188 Sally P. Stabler Recent investigations have shown that hyperhomo- cysteinemia is a risk factor for osteoporosis and frac- tures [99,100] and combination vitamin replacement in stroke patients resulted in fewer fractures [101]. REFERENCES 1. Stabler SP, Allen RH. Megaloblastic anemias. In Goldman L, Ausiello D, eds, Cecil Textbook of Medicine, 22nd edn (Philadelphia, PA: Saunders, 2004), 1050–7. 2. Mudd SH, Levy HL, Kraus JP. Disorders of transsulfu- ration. In Scriver CS, Beaudet AL, Sly WS, Valle D, eds, The Metabolic & Molecular Bases of Inherited Disease, 8th edn (New York, NY: McGraw Hill, 2001), Vol. 1: 2007–56. 3. Rosenblatt DS, Fenton WA. Inherited disorders of folate and cobalamin transport and metabolism. In Scriver CS, Beaudet AL, Sly WS, Valle D, eds, The Metabolic & Molecular Bases of Inherited Disease, 8th edn (New York, NY: McGraw-Hill, 2001), Vol. 1: 3897–934. 4. Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of cobalamin defi ciency: II. 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It is attrac- tive to hypothesize that the reversal of anemia may effect compression of morbidity, which is the main goal of geriatric medicine [2,3]. More prolonged health and independence may improve the quality of life and reduce the management cost of the older aged person. After studying the epidemiology of anemia and aging, this chapter explores the adverse conse- quences of anemia in the elderly and the outcomes of anemia management. Epidemiology and causes of anemia in older age Defi nition of anemia The World Health Organization (WHO) defi nes anemia as hemoglobin levels lower than 12 g/dL in women and 13.5 g/dL in men [4]. In older people, however, this defi nition should be revised based on two types of fi ndings: • People of different ethnic origins may have differ- ent levels of hemoglobin in homeostatic condi- tions. In the NHANES III study, the prevalence of anemia was much higher among older African- Americans than among white, Asian, or Hispanic elderly (Fig. 15.1) [4]. In the same database Patel et al. [5] demonstrated that mild anemia was not associated with adverse outcomes in blacks. These fi ndings suggest that hemoglobin levels may be lower in black individuals than in other ethnic groups in normal conditions. • For women aged 65 and older followed prospec- tively in the Women’s Health and Aging Studies (WHAS), the risk of mortality, disability, and functional impairment increased inversely with hemoglobin levels, when these dropped below 13 g/dL [6,7]. The EPESE [8] and the InCHIANTI [9] studies demonstrated the best level of physi- cal performance in the elderly when hemoglobin levels were between 13 and 14.5 g/dL, in both men and women. These fi ndings indicate that the WHO defi nition of anemia is too restrictive, at least for post-menopausal white women. Prevalence and incidence of anemia in the older aged person For the following discussion, the WHO defi nition of anemia is adopted, and the data that contradict this defi nition in different studies will be mentioned. In the NHANES III study [4] the prevalence of anemia was approximately 9.5% in individuals aged 65 and older, and it increased with age. Anemia was more common in older men than in older women, but the difference between the sexes disap- peared if one considered anemic the women whose hemoglobin levels were lower than 13 g/dL. In the Olmsted County studies, which involved 95% of the 192 15 Consequences of chronic anemia in the older person Lodovico Balducci Blood Disorders in the Elderly, ed. Lodovico Balducci, William Ershler, Giovanni de Gaetano. Published by Cambridge University Press. © Cambridge University Press 2008. Consequences of chronic anemia 193 population of that county, the prevalence of anemia was somewhat higher than in NHANES III. This dis- crepancy might have been due to the fact that the whole population of the county, including the sick- est individuals, was accounted for. The Olmsted County studies reported an increase in both preva- lence and incidence of anemia with age [10,11]. An Italian cross-sectional study showed that the prevalence of anemia was 9.2% for individuals aged 65 and over [12]. While the prevalence of anemia increased with age, the mean levels of hemoglobin were maintained remarkably constant at least up to age 85, suggesting that anemia, even mild anemia, is not a consequence of age. Other studies contra- dict this