinc and Copper Concentrations for the Hospitalized Subjects by Diagnosis and the Healthy Subjects
Elderly and Serum Zinc and Copper Concentrations
VOL. 26, NO. 6
Elderly and Serum Zinc and Copper Concentrations compared them to healthy controls of the same age and from the same region. Our survey found that hospitalized but not healthy subjects frequently present low serum zinc levels and, in agreement with Schmuck et al. [18], Scrinivas et al. [19], and Dey et al. [20], hospitalized subjects had markedly lower values than healthy controls. As reported by Mezzetti et al [21], the significantly decreased serum zinc in diseased elderly suggests that diseases more than aging per se, is associated with lower serum zinc status. In addition, zinc values were less likely to be low in the patients with mental disturbances or nervous system disease. This was consistent with the results from other studies which have shown that low zinc level was nearly always noted in diseased elderly [22,23] with the exception in subjects with mental illness [24]. The decrease in serum zinc was very evident in patients with respiratory disease. It was generally recognized that plasma zinc concentrations are influenced by pulmonary infections [25]. This is probably due to the release of cytokines, which stimulates metallothionein synthesis and leads to hepatic sequestration of circulating zinc [26]. While the major variables affecting serum zinc concentrations are age, diet and gender [27], changes in plasma zinc can be secondary to modification in zinc binding proteins or to changes in the distribution among tissues. Most of the zinc in serum being linked to albumin [28], the lower serum zinc observed would be partly explained by the decreased serum albumin concentration in the patients studied. In addition, a lower BMI observed in patients than in healthy elderly and a significant correlation with BMI and serum zinc value reported within the patient group suggests an association between low zinc level and malnutrition [29] among the diseased group. The decrease in serum zinc concentration is often accompanied by an increase in copper level [9]. Accordingly, several studies have reported elevated serum copper levels during aging [30 –32]. Serum copper was increased particularly for patients suffering from cardiovascular diseases, cancers, and respiratory diseases. It is well acknowledged that serum copper increases in many physiological or pathological conditions such as cardiovascular diseases [30,32,33] and various cancers [34,35]. An increased copper/zinc ratio was observed for all categories of diseases. In agreement with other studies, advanced age and advanced age-related diseases such as cancers at different sites [16,36], acute myocardial infarction [37], and other degenerative diseases [38] are associated with a higher copper/ zinc ratio [21]. It was more likely due to lower serum zinc levels than higher serum copper levels as a higher level for copper was observed in only a few disease categories. We conclude that elderly patients are at elevated risk of low zinc values but not for copper. The significantly lower values of serum zinc found in the hospitalized elderly and not in healthy elderly are likely to be related to disease rather than to aging.
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
In addition to other classic anthropometric (BMI) and biological (serum proteins) nutritional parameters, copper/zinc ratio may be a useful marker of malnutrition of elderly at hospital admission.
ACKNOWLEDGEMENT This investigation has been supported by a grant from the DRASS of the Lorraine and by the Fondation de l’Avenir.
REFERENCES 1. Ikmekcioglu C: The role of trace elements for the health of elderly individuals. Die Nahrung 45:309–316, 2001. 2. Munro HN, Suter PM, Russell RM: Nutritional requirements of the elderly. Annu Rev Nutr 7:23–49, 1987. 3. Monget AL, Galan P, Preziosi P, Keller H, Bourgeois C, Arnaud J, Favier A, Hercberg S: Micronutrient status in elderly people. Geriatrie/Min Vit Aux Network. Int J Vitam Nutr Res 66:71–76, 1996. 4. McMaster D, McCrum E, Patterson CC, Kerr MM, O’Reilly D, Evans AE, Love A H: Serum copper and zinc in random samples of the population of Northern Ireland. Am J Clin Nutr 56:440–446, 1992. 5. Milne DB, Johnson PE: Assessment of copper status: effect of age and gender on reference ranges in healthy adults. Clin Chem 39:883–887, 1993. 6. Prasad AS, Fitzgerald JT, Hess JW, Kaplan J, Pelen F, Dardenn M: Zinc deficiency in elderly patients. Nutrition 9:218–224, 1993. 7. Artacho R, Ruis-Lopez MD, Gamez C, Puerta A, Lopez MC: Serum concentration and dietary intake of Zn in healthy institutionalized elderly subjects. Sci Environ 205:159–165, 1997. 8. Chapman KM, Ham JO, Pearlman RA: Longitudinal assessment of the nutritional status of elderly veterans. J Gerontol A Biol Sci Med Sci 51:B261–269, 1996. 9. Marniemi J, Ja¨rvisalo J, Toikka T, Ra¨iha¨ I, Ahotupa M, Sourander L: Blood vitamins, mineral elements and inflammation markers as risk factors of vascular and non-vascular disease mortality in an elderly population. Int J Epidemiol 27:799–807, 1998. 10. Del Corso L, Pastine F, Protti MA, Romanelli AM, Moruzzo D, Ruocco L, Pentimone F: Blood zinc, copper and magnesium in aging. A study in healthy home-living elderly. Panminerva Medica 42:273–277, 2000. 11. Savarino L, Granchi D, Ciapetti G, Cenni E, Ravaglia G, Forti P, Maioli F, Mattioli R: Serum concentrations of zinc and selenium in elderly people: results in healthy nonagenarians/centenarians. Exp Gerontol 36:327–339, 2001. 12. Smorgon C, Mari E, Atti AR, Dalla Nora E, Zamboni P F, Calzoni F, Passaro A, Fellin R: Trace elements and cognitive impairment: an elderly cohort study. Arch Gerontol Geriatr Suppl 9:393–402, 2004. 13. Peck MD, Alexander JW: Interaction of protein and zinc malnutrition with the murine response to infection. J Parenter Enteral Nutr 6:232–235, 1992.
