Low Serum Selenium Is Associated with Anemia Among Older Adults in the United States

ORIGINAL ARTICLE Low serum selenium is associated with anemia among older adults in the United States

RD Semba1, MO Ricks1, L Ferrucci2, Q-L Xue1, JM Guralnik3 and LP Fried1

1The Johns Hopkins Medical Institutions, Baltimore, MD, USA; 2Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA and 3Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, MD, USA

Objective: We hypothesized that low serum selenium was associated with anemia in humans. Subjects: A total of 2092 adults aged 65 and older, in the third National Nutrition Examination Survey, Phase 2 (1991–1994) (NHANES III). Methods: Examination of the relationship between serum selenium and hematological indices in NHANES III. Results: Anemia, defined by World Health Organization criteria, was present in 12.9%. Mean serum selenium among non-anemic and anemic adults was 1.60 and 1.51 mmol lÀ1 (P ¼ 0.0003). The prevalence of anemia among adults in the lowest to highest quartiles of serum selenium was 18.3, 9.5, 9.7 and 6.9%, respectively (P ¼ 0.0005). The proportion of adults in the lowest quartile of selenium among those who were non-anemic or who had anemia due to nutritional causes, chronic inflammation, renal disease or unexplained anemia was 9.9, 27.5, 17.5, 24.0 and 15.4%, respectively. An increase in loge selenium was associated with a reduced risk of anemia (odds ratio per one standard deviation increase 0.75, 95% confidence interval 0.58–0.97, P ¼ 0.03), adjusting for age, race, education, body mass index and chronic diseases. Conclusion: Low serum selenium is independently associated with anemia among older men and women in the United States. European Journal of Clinical Nutrition (2009) 63, 93–99; doi:10.1038/sj.ejcn.1602889; published online 5 September 2007

Keywords: aging; anemia; inflammation; hemoglobin; selenium

Introduction carrying capacity of the blood that occurs with anemia may account for fatigue, cardiovascular complications and Anemia is common in older adults, and the prevalence of impaired physical performance (Lipschitz, 2003). Anemia anemia increases with advancing age (Beghe´ et al., 2004; among older adults is caused by renal failure, chronic Woodman et al., 2005). Among older adults, anemia has inflammation and nutritional deficiencies, and about been associated with a wide spectrum of adverse outcomes one-third of the anemia is unexplained (Guralnik et al., 2004). (Lipschitz, 2003), including reduced quality of life (Thomas, Selenium is an essential trace element and a normal 1998; Valderrabano, 2000), decreased muscle strength constituent of the diet. Selenium is a component of (Cesari et al., 2004), increased disability (Penninx et al., selenoproteins, including selenoenzymes such as glu- 2004), higher risk of Alzheimer’s disease (Beard et al., 1997) tathione peroxidase, selenoprotein-P and thioredoxin and increased all-cause mortality among nursing home reductase (Zimmermann and Ko¨hrle, 2002; Moghadaszadeh residents (Kikuchi et al., 2001), and among moderately to and Beggs, 2006). Serum selenium concentrations seem to severely disabled women living in the community (Chaves decrease with age (Savarino et al., 2001; Bates et al., 2002) et al., 2004). Anemia has also been linked with congestive and are lower in persons with chronic diseases (Bates et al., heart failure (Silverberg et al., 2000) and impaired cognitive 2002). Low serum selenium concentrations have been function (Nissenson, 1992). The reduction of oxygen- associated with increased mortality from cancer (Kok et al., 1987; Kornitzer et al., 2004) and all-cause mortality among older women living in the community (Ray et al., 2006). Low Correspondence: Dr RD Semba, Johns Hopkins University, 550 North Broadway, activity of glutathione peroxidase, a major selenoenzyme, Suite 700, Baltimore, MD 21205, USA. was associated with increased risk of cardiovascular E-mail: [email protected] Received 31 January 2007; revised 22 July 2007; accepted 23 July 2007; events among adults with suspected coronary artery disease published online 5 September 2007 (Blankenberg et al., 2003). Serum selenium and anemia RD Semba et al 94 Animal and human studies suggest that there is a link et al. (2004) in the same study population. Anemia was between selenium deficiency and anemia. Among animals, divided into types of anemia to gain insight into serum selenium deficiency is associated with anemia in hens selenium concentrations within each type of anemia that (Latshaw et al., 1977) and cattle (Morris et al., 1984), but was previously described (Guralnik et al., 2004). Among not rats (Hu et al., 1984). In humans, selenium deficiency anemic adults, iron-deficiency anemia was defined as having may contribute to anemia among dialysis patients (Hampel two or three of the following criteria: transferrin saturation et al., 1985), adults with pulmonary tuberculosis (van Lettow rate less than 15%, serum ferritin concentration o12 ng mlÀ1 et al., 2005), adults in Vietnam (Van Nhien et al., 2006) and and erythrocyte protoporphyrin concentration greater than disabled older women living in the community (Semba et al., 1.24 mM (Looker et al., 1997), folate-deficiency anemia was 2006). However, no information is currently available on defined as red blood cell folate o232.49 nmol lÀ1 or serum À1 serum selenium concentrations and the risk of anemia in the folate o5.89 nmol l , and anemia due to vitamin B12 À1 older population. We hypothesized that low serum selenium deficiency was defined as serum B12 o200 pg ml . Red levels are associated with low hemoglobin among older blood cell folate was used for those who were seen in the adults. To examine this hypothesis, we characterized serum mobile examination center, and serum folate was used as the selenium and hemoglobin among older adults in the indicator of folate status for those in the modified home third National Health and Nutrition Examination Survey examination with phlebotomy, since red blood cell folate (1988–1994) (NHANES III). was not measured in the home visits. Nutritional anemia was defined as anemia due to either iron deficiency, folate

