It is estimated that more than 3 million Americans age 65 years and older are anemic, with anemia being highly prevalent in noninstitutionalized, ambulatory older adult populations. The Third National Health and Nutrition Examination Survey (NHANES III) study revealed that the prevalence of anemia in men and women older than age 65 years was 11% and 10.2%, respectively, and rose rapidly after age 50 years, approaching a rate greater than 20% in those individuals age 85 years or older. This finding has been validated in other population-based studies, most of which have shown that the degree of anemia in older adults is relatively mild, with most patients presenting with Hgb >10 g/dL.
Race appears to significantly influence Hgb levels. In NHANES III, the prevalence of anemia using WHO criteria was found to be 3 times higher in non-Hispanic blacks compared with non-Hispanic whites. Examination of Hgb, hematocrit (Hct), and mean corpuscular volume (MCV) in 1491 black individuals as compared with more than 31,000 white subjects in the Kaiser Permanente database revealed that all 3 parameters were lower in blacks than in age-matched whites, whereas the serum ferritin was higher. Although racial genetic variation may influence an individual’s ability to respond to anemic triggers, it is likely that additional factors besides race significantly contribute to the risk of anemia across various populations.
Etiology and Risk Factors
There are presently no studies specifically designed to address causality in older individuals with anemia. The high frequency of comorbid conditions in older populations has also confounded our ability to identify which mechanisms, if any, independently predispose to age-associated reductions in Hgb. Although there appears to be a component of age-related anemia even in healthy individuals, the incidence is much higher in patients with comorbid disease. NHANES III revealed that anemia in older adults is comprised of 3 broad categories: one-third have anemia as a result of nutritional deficiencies (iron, folic acid, or vitamin B12); one-third have anemia of inflammation (AI) on the basis of iron studies; and one-third have unexplained anemia (UA). It is important to remember that these definitions of anemia in NHANES III were based solely on laboratory parameters without the benefit of clinical examination or bone marrow biopsies, making it difficult to evaluate the full clinical impact of anemia in this population. Furthermore, a “hierarchical” categorization of parameters was used to define anemia subtypes, making it difficult to address the independent contributions of factors in subjects with anemia caused by multiple etiologies.
A Stanford University study examining the etiology of anemia defined by WHO criteria in 190 community-dwelling people age 65 or older also found a high prevalence of UA, comprising 35% of participants, a proportion of whom demonstrated mild increases in inflammatory markers and lower-than-expected erythropoietin (EPO) levels compared to nonanemic controls. In contrast to the NHANES III study, participants in the Stanford study underwent a comprehensive evaluation of their anemia, including a complete history and physical examination, laboratory evaluation, and peripheral blood smear review.
AI has historically been termed the “anemia of chronic disease” and is most commonly seen in chronic illnesses, including infection, rheumatologic disorders, and malignancy. It is classically characterized biochemically by the presence of low serum iron and low iron-binding capacity in the setting of an elevated serum ferritin. Although the etiology of classical AI has been attributed to decreased red cell survival, disordered iron-limited erythropoiesis, and progressive EPO resistance of erythroid progenitors, the relative role and interplay of these three mechanisms in the development of anemia remain unknown, as are the potential common pathways that may link them.
Our understanding of AI has been transformed by the discovery of the antimicrobial peptide hepcidin, which is synthesized in the liver and is a key regulator of iron metabolism. In humans, increased hepcidin production has been found in patients with inflammatory disease, infections, and malignancy. NHANES III preceded the identification of hepcidin, and the contribution of hepcidin to anemia was not assessed. Regulation of hepcidin synthesis is complex and involves several inflammatory-mediated cellular pathways, including interleukin 6 (IL-6), which is the primary inflammatory mediator of hepcidin synthesis and is thought to mediate iron-limited erythropoiesis in patients with both acute and chronic inflammatory states. However, recent studies have failed to correlate hepcidin and stimulatory cytokines like IL-6 or inflammatory markers like C-reactive protein, raising questions about the relative contributions of hepcidin-dependent and -independent pathways to the pathogenesis of AI. Future mechanistic studies will be necessary to fully characterize the contribution of increased hepcidin levels in cohorts of older patients with AI and to determine its utility as a clinical diagnostic biomarker of inflammatory anemia.
Unexplained anemia in older adults—
UA typically presents as a mild anemia characterized predominantly as hypoproliferative, with a low reticulocyte count and low reticulocyte index, suggesting absence of the bone marrow’s normal compensatory response to a low red cell mass environment. The pathophysiology of UA in the older adults is poorly understood, and it remains primarily a diagnosis of exclusion.
The role of a chronic proinflammatory state in the pathogenesis of UA in older adults has stirred much debate. There is strong evidence that many markers of inflammation, including tumor necrosis factor-α and IL-6, are increased in the older population regardless of health status. However, studies detailing evidence for chronic inflammation contributing to UA have been few in number and limited by small sample sizes and diverse study designs. Presently, the available data would argue against a role for chronic inflammation in the etiology of UA in older adults.