653
Elderly and Serum Zinc and Copper Concentrations 14. Organisation Mondiale de la Sante´: Classification internationale des maladies. 9e`me re´vision, Vol 1, Gene`ve, 1975. 15. de Jong N, Gibson RS, Thomson CD, Ferguson EL, McKenzie JE, Green TJ, Horwath CC: Selenium and zinc status are suboptimal in a sample of older New Zealand women in a communitybased study. J Nutr 131:2677–2684, 2001. 16. Poo JL, Rosas-Romero R, Montemayor AC, Isoard F, Uribe M: Diagnostic value of the copper/zinc ratio in hepatocellular carcinoma: a case control study. J Gastroenterol 38:104–105, 2003. 17. Mancini G, Carbonara AO, Hermans JF: Immunochemical quantification of antigens by single radial immunodiffusion. Immunochemistry 2:235, 1965. 18. Schmuck A, Roussel AM, Arnaud J, Ducros V, Favier A, Franco A: Analyzed dietary intakes, plasma concentrations of zinc, copper, and selenim, and related antioxidant enzyme activities in hospitalized elderly women. J Am Coll Nutr 15:462–468, 1996. 19. Scrinivas U, Braconnier H, Jeppsson B, Abdulla M, Akesson B, Ockerman PA: Trace element alterations in infectious diseases. Scan J Clin Lab Invest 48:495–500, 1988. 20. Dey DK, Rothenberg E, Sundh V, Bosaeus I, Steen B: Height and body weight in the elderly. I. A 25-year longitudinal study of a population aged 70 to 95 years. Eur J Clin Nutr 53:905–914, 1999. 21. Mezzetti A, Pierdominico SD, Costantini F, Romano F, De Cesare D, Cuccurullo F, Imbastaro T, Riario-Sforza G, Di Giacomo F, Zuliani G, Fellin R: Copper/zinc ratio systemic oxidant load: effect of aging and aging-related degenerative diseases. Free Radical Biol Med 25:676–681, 1998. 22. Zowczak M, Iskra, M, Torlinski L, Cofta S: Analysis of Serum Copper and Zinc Concentrations in Cancer Patients. Biol Trace Elem Res 82:1–8, 2001. 23. Giles L, Smiciklas-Wright H, Fosmire G, Cerr J: Variations in plasma zinc in older men and women. Biol Trace Elem Res 41:235–243, 1994. 24. Favier A: Zinc et vieillissement. Age & Nutrition 5: 48–64, 1994. 25. Pepersack T, Rotsaert P, Benoit F, Willems D, Fuss M, Bourdoux P, Duchateau J: Prevalence of zinc deficiency and it clinical relevance among hospitalized elderly. Arch Gerontol Geriatr 33: 243–253, 2001.
654
26. Rofe AM, Philcox JC, Coyle P: Trace metal, acute phase and metabolic response to endotoxin in metallothionein-null mice. Biochem J 314:793–797, 1996. 27. Ghayour-Morbahan M, Taylor A, New SA, Lamb DJ, Ferns GA: Determinants of serum copper, zinc and selenium in healthy subjects. Ann Clin Biochem 42:364–375, 2005. 28. Hotz C, Peerson JM, Brown KH: Suggested lower cuttofs of serum zinc concentrations for assessing zinc status: reanalysis of the second National Health and Nutrition Examination Survey data (1976–1980). Am J Clin Nutr 78:756–764, 2003. 29. Pinna K, Woodhouse LR, Sutherland B, Shames DM, King JC: Exchangeable zinc pool masses and turnover are maintained in healthy men with low zinc intakes. J Nutr 131:2288–2294, 2001. 30. Baumgartner TG: Trace elements in clinical nutrition. Nutr Clin Pract 8:251–263, 1993. 31. Arnaud J, Chappuis P, Jaudon MC, Bellanger J: Marqueurs biologiques nutritionnels des carences en zinc, cuivre et se´le´nium. Ann Biol Clin 51:589–604, 1993. 32. Milne B: Assessment of copper nutritional status. Clin Chem 40: 479–484, 1994. 33. Strain JJ: Newer aspects of micronutrients in chronic disease: copper. Proc Nutr Soc 53:583–598, 1994. 34. Kok FJ, Van Duijn CM, Hofman A, Van Der Voet GB, De Wolff FA, Paays CHC, Valkenburg HA: Serum copper and zinc and the risk of death from cancer and cardiovascular disease. Am J Epidemiol 128:352–359, 1988. 35. Overvad K, Wang DY, Olsen J, Allen DS, Thorling EB, Bulbrook RD, Hayward JL: Copper in human mammary carcinogenesis: a case-cohort study. Am J Epidemiol 137:409–414, 1993. 36. Gupta SK, Singh SP, Shukla VK: Copper, zinc, and Cu/Zn ratio in carcinoma of the gallbladder. J Surg Oncol 91:204–208, 2005. 37. Vilanova A, Gutierrez C, Serrat N, Raga X, Paternain JL: Metallothionein, zin and copper levels-relationship with acute myocardial infarction. Clin Biochem 30:235–238, 1997. 38. Madaric A, Ginter E, Kadrabova J: Serum copper, zinc and copper/zinc ratio in males: influence of aging. Physiol Res 43: 107–111, 1994.
Received October 3, 2005; revision accepted May 18, 2006.
VOL. 26, NO. 6