deficiency or deficiency in vitamin B12. Among anemic Methods adults, the anemia due to chronic inflammation was defined as serum iron o60 mgdlÀ1, creatinine clearance The study population consisted of men and women who X30 ml minÀ1 and no evidence of iron deficiency. Anemia participated in phase 2 of NHANES III (1991–1994). Subjects due to renal disease was defined in the presence of creatinine were sampled using a stratified, multistage probability design clearance o30 ml minÀ1. Unexplained anemia was defined

that was representative of a national probability sample of as anemia that was not due to iron, folate or vitamin B12 the civilian noninstitutionalized population of the United deficiencies or due to the anemia of chronic inflammation or States (National Center for Health Statistics, 1994). A full renal disease. The quartiles of selenium were based upon all assessment in NHANES III included a home interview and participants aged 65 or greater and were defined with cutoffs examination, including phlebotomy in a mobile examina- of p1.33, 41.33; p1.49, 41.49 and p1.65, 41.65 mmol lÀ1. tion center. Some people were unable to come to the mobile The National Center for Health Statistics was the source for examination center and underwent a modified home the original data files used in this analysis (US Department of examination that included phlebotomy. Health and Human Services, 1996). Prevalence rates and Laboratory methods for NHANES III have been described distributions were estimated for the US population using in detail elsewhere (Gunter et al., 1996) and are briefly probability weights specific to NHANES III. Descriptive summarized. Hemoglobin was measured using a Coulter-S- statistics were used to characterize the study population, Plus Jr electronic counter (Coulter Electronics, Hialeah, FL, provide information on the distribution of biochemical USA). Serum iron was measured colorimetrically (Alpkem measurements of micronutrients and calculate the preva- RFA Analyzer, Clackamas, OR, USA). Serum ferritin was lence of deficiencies. w2- and trend tests were used to measured using the Quantimmune Ferritin IRMA kit examine the associations between anemia and dichotomized (Bio-Rad Laboratories, Hercules, CA, USA). Folate and covariates. Univariate and multivariate logistic regression

vitamin B12 were measured using the Quantaphase Folate was used to examine the relationship between selenium radioassay kit (Bio-Rad). Serum creatinine was measured by and anemia, with sequential models adjusting for demo- the Jaffe reaction using a Hitachi model 737 multichannel graphic, chronic disease, nutritional and inflammation analyzer (Boehringer Mannheim Diagnostics, Indianapolis, variables that were significant (Po0.05) in univariate

IN, USA), and creatinine clearance was computed using the analyses. Selenium was transformed by loge to achieve a Cockroft–Gault equation: creatinine clearance (ml minÀ1) ¼ normal distribution. To assess the relative strength of ((140Àage) Â kg body weight)/(mg dlÀ1 plasma creatinine Â 72). associations between selenium and anemia, odds ratios and A 15% reduction was given for women (Cockcroft and 95% confidence intervals (CIs) associated with one standard

Gault, 1976). Serum selenium was measured using a graphite deviation increase in loge selenium were reported. Simple furnace atomic absorption spectrometer (PerkinElmer, and multiple linear regression was used to examine the Shelton, CT, USA) with Zeeman background correction relationship of selenium and other risk factors with hemo- (Niskar et al., 2003). globin. Variables that were associated with hemoglobin at a Anemia was defined as hemoglobin o12 g dlÀ1 for women level of Po0.05 were included as covariates in final multi- and o13 g dlÀ1 for men (World Health Organization, 1968). variate linear regression models. Standardized b’s were Different pathophysiological types of anemia were distin- also reported for each predictor to show the strength of guished according to the criteria already used by Guralnik the associations.