conclusion, however. In a cohort study of Japanese aging individuals the levels of hemo- globin decreased by an average 0.036 g/dL per year for women and by 0.04 g/dL for men between the ages of 70 and 80, in the absence of any disease [13]. Similar fi ndings were reported among Swedish healthy individuals aged 70–88 [14]. Clearly, even if there is a drop in the hemoglobin levels in normal aging, this decline is modest. The increased preva- lence and incidence of anemia with age cannot be accounted for by aging itself, and is best explained by increased prevalence of chronic diseases that may cause anemia. Not surprisingly, the prevalence of anemia was higher among older individuals living in an adult living facility than among home-dwelling elders [15–17]. Causes of anemia in the aged The most common causes of anemia in older indi- viduals in the NHANES III [4] and the Olmsted county [10] studies are shown in Table 15.1. Anemia of unknown cause accounted for approximately 30% of cases. Undoubtedly, more causes might have been unearthed by more complete diagnostic investigations. Aging is associated with an almost universal decline in glomerular fi ltration rate (GFR), which may not be associated with increased serum creatinine levels, due to age-related sarcopenia [18]. Renal insuffi ciency may explain many of these cases, as the production of erythropoietin declines for GFR Ͻ60 mL/minute [19]. As aging is a chronic Table 15.1. Causes of anemia, as reported in two cross- sectional studies. Olmsted NHANES III [4] Cause County [10] (%) (%) Infection 23 — Anemia of chronic 17 20 disease (anemia of chronic infl ammation) Iron defi ciency 8 20 Nutritional 8 14 Chronic kidney disease 8 12 Unexplained 36 34 0 5 10 15 20 25 30 White Black Hispanic Others Men Women Total Figure 15.1 Prevalence of anemia among different populations aged 65 and older. 194 Lodovico Balducci and progressive infl ammation, anemia of chronic infl ammation may also account for unexplained causes of anemia. Ferrucci et al. demonstrated a condition of relative erythropoietin insuffi ciency in older individuals [20] (Fig. 15.2). When the circulat- ing levels of erythropoietin were plotted against the levels of hemoglobin and the levels of infl ammatory cytokines one could observe that: • In the absence of infl ammation, erythropoietin levels were lowest for normal hemoglobin levels and increased proportionally with the drop in hemoglobin. This inverse relation of circulating levels of erythropoietin and hemoglobin is com- monly seen in patients with iron defi ciency. • In the presence of infl ammation, the circulating levels of erythropoietin were abnormally high for normal levels of hemoglobin, but failed to increase in the presence of anemia. These data suggest that the sensitivity of erythropoietic pre- cursors to erythropoietin is decreased and that the maximal capacity to produce erythropoietin is also decreased. Both effects may be mediated by the infl ammatory cytokines. Early myelodysplasia may also have accounted for a small number of cases of anemia of unknown cause [4]. It is important to notice that many causes of ane- mia in older individuals are reversible. When a source of bleeding is not immediately recognized, the diagnosis of iron defi ciency should always trigger investigations of chronic occult bleed- ing from the gastrointestinal tract. In addition to cancer and ulcers, chronic bleeding in older indi- viduals may be due to diverticuli or angiodyspla- sia of the large bowel. Iron defi ciency secondary to Helicobacter pylori has been recently described [21], but its prevalence in older individuals is unknown. The absorption of food iron decreases with age due to gastric achylia and also to increased circulating levels of hepcidin [22]. This is an enzyme that destroys fer- roportin, a protein responsible for carrying the iron from the gastrointestinal tract into the circulation. Incidence and prevalence of cobalamin defi ciency increase with age [23,24], due to inability to digest food-bound vitamin. The gastric secretion of both hydrochloric acid and pepsin, which are essential to the digestion of vitamin B 12 , decline with age. When the concentration of red blood cell folates is normal, anemia may not be present and the main conse- quences of cobalamin defi ciency are neurological, including dementia and posterior column lesions. Not surprisingly, anemia of chronic infl ammation is a common