As anemia is the most common hematologic abnormality in patients with myelodysplastic syndromes (MDS), a heterogenous group of disorders that primarily affects older adults, it is appealing to surmise that MDS may be an important contributor to the pathogenesis of UA. On the contrary, evidence from small studies suggests that MDS may play only a limited role in the etiology of UA, with prevalence of MDS in older adults with UA thought to be in the range of 5% to 16%. These data are limited by small sample sizes, heterogeneity of MDS, and reflect present diagnostic limitations in identifying subjects with low-grade, subclinical MDS.
Erythropoietin resistance and aging—
EPO is the major cytokine influencing red cell development and is induced in the setting of anemia through an oxygen sensing mechanism in the kidney. Impaired EPO responsiveness of hematopoietic stem cells has been implicated in the pathophysiology of anemia in older adults, with some, but not all, studies showing increased EPO levels with age, even in healthy adults. The Baltimore Longitudinal Study on Aging demonstrated that EPO levels rose with age in healthy, nonanemic individuals, and that the slope of the rise was greater for individuals without diabetes or hypertension. Those with anemia also had a lower slope of rise, suggesting that anemia reflected a failure of a normal age-related compensatory rise in EPO levels. Reduced EPO levels have been preferentially associated with UA in older adults, but the mechanism for this inadequate EPO response remains to be determined and the findings of these studies need to be confirmed in larger cohorts of older patients.
This progressive EPO resistance may reflect a cell intrinsic feature of aging hematopoietic stem cells and/or the combined effects of age-associated comorbidities that promote inflammatory-mediated impairment of normal EPO-dependent cellular pathways, decreased EPO production, and/or decreased EPO-sensitivity of bone marrow erythroid progenitors. We surmise that in some aging patients with chronic inflammation, sufficient hepcidin expression may induce the classic biochemical iron profile of AI, whereas in others hepcidin-independent proinflammatory pathways promote either EPO insufficiency or EPO resistance of committed erythroid progenitors and development of UA. Supporting this hypothesis is the observation that concomitant administration of EPO and intravenous iron can ameliorate anemia in some patients with AI.
Anemia and inflammation are strongly associated with and may contribute to the development of “frailty,” a poorly defined syndrome of older adults associated with weight loss, impaired mobility, generalized weakness, and poor balance. A systematic review of the literature suggests that elevated proinflammatory markers are associated with development of frailty. A pilot study examining 11 frail and 19 nonfrail individuals age 74 years or older found that frail subjects had significantly higher serum IL-6 levels and lower Hgb and Hct than did nonfrail subjects. In addition, an inverse correlation between serum IL-6 level and Hgb was noted only in frail subjects, suggesting that IL-6-mediated pathways and possibly increased hepcidin may provide a common pathway for anemia development in the setting of frailty.
Our group examined the association of vitamin D deficiency with anemia in adults age 60 years or older in NHANES III. Anemia was defined according to WHO criteria and subdivided into the following subtypes (nutritional, AI, UA, chronic renal disease). Reviewing data on 5100 participants, we found that vitamin D deficiency was associated with anemia independent of age, sex, and race/ethnicity, with the odds for anemia being increased approximately 60% in the presence of vitamin D deficiency. Furthermore, among those with anemia, vitamin D deficiency was most prevalent among those with AI, with the risk of AI significantly increased in vitamin D deficient versus nondeficient participants. Although this population based study demonstrates an association between vitamin D deficiency and anemia in older adults, there are no data to suggest a causal role for vitamin D deficiency in the pathogenesis of elderly anemia.
A recent analysis of 1036 subjects age 65 years or older in the InChianti Study found an association between elevated carboxymethyl-lysine and decreased plasma selenium and anemia. Of 472 participants who were nonanemic at enrollment, 15.3% developed anemia over a 6-year follow-up period, with incident anemia being significantly associated with the highest quartile elevation in plasma carboxymethyl-lysine and the lowest quartile of plasma selenium levels. Although this study raises the intriguing possibility that anemia may be associated with parameters of oxidative stress, no causal relationship has been shown to date.
Anemia is the most common hematologic complication of HIV infection and is associated with decreased survival, increased progression of disease, and decreased quality of life. As the population of those infected with HIV continues to age, individuals are at risk for anemia related to HIV as well as the anemia of aging. The etiology of anemia in the setting of HIV infection is multifactorial and includes opportunistic infections, decreased EPO levels, effects on the kinetics of hematopoietic cell differentiation, nutritional deficiency, and associated malignancy and medications. Our group has found that a high-expressing single nucleotide polymorphism in the leptin gene was independently associated with anemia in HIV+ but not HIV– subjects. Although our study provides novel insight into the association between genetic variability in the leptin gene and anemia in HIV+ individuals, future studies are required to determine whether aberrant leptin signaling plays a causal role in anemia development or alters EPO responsiveness.