European Journal of Clinical Nutrition Serum selenium and anemia RD Semba et al 95 Results model 2, for example, each one-unit increase in loge selenium was associated with an increase of 7.39 g lÀ1 There were 2092 adults (934 men and 1158 women) in phase hemoglobin, and male was associated with a 10.09 g lÀ1 2 of NHANES III who had measurements of hemoglobin, increase in hemoglobin. A level of education o12 years was serum selenium and other blood tests to characterize the associated with a decrease of 0.98 g lÀ1 of hemoglobin. causes of anemia. Overall, 270 (12.9%) of the participants Selenium was related to hemoglobin in a final model were anemic. The main characteristics of study participants (model 3) (P ¼ 0.06) that was adjusted for demographic are shown in Table 1 according to anemia status. Compared factors, BMI and chronic diseases. to participants who were not anemic, those anemic were Among the 270 anemic participants, the proportion of older (P ¼ 0.007), more likely to have education o12 years anemia due to nutritional causes, chronic inflammation, (P ¼ 0.01), to be black (Po0.001) and more often affected by renal disease and unexplained anemia was 35.9, 20.4, 16.3 osteoarthritis (P ¼ 0.01), diabetes (P ¼ 0.003) and renal and 27.4%, respectively. The characteristics of participants disease (Po0.0001). Serum selenium levels were lower in who were non-anemic and who had various types of anemia anemic compared with non-anemic adults (P ¼ 0.0003).

There were borderline differences in body mass index (BMI) 20 between anemic and non-anemic adults (P ¼ 0.09), and no significant differences in the prevalence of smoking, hyper- p <0.0001 tension, congestive heart failure, stroke, angina, cancer, 15 myocardial infarction and cardiovascular disease. The prevalence of anemia was highest in the lowest quartile and lowest in the highest quartile of serum selenium (Figure 1). Multivariate logistic regression models were used to 10 examine the relationship between different risk factors and anemia (Table 2). Selenium was strongly and independently associated with anemia in models adjusted for demographic 5 factors (model 2) and demographic factors and chronic Proportion with anemia (%) diseases (model 3). Multiple linear regression models were also used to examine the relationship between 0 serum selenium and hemoglobin (Table 3). Selenium was Quartile1 Quartile 2 Quartile 3 Quartile 4 significantly associated with hemoglobin in a model Figure 1 Proportion of adults with anemia by quartile of serum that was adjusted for demographic factors (model 2). In selenium in NHANES III, Phase 2, 1991–1994.

Table 1 Characteristics of adults X65 years with and without anemia in NHANES III, Phase 2, 1991–1994

Characteristicsa Anemic (N ¼ 270) Non-anemic (N ¼ 1822) P-value

Age (years) 75.2 (0.6) 73.6 (0.2) 0.007 Sex, women (%) 48.1 58.2 0.026 Race, Black (%) 19.1 6.8 o0.0001 Body mass index, kg mÀ2 (%) o18.5 4.2 2.8 0.09 18.5–24.9 31.7 34.4 25.0–29.9 46.7 37.6 X30 17.4 25.2 Education o12 years (%) 53.1 41.8 0.01 Current smokers (%) 14.3 23.2 0.13 Serum selenium (mmol lÀ1)b 1.51 (1.47, 1.56) 1.60 (1.59, 1.61) 0.0003 Hypertension (%) 52.3 46.5 0.21 Osteoarthritis (%) 28.3 16.4 0.01 Diabetes (%) 20.3 11.3 0.003 Congestive heart failure (%) 10.8 7.5 0.16 Stroke (%) 9.9 8.4 0.5 Angina (%) 34.9 31.9 0.5 Cancer (%) 24.3 21.7 0.5 Myocardial infarction (%) 13.4 12.9 0.87 Cardiovascular disease (%) 42.9 39.9 0.51 Renal disease (%) 21.2 5.6 0.0001 aPopulation-weighted means and percentages. bGeometric mean (95% CI).