form of anemia in the elderly, as the prevalence of chronic diseases increases with age. As mentioned before, anemia of chronic infl ammation may be present even in the absence of detectable diseases, as aging itself is associated with increased concentration of infl ammatory markers in the circu- lation [25]. Infl ammation portends the two mecha- nisms of this form of anemia: relative erythropoietin defi ciency and decreased iron mobilization, due to increased concentration of hepcidin in the circula- tion [26]. At least some forms of anemia of chronic infl ammation, such as cancer-related anemia, may be reversed by a combination of pharmacological doses of erythropoietin and intravenous iron [27,28]. This treatment strategy is controversial, however, as it has been associated with increased mortality, 8 0 1 2 3 4 5 10 12 14 16 18 Hemoglobin (g/dL) Log (EPO) (mU/mL) Inflammatory Markers in ther Upper Tertile 0–1 2 3 4 Figure 15.2 Relationship between the levels of hemoglobin, circulating erythropoietin (EPO), and circulating infl ammatory marker in the InCHIANTI study. From Ferrucci et al. (2005) [20], with permission. Consequences of chronic anemia 195 whose causes include thromboembolic phenomena and possibly stimulation of cancer growth [29–31]. The role of hypogonadism in the pathogenesis of anemia of older individuals has been highlighted by Ferrucci et al. in the InCHIANTI study. These investi- gators found low levels of circulating testosterone in three-quarters of older men and women with ane- mia [32]. In addition, low testosterone levels were highly predictive of future development of anemia in non-anemic subjects. The possibility of prevent- ing or reversing anemia with testosterone replace- ment needs to be studied. Even anemia of myelodysplasia may be reversed in some cases. Lenalidomide induces a complete hematologic and cytogenetic response in 80% of patients with refractory anemia and 5q(Ϫ) cytoge- netic abnormalities [33]. Transfusion independence and more prolonged survival result from this treat- ment. Lenalidomide may also be active in a smaller portion of patients with different forms of refrac- tory anemia. Transfusion independence may also be achieved in more advanced forms of myelodys- plasia with the nucleotide analogs azacytidine and decitabin [34]. Consequences of anemia The clinical consequences of anemia are listed in Table 15.2. Anemia and mortality Anemia was an independent risk factor for mortal- ity in older individuals, according to seven cohort studies (Table 15.3) [6,10,35–39]. The results of two studies are particularly provocative, as they sug- gest a revision of the WHO defi nition of anemia in older women. The WHAS reported an increased risk of mortality for hemoglobin levels Ͻ13.4 g/dL in home-dwelling women aged 65 and over followed for an average of 11 years [6]. Zakai et al. found that mortality was increased for hemoglobin levels lower than 12.7 g/dL for women and 13.5 g/dL for men [37]. In all studies the risk of mortality appeared to be independent of coexisting diseases causing ane- mia. Anemia could be interpreted as a marker of frailty, a condition associated with critically reduced functional reserve and increased vulnerability to environmental injury [40]. Anemia and functional dependence Preservation of function (prolongation of active life expectancy) is a major goal of geriatric medicine, and the identifi cation of reversible causes and mech- anisms of functional dependence is a research pri- ority. Is anemia a cause of functional dependence? Several studies seem to indicate that this is the case. The WHAS, EPESE, and InCHIANTI studies dem- onstrated that among elderly people living at home anemia was associated with mobility impairment and with dependence in instrumental activities Table 15.2. Consequences of anemia. Increased risk of mortality Increased risk of functional dependence Increased risk of dementia Increased risk of delirium Increased risk of chemotherapy-related toxicity Increased risk of congestive heart failure and coronary death Increased risk of falls Table 15.3. Studies reporting an association of anemia and mortality in the older aged person. Hb level used to Author Age of subjects defi ne anemia Ania et al. 1997 [10] Ͼ70 Ͻ12 Izaks et al. 1999 [35] Ͼ85 Ͻ12 Kikuchi et al. 2001 [36] Ͼ70 Ͻ12 Chaves et al. 2002 [6] Ͼ65 Ͻ13.4 Zakai et al. 2005 [37] Ͼ65 Ͻ13.7 men Ͻ12.6 women Penninx et al. 2006 [38] Ͼ65 WHO criteria Culleton et al. 2006 [39] Ͼ65 WHO criteria 196 Lodovico Balducci of daily living (IADLs) [7–9]. Of special interest, the risk of mobility and functional decline increased inversely with hemoglobin levels lower than 13 g/dL, in both men and women. Again, these fi ndings emphasize the inadequacy of the WHO defi nition of anemia, at least for older women. In cancer patients Luciani et al. demonstrated that anemia was associated with dependence in activities of daily living (ADL) and IADL [41], and in assisted living facilities a strong correlation of ane- mia and functional dependence was also observed [17,42]. In hospitalized elderly patients, anemia has been associated with delayed rehabilitation [43]. It is not clear whether anemia is itself a cause of func- tional dependence or is a marker of more advanced aging and of frailty. Reversal of anemia of chronic infl ammation with erythropoietic growth factors has been shown to lead to improved quality of life and reduced fatigue [44–46]. The effects of anemia cor- rection on functional dependence have never been studied, however. Reversal of anemia of chronic infl ammation in older individuals should not be attempted outside the context of well-controlled randomized clinical trials, in view of the potential adverse effects of erythropoietic growth factors. Anemia and therapeutic complications Anemia has been associated with increased risk of medical and surgical complications. In fi ve studies conducted in cancer patients anemia was associ- ated with increased risk of myelotoxicity and non- myelotoxic complications [47–51]. One possible explanation is that the concentration of circulating free drugs increases in the presence of anemia, as the majority of anti-neoplastic agents are bound to red blood cells. Seemingly, hypoxia may also enhance the susceptibility of normal tissues to the toxicity of chemotherapy. At present, there is no proof that correction of anemia with erythropoietic growth fac- tors or transfusions prevents the complications of anti-neoplastic treatment. Once more, anemia may represent a marker of frailty in older cancer patients rather than a cause of increased toxicity. In hospi- talized older patients anemia has been associated with increased incidence of delirium [52,53]. Brain hypoxia as well as increased circulating free drugs may have been responsible, at least in part, for this complication. Of special interest in older patients is the infl uence of anemia on the outcome of hip fractures. Anemia was present in approximately 30% of patients who suffered a hip fracture [54,55], and many more patients became anemic during hospitalization. In a consecutive cohort of 550 patients who underwent surgery for hip fracture and survived to discharge between 1997 and 1998, Halm et al. [55] reported an average drop in hemoglobin of 2.8 g/dL, after surgery. Seemingly surgical bleeding, hemodilution from intravenous fl uids, repeated phlebotomies, and inad- equate nutrition were responsible for this change. The infl uence of anemia on surgical outcome is con- troversial, however. Some authors have reported that postoperative anemia was associated with increased risk of death and hospital readmission [54–56], and with delayed and incomplete walking rehabilita- tion [57,58]. Other authors failed to fi nd an associa- tion between anemia at discharge, death, functional dependence, and walking impairment [59]. The effects of blood transfusions on outcome are also unclear. According to one study, postoperative blood transfusions reduced the readmission rate to the hospital, especially for patients whose hemo- globin levels had dropped below 10 g/dL [55], but had little effect on mortality and recovery of mobil- ity. Other authors expressed concern that blood transfusion might impair the immune system and delay recovery [60–62]. Anemia and heart disease The infl uence of anemia on the pathogenesis and outcome of congestive heart failure (CHF), and on the outcome of coronary artery disease, has been studied – as has the role of CHF in the pathogenesis of anemia. The association of chronic anemia and CHF is well known [63–67]. Of interest, the prevalence of anemia increases with the severity of symptoms [68] and of diastolic dysfunction [69]. Consequences of chronic anemia 197 In patients undergoing hemodialysis, anemia has been associated with increased risk of left ventricular hypertrophy and CHF that may be pre- vented when anemia is corrected with erythropoi- etin [65–67,70]. The infl uence of heart failure in the pathogenesis of anemia is less clear. It may include fl uid retention and hemodilution, bone marrow hypoxia, increased level of infl ammatory cytokines in the circulation, reduced production of erythro- poietin from declining GFR, and sarcopenia [71]. Iron defi ciency may also occur due to decreased absorption from edema of the bowel wall. In addi- tion, some of the drugs used to manage CHF can cause anemia. For example, ACE inhibitors may inhibit the synthesis of erythropoietin [72] and may increase the concentration in the circulation of the tetrapeptide Ac-SDKP, which inhibits erythro- poiesis [73]. Irrespective of its causes, anemia in patients with CHF is associated with increased mortality, increased risk and duration of hospitalization [68– 70,74–77], and reduced tolerance of exercise [78]. In at least one study [79], a decline of hemoglobin over a 12-month period was associated with increased morbidity and mortality in patients with CHF. Anemia may worsen CHF through a number of mechanisms, including increased ventricular preload, myocardial hypoxia, increased cardiac work. Of particular interest is the release of neuro- hormones and cytokines that are toxic to the myo- cardium. It remains unclear whether the association between anemia and poor outcomes in CHF patients is causal, or whether anemia is merely a marker of risk. It cannot be excluded that hemoglobin is the marker of some other adverse factors among CHF patients, such as higher circulating cytokines and chemokines, which are associated with greater disease severity. However, anemia could aggravate CHF through a number of mechanisms, including exacerbation of myocardial and peripheral hypoxia, increased venous return and cardiac work, and consequent left ventricular hypertrophy [80]. Of interest, increased levels of circulating erythropoi- etin portend a poor prognosis in patients with CHF, seemingly because they refl ect the level of tissue hypoxia [20]. The role of anemia in the pathogenesis of CHF is well documented by clinical trials. In patients undergoing hemodialysis, correction of anemia with erythropoietin prevented the development of left ventricular hypertrophy and CHF [70]. In patients with CHF, correction of anemia with eryth- ropoietin improved symptoms and functional class and reduced the risk of hospitalization [68]. In a small randomized controlled study a three-month treatment with erythropoietin was associated with improvement in submaximal and maximal exer- cise capacity [81]. It is unknown whether correc- tion of anemia may lead to improved survival and other long-term outcomes. It should be underlined that the benefi cial effects of erythropoietin may be partly independent from the correction of anemia, as erythropoietin may have a free-radical scaveng- ing effect that protects the vascular endothelium, an anti-infl ammatory effect, and it may improve the myocardial trophism [81–83]. The benefi ts of red-blood-cell transfusions in patients with CHF are controversial. Though widely broadcast, the recommendation to transfuse CHF patients with hemoglobin levels lower than 10 g/dL is not evidence-based [84]. The interaction of anemia with coronary heart disease (CHD) is not clear. In general, patients with CHD are more likely to be anemic than age- and sex-matched controls. The pathogenesis of anemia may be related in part to increased concentration of circulating infl ammatory cytokines in acute coro- nary syndrome. The average prevalence of anemia in patients with myocardial infarction is 15%, and 50% among those 75 and older [85]. For percutane- ous coronary angioplasty patients, the prevalence of anemia varies between 15 and 31% [86,87]. In patients with acute coronary syndrome anemia is an independent risk factor for mortality [85]: in the presence of ST elevation in the electrocardiogram the mortality risk is inversely related to the levels of hemoglobin below 14 g/dL. In addition, anemia is an independent risk factor for mortality, procedural complications, more prolonged hospitalization, and [...]