European Journal of Clinical Nutrition Serum selenium and anemia RD Semba et al 96 Table 2 Multivariate logistic regression models of risk factors for anemia are shown in Table 4. The participants with anemia due to among adults X65 years in NHANES III, Phase 2, 1991–1994 renal disease tended to be the oldest (P ¼ 0.0003) and had the À2 Variable ORa 95% CI P-value highest proportion with BMI o18.5 kg m (P ¼ 0.007). Mean selenium concentrations were lowest among those Model 1 with anemia due to nutritional causes and anemia of chronic Log selenium 0.68 0.56–0.84 o0.0001 inflammation and highest among those who were non- anemic (P ¼ 0.009). The prevalence of hypertension was Model 2 Log selenium 0.74 0.60–0.91 0.005 highest among participants who had anemia of chronic Age (years) 1.04 1.01–1.07 0.005 inflammation (P ¼ 0.02), and the prevalence of diabetes was Male 1.60 1.10–2.35 0.015 highest among those with anemia of chronic inflammation Black 2.97 2.04–4.33 o0.0001 or unexplained anemia (P ¼ 0.02). The proportion of adults Education o12 years 1.21 0.81–1.80 0.36 who were in the lowest quartile of serum selenium in the Model 3 categories of non-anemic and anemia due to nutritional Log selenium 0.75 0.58–0.97 0.03 causes, chronic inflammation and/or renal disease, and Age (years) 0.99 0.96–1.04 0.87 unexplained anemia are shown in Figure 2. The highest Male 1.27 0.79–2.05 0.32 Black 3.23 1.95–5.35 o0.0001 proportion of participants with low selenium was in those Education o12 years 1.14 0.69–1.86 0.61 with anemia due to nutritional causes and anemia due to À2 b Body mass index (kg m ) renal disease. o18.5 0.80 0.23–2.78 0.73 25.0–29.9 1.54 0.88–2.71 0.13 X30 1.08 0.52–2.25 0.83 Diabetes mellitus 1.39 0.30–0.74 0.30 Discussion Cardiovascular disease 0.86 0.53–1.40 0.55 Renal disease 5.48 2.63–11.41 o0.0001 This study shows that low serum selenium is an independent Osteoarthritis 2.37 1.28–4.38 0.006 risk factor for anemia among older men and women living in Abbreviations: CI, confidence intervals; OR, odds ratio. the community in the United States. Low selenium has not a OR per 1 s.d. increase in loge selenium. usually been considered as a possible cause of anemia in bBMI of 18.5–24.9 kg mÀ2 is the reference category. older adults (Balducci, 2003; Guralnik et al., 2004) and has only been previously implicated in anemia among patients on hemodialysis (Hampel et al., 1985) or with pulmonary tuberculosis (van Lettow et al., 2005). However, a correlation Table 3 Multiple linear regression models of selenium and other risk between low plasma selenium concentrations and low factors with hemoglobin (g dlÀ1) as the outcome, among adults X65 hemoglobin had already been noted in the British National years in NHANES III, Phase 2, 1991–1994 Diet and Nutrition Survey among 1134 men and women Variable Coefficient s.e. Standardized b P-value aged 65 years and older (Bates et al., 2002), and more recently low serum selenium was found to be associated with Model 1 anemia among older disabled women living in the commu- Log selenium 9.72 2.88 0.103 0.001 nity (Semba et al., 2006). A potential biological mechanism by which low selenium Model 2 Log selenium 7.39 2.70 0.078 0.006 could contribute to anemia is through maintenance of an Age (years) À0.16 0.05 À0.079 0.002 optimal concentration of glutathione peroxidase, a key Male 10.09 0.76 0.371 o0.0001 antioxidant selenoenzyme, in erythrocytes (Chow and Black À6.83 0.86 À0.136 o0.0001 Chen, 1980). Glutathione peroxidase protects hemoglobin Education o12 years À0.99 0.73 À0.036 0.18 against oxidation in erythrocytes (Nagababu et al., 2003). Model 3 Although there is little direct evidence that serum selenium Log selenium 5.52 2.94 0.061 0.06 is related to erythrocyte and hemoglobin stability in hu- Age (years) À0.03 0.06 À0.015 0.63 mans, there is a possible relevant example of erythrocyte Male 10.65 0.82 0.410 o0.0001 Black À6.49 1.02 À0.124 o0.0001 damage due to increased oxidative stress in animals (McPhail Education o12 years À0.81 0.81 À0.031 0.31 and Sibbald, 1992) with protection by selenium. Livestock À2 a Body mass index (kg m ) that forage on Brassica (mustard, rape) are susceptible to o18.5 0.02 1.96 0.001 0.99 brassica anemia in which oxidative stress causes excessive 25.0–29.9 0.09 0.94 0.004 0.92 X30 1.81 1.07 0.585 0.09 erythrocyte damage (Prache, 1994), and selenium supple- Diabetes mellitus À0.58 1.24 À0.014 0.63 mentation has been shown to protect animals against Cardiovascular disease 0.31 0.80 0.011 0.69 erythrocyte damage (Rotruck et al., 1972; Gutzwiller, 1991, Renal disease À4.55 1.68 À0.089 0.007 1998). If low serum selenium levels are associated with Osteoarthritis À2.94 1.15 À0.086 0.01 reduced lifespan of erythrocytes in humans, then it would be aBMI of 18.5–24.9 kg mÀ2 is the reference category. anticipated that selenium deficiency would be associated