... death [54 ,55 ] In response to in ammatory stimuli, TNF-α and IL-1 induce the production of IL-6 This in turn inhibits the secretion of IL-1 and TNF-α, activates the production of acute-phase reactants from the liver, and stimulates the hypothalamic–pituitary– adrenal axis to control in ammation [51 ] IL-6 plays a role in both the innate and acquired immune response It is a critical component of the acutephase... depression in 54 55 56 57 58 59 60 61 62 63 64 65 66 older people living in the community J Am Geriatr Soc 1999; 47: 6–11 Harris TB, Ferrucci L, Tracy RP, et al Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly Am J Med 1999; 106: 50 6–12 Volpato S, Guralnik JM, Ferrucci L, et al Cardiovascular disease, interleukin-6, and risk of mortality in older women: the. .. antibody to IL-6 [28] In cell models TNF-α reduced the induction of DMT-1 in the enterocytes, thereby causing reduction in intestinal iron transport [83] As mentioned above, cytokines also play a major role in regulating iron transport in monocytic cells Cytokines increase both TfR-mediated and non-TfR-mediated iron uptake by macrophages In ammatory cytokines also downregulate ferroportin expression... Res 2006; 18: 4 85 92 43 Maraldi C, Volpato S, Cesari L, et al Anemia and recovery from disability in activities of daily living in hospitalized older persons J Am Geriatr Soc 2006; 54 : 632–6 44 Gabrilove JL, Cleeland CS, Livingston RB, et al Clinical evaluation of once-weekly dosing of epoetin alfa in 45 46 47 48 49 50 51 52 53 54 55 56 57 chemotherapy patients: improvements in hemoglobin and quality... with the uptake of dietary iron in the ferrous form by the intestinal cells with the help of DMT-1 (divalent metal transporter), and it is transported in blood by transferrin, which delivers iron for erythropoiesis in bone marrow by binding to the transferrin receptor (TfR) The interactions of these proteins regulate transferrin uptake and ferritin translation based on intracellular iron [79] Much of the. .. osteopenia, and low-grade anemia) [5] Indeed, certain findings in anemic elderly individuals bear close resemblance to those of anemia of in ammation, suggesting that similar pathologic processes may be operating in the elderly Definition and prevalence of anemia in the elderly Many investigators have relied on the established World Health Organization (WHO) criteria for Blood Disorders in the Elderly, ed Lodovico... with in ammation exhibited suppression of colony-forming units (CFU-E), and this effect was reversed by using antibodies against TNF-α and or interferon gamma [50 ] Interleukin 6 (IL-6): a prototype mediator of age-associated anemia IL-6 is a 26 kDa in ammatory cytokine that exhibits marked pleiotropy It plays a role in the regulation of in ammation, and in endocrine and metabolic functions including... burstforming unit-erythroid (BFU-E) and in much higher density on its progeny, the colony-forming uniterythroid (CFU-E) [40,41] Erythropoietin bound to its receptor promotes the viability of CFU-E by inhibiting apoptosis [38,42], resulting in increased production of red blood cells Recombinant human erythropoietin (rHuEPO) has the identical amino-acid sequence of endogenous erythropoietin and demonstrates the. .. living disability [ 65] , depression [53 ], and mortality [54 ] IL-6 and anemia In a pilot study, Leng and colleagues [66] reported that the frailty phenotype (as defined by their screening criteria) is associated with high IL-6 and low hemoglobin levels This intriguing finding lends support to the emerging hypothesis regarding the importance of this particular cytokine in the pathogenesis of AU The exact pathophysiology... 20 05; 53 : 1360 5 Bertero MT, Caligaris-Cappio F Anemia of chronic disorders in systemic autoimmune diseases Haematologica 1997; 82: 3 75 81 Goodnough LT, Price TH, Parvin CA The endogenous erythropoietin response and the erythropoietic response to blood loss anemia: the effects of age and gender J Lab Clin Med 19 95; 126: 57 –64 Andrews NC Anemia of in ammation: the cytokine– hepcidin link J Clin Invest . impairment [52 ], depression [53 ], and death [54 ,55 ]. In response to in ammatory stimuli, TNF-α and IL-1 induce the production of IL-6. This in turn inhibits the secretion of IL-1 and TNF-α, activates. Lipsic E, Westenbrink BD, et al. Levels of hematopoiesis inhibitor N-acetyl-seryl-aspartyl- lysyl-proline partially explain the occurrence of ane- mia in heart failure. Circulation 20 05; 112: 1743–7. . of the acute- phase in ammatory response, stimulating the pro- duction of acute-phase proteins such as C-reactive protein (CRP), serum amyloid A, fi brinogen, com- plement, and α 1 -antitrypsin.