European Journal of Clinical Nutrition Serum selenium and anemia RD Semba et al 97 Table 4 Serum selenium levels in the types of anemia among adults X65 Years in NHANES III, Phase 2, 1991–1994a

Characteristicsb,c Non-anemic Anemia due to nutritional Anemia of chronic Anemia due to Unexplained P-value causes inflammation renal disease anemia

N 1822 97 55 44 74 Age (years) 73.9 (0.2) 75.7 (1.1) 72.3 (0.8) 81.0 (1.9) 74.3 (0.9) 0.0003 Black (%) 6.8 18.5 22.2 23.4 16.2 o0.0001 Women (%) 58.2 45.2 56.7 61.0 40.9 0.08

Body mass index (kg mÀ2,%) o18.5 2.8 8.1 1.7 10.3 0 0.007 18.5–24.9 34.4 29.6 22.4 55.1 30.7 25–29.9 37.6 49.3 46.9 31.9 49.5 X30 25.2 13.0 30.5 2.7 19.9 Education o12 years (%) 41.8 59.0 57.6 52.2 44.6 Selenium (mmol lÀ1) 1.60 (1.59, 1.61) 1.50 (1.42, 1.57) 1.50 (1.40, 1.61) 1.54 (1.40, 1.68) 1.54 (1.47, 1.60) 0.009 Hemoglobin (g lÀ1) 141.7 (0.4) 114.8 (1.6) 117.0 (1.5) 111.0 (1.8) 117.8 (1.2) o0.0001 Current smokers (%) 23.2 28.0 6.8 15.3 6.5 0.08

Chronic diseases (%) Hypertension 46.5 53.0 69.4 65.5 36.2 0.02 Osteoarthritis 16.4 27.7 31.1 12.7 32.3 0.06 Diabetes 11.3 16.9 23.7 15.0 23.9 0.02

Congestive heart Failure 7.5 8.2 20.3 11.8 7.4 0.11 Stroke 8.4 8.2 9.0 11.2 11.7 0.82 Angina 31.9 43.7 31.3 38.2 26.4 0.42 Myocardial infarction 12.9 15.8 16.3 5.6 12.1 0.78 Cardiovascular disease 39.9 48.5 38.9 53.0 35.4 0.53 Cancer 21.7 21.3 28.6 13.2 29.1 0.52 aWeighted analysis for all means and percentages using NHANES III weights. bMean (s.e.) for age and hemoglobin. cGeometric mean (CI) for selenium.

30 Another mechanism by which selenium could potentially contribute to anemia is through modulation of inflamma-

25 tion. Low serum selenium concentrations were found in adults with anemia of chronic inflammation. Low serum selenium concentrations among disabled older women 20 living in the community were predictive of subsequent rises in interleukin (IL)-6 (Walston et al., 2006). Thus, selenium

% 15 could potentially play a role in the anemia of chronic inflammation through its relationship with the upregulation 10 of IL-6 through the redox-sensitive transcription factor nuclear factor-kB. In turn, IL-6 has been implicated in the

5 upregulation of hepcidin, the iron regulatory hormone that blocks iron absorption in the gut and iron release from macrophages and the liver (Roy and Andrews, 2005). The 0 Non-Anemic Nutritional Anemia Chronic Renal Unexplained role of hepcidin in the anemia of chronic inflammation is Causes Inflammation Disease Anemia not well understood, and little is known is about the Figure 2 Proportion of adults X65 years in the lowest selenium relationship between selenium levels, hepcidin and anemia. quartile by anemia status in NHANES III, Phase 2, 1991–1994. Another possible mechanism by which selenium could be involved in the pathogenesis of anemia is through heme with an increased reticulocyte count and high-erythro- oxygenase-1. Low selenium status can upregulate the activity poietin levels. Studies in selenium-deficient pigs suggest that of hepatic heme oxygenase-1, which catalyzes the initial step selenium deficiency limits erythropoiesis but does not affect of heme catabolism and reduces heme to biliverdin, carbon red cell half-life (Fontaine et al., 1977). Further studies are monoxide and free divalent iron (Mostert et al., 2003; Tron needed to examine this issue. et al., 2005). Whether upregulation of heme oxygenase-1

European Journal of Clinical Nutrition Serum selenium and anemia RD Semba et al 98 plays a role in the relationship of low serum selenium to values were not significantly associated with taking a anemia is not known. supplement that contained selenium (Niskar et al., 2003). Given that the study design of NHANES III is cross- Except for overt clinical selenium deficiency, the health sectional, the direction of the association between low serum consequences of an inadequate selenium intake are incom- selenium levels and anemia cannot be absolutely deter- pletely understood, and further work is needed to define mined. It is possible that anemia causes low serum selenium optimal selenium status in the elderly population. concentrations through some uncharacterized mechanism, In conclusion, low serum selenium was independently but there is less evidence to support such a biological associated with anemia among older men and women living explanation. The data from animal studies suggest that in the community. This study raises a potentially important selenium deficiency causes anemia (Rotruck et al., 1972; public health question: has selenium deficiency been over- Latshaw et al., 1977; Morris et al., 1984; Gutzwiller, 1991, looked as a cause of anemia among older adults? This study 1998), but whether the same biological mechanism is found may represent a first important step toward determining in humans would need to be determined by well-designed whether selenium deficiency is a potential cause of anemia controlled clinical trials. among older adults. To our knowledge, it is not known In this study, low levels of serum selenium occurred across whether improving dietary selenium intake will increase all types of anemia. Anemia in older adults is multifactorial, hemoglobin concentrations among older adults with and according to one hypothesized mechanism, a reduced low serum selenium concentrations. Further work is needed half-life of erythrocytes related to low selenium could to corroborate these findings in other populations, provide predispose in a general way to anemia. The association evidence for longitudinal causal associations, identify between low serum selenium and anemia may reflect the underlying biological mechanisms and determine whether complex multisystem decline that occurs with aging and improving selenium status has an impact upon anemia in may possibly be caused by diverse biological mechanisms older adults. rather than the specific mechanisms described above. This study was sponsored by National Institute on Aging, The dietary intake of selenium varies widely worldwide, as National Institutes of Health (R01 AG027012, R01 AG029148 selenium concentrations in plant-based foods reflect the and Intramural Research Branch). concentrations of selenium in the soil where the plants were grown. The selenium concentrations in animal sources of food, in turn, depend upon the selenium content of the plants used for forage, or whether animal feed was fortified References with selenium. Clinical selenium deficiency is rare and is seen in Keshan disease, an endemic cardiomyopathy found Balducci L (2003). Epidemiology of anemia in the elderly: informa- in low-selenium areas of China where affected persons may tion on diagnostic evaluation. J Am Geriatr Soc 51, S2–S9. have serum selenium o0.25 mmol lÀ1 (20 mglÀ1) (Food and Bates CJ, Thane CW, Prentice A, Delves HT (2002). Selenium status and its correlates in a British National Diet and Nutrition Survey: Nutrition Board, 2000). The current dietary requirements people aged 65 years and over. J Trace Elem Med Biol 16, 1–8. for selenium by the Food and Nutrition Board of the Institute Beard CM, Kokmen E, O’Brien PC, Anı´a BJ, Melton III LJ (1997). Risk of Medicine are based in part upon maintenance of optimal of Alzheimer’s disease among elderly patients with anemia: levels of selenoproteins in blood, especially plasma population-based investigations in Olmsted County, Minnesota. Ann Epidemiol 7, 219–224. glutathione peroxidase (Food and Nutrition Board, 2000). Beghe´ C, Wilson A, Ershler WB (2004). Prevalence and outcomes of The selenium requirement for prevention of chronic anemia in geriatrics: a systematic review of the literature. Am J Med disease has not yet been definitively determined (Thomson, 116, 3S–10S. 2004). In addition, the selenium requirements for older Blankenberg S, Rupprecht HJ, Bickel C, Torzewski M, Hafner G, Tiret L et al. (2003). Glutathione peroxidase 1 activity and cardiovas- adults are largely extrapolations from the middle-aged cular events in patients with coronary artery disease. N Engl J Med population (Thomson, 2004). The activity of glutathione 349, 1605–1613. peroxidase appears to be optimal when serum selenium Cesari M, Penninx BW, Lauretani F, Russo CR, Carter C, Bandinelli S concentrations are at least 1.27 mmol lÀ1 (100 mglÀ1)or et al. (2004). Hemoglobin levels and skeletal muscle: results from the InCHIANTI study. J Gerontol A Biol Sci Med Sci 59, 238–241. greater (Food and Nutrition Board, 2000). The baseline Chaves PHM, Xue QL, Guralnik JM, Ferrucci L, Volpato S, Fried LP serum selenium concentrations at which there appeared to (2004). What constitutes normal hemoglobin concentration in be a protective effect of selenium supplementation against community-dwelling disabled older women? J Am Geriatr Soc 52, cancer in two US trials were 1.34–1.54 mmol lÀ1 (Thomson, 1811–1816. Chow CK, Chen CJ (1980). Dietary selenium and age-related 2004). It is notable that in the present study, the highest susceptibility of rat erythrocytes to oxidative damage. JNutr110, prevalence of anemia was found among older subjects from 2460–2466. NHANES III who were in the lowest quartile of serum Cockcroft DW, Gault MH (1976). Prediction of creatinine clearance selenium, which was o1.33 mmol lÀ1 and would be consid- from serum creatinine. Nephron 16, 31–41. Fontaine M, Valli VE, Young LG (1977). Studies on vitamin E ered in the suboptimal range. It has been previously reported and selenium deficiency in young pigs. III. Effects on kinetics that 13.8% of NHANES III participants were taking supple- of erythrocyte production and destruction. Can J Comp Med ments that contained selenium, but that serum selenium 41, 57–63.

European Journal of Clinical Nutrition Serum selenium and anemia RD Semba et al 99 Food and Nutrition Board and Institute of Medicine (2000). Dietary Penninx BWJH, Pahor M, Cesari M, Corsi AM, Woodman RC, Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Bandinelli S et al. (2004). Anemia is associated with disability and National Academy Press: Washington, DC. decreased physical performance and muscle strength in the Gunter EW, Lewis BG, Koncikowski SM (1996). Laboratory Procedures elderly. J Am Geriatr Soc 52, 719–724. Used for the Third National Health and Nutrition Examination Survey Prache S (1994). Haemolytic anaemia in ruminants fed forage (NHANES III), 1988–1994. Centers for Disease Control and Brassicas: a review. Vet Res 25, 497–520. Prevention: Hyattsville, MD. Ray AL, Semba RD, Walston J, Ferrucci L, Cappola AR, Ricks MO et al. Guralnik JM, Eisenstaedt RS, Ferrucci L, Klein HG, Woodman RC (2006). Low serum selenium and total carotenoids predict (2004). Prevalence of anemia in persons 65 years and older in the mortality among older women living in the community: the United States: evidence for a high rate of unexplained anemia. Women’s Health and Aging Studies. J Nutr 136, 172–176. Blood 104, 2263–2268. Rotruck JT, Pope AL, Ganther HE, Hoekstra WG (1972). Prevention of Gutzwiller A (1991). Einfluss der Selenversorgungslage der Ziege die oxidative damage to rat erythrocytes by dietary selenium. J Nutr Resistenz der Erythrozyten gegen oxidative Scha¨digung. Schweiz 102, 689–696. Arch Tierheilk 133, 157–161. Roy CN, Andrews NC (2005). Anemia of inflammation: the hepcidin Gutzwiller A (1998). Erythrocyte resistance to oxidative damage and link. Curr Opin Hematol 12, 107–111. leucocyte capacity to reduce nitroblue tetrazolium in selenium- Savarino L, Granchi D, Ciapetti G, Cenni E, Ravaglia G, Forti P et al. deficient cattle. Zentralbl Veterinarmed A 45, 271–278. (2001). Serum concentrations of zinc and selenium in elderly Hampel G, Schaller KH, Rosenmu¨ller M, Oefele C (1985). Selenium- people: results in healthy nonagenarians/centenarians. Exp deficiency as contributing factor to anemia and thrombocyto- Gerontol 36, 327–339. penia in dialysis patients. Life Support Syst 3 (Suppl 1), 36–40. Semba RD, Ferrucci L, Cappola AR, Ricks MO, Ray AL, Xue QL Hu ML, Chung C, Spallholz JE (1984). Hematologic data of selenium- et al. (2006). Low serum selenium is associated with anemia deficient and selenium-supplemented rats. J Inorg Biochem 22, among older women living in the community. Biol Trace Elem Res 165–173. 112, 97–107. Kikuchi M, Inagaki T, Shinagawa N (2001). Five-year survival of older Silverberg DS, Wexler D, Blum M, Keren G, Sheps D, Leibovitch E people with anemia: variation with hemoglobin concentration. et al. (2000). The use of subcutaneous erythropoietin and J Am Geriatr Soc 49, 1226–1228. intravenous iron for the treatment of anemia of severe, resistant Kok FJ, de Bruijn AM, Vermeeren R, Hofman A, van Laar A, de Bruin congestive heart failure improves cardiac and renal function and M et al. (1987). Serum selenium, vitamin antioxidants, and functional cardiac class, and markedly reduces hospitalizations. cardiovascular mortality: a 9-year follow-up study in the Nether- J Am Coll Cardiol 35, 1737–1744. lands. Am J Clin Nut 45, 462–468. Thomas ML (1998). Impact of anemia and fatigue on quality of life in Kornitzer M, Valente F, de Bacquer D, Neve J, de Backer G (2004). cancer patients: a brief review. Med Oncol 15 (Suppl 1), S3–S7. Serum selenium and cancer mortality: a nested case–control study Thomson CD (2004). Assessment of requirements for selenium within an age- and sex-stratified sample of the Belgian adult and adequacy of selenium status: a review. Eur J Clin Nutr 58, population. Eur J Clin Nutr 58, 98–104. 391–402. Latshaw JD, Ort JF, Diesem CD (1977). The selenium requirements of Tron K, Novosyadlyy R, Dudas J, Samoylenko A, Kietzmann T, the hen and effects of a deficiency. Poultry Sci 56, 1876–1881. Ramadori G (2005). Upregulation of heme oxygenase-1 gene by Lipschitz D (2003). Medical and functional consequences of anemia turpentine oil-induced localized inflammation: involvement of in the elderly. J Am Geriatr Soc 51, S10–S13. interleukin-6. Lab Investig 85, 376–387. Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson CL (1997). US Department of Health and Human Services (DHHS) (1996). Prevalence of iron deficiency in the United States. JAMA 277, National Center for Health Statistics. Third National Health and 973–976. Nutrition Examination Survey, 1988–1994, NHANES III Laboratory McPhail DB, Sibbald AM (1992). The role of free radicals in brassica- Data File (CD-ROM). Public Use Data File Documentation Number induced anaemia of sheep: an ESR spin trapping study. Free Radic 76200. Centers for Disease Control and Prevention: Hyattsville, Res Commun 16, 277–284. MD. Moghadaszadeh B, Beggs AH (2006). Selenoproteins and their impact Valderrabano F (2000). Quality of life benefits of early anaemia on human health through diverse physiological pathways. treatment. Nephrol Dial Transplant 15 (Suppl 3), 23–28. Physiology 21, 307–315. van Lettow M, West CE, van der Meer JWM, Wieringa FT, Semba RD Morris JG, Cripe WS, Chapman Jr HL, Walker DF, Armstrong JB, (2005). Low plasma selenium concentrations, high plasma human Alexander Jr JD et al. (1984). Selenium deficiency in cattle immunodeficiency virus load and high interleukin-6 concentra- associated with Heinz bodies and anemia. Science 223, 491–493. tions are risk factors associated with anemia in adults presenting Mostert V, Hill KE, Burk RF (2003). Loss of activity of the with pulmonary tuberculosis in Zomba district, Malawi. Eur J Clin selenoenzyme thioredoxin reductase causes induction of hepatic Nutr 59, 526–532. heme oxygenase-1. FEBS Lett 541, 85–88. Van Nhien N, Khan KC, Yabutani T, Ninh NX, Kassu A, Huong BT Nagababu E, Chrest FJ, Rifkind JM (2003). Hydrogen-peroxide- et al. (2006). Serum levels of trace elements and iron deficiency induced heme degradation in red blood cells: the protective roles anemia in adult Vietnamese. Biol Trace Elem Res 111, 1–9. of catalase and glutathione peroxidase. Biochim Biophys Acta 1620, Walston J, Xue Q, Semba RD, Ferrucci L, Cappola A, Ricks M et al. 211–217. (2006). Serum antioxidants, inflammation, and total mortality in National Center for Health Statistics (1994). Plan and Operation of the older women. Am J Epidemiol 163, 18–26. Third National Health and Nutrition Examination Survey, 1988–94. Woodman R, Ferrucci L, Guralnik J (2005). Anemia in older adults. National Center for Health Statistics: Hyattsville, MD. Curr Opin Hematol 12, 123–128. Niskar AS, Paschal DC, Kieszak SM, Flegal KM, Bowman B, Gunter World Health Organization (1968). Nutritional Anemia: Report of a EW et al. (2003). Serum selenium levels in the US population. WHO Scientific Group. World Health Organization: Geneva, Third National Health and Nutrition Examination Survey, 1998– Switzerland. 1994. Biol Trace Elem Res 91, 1–10. Zimmermann MB, Ko¨hrle J (2002). The impact of iron and selenium Nissenson AR (1992). Epoietin and cognitive function. Am J Kidney deficiencies on iodine and thyroid metabolism: biochemistry and Dis 20 (Suppl 1), 21–24. relevance to public health. Thyroid 12, 867–878.

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