43: Anemia

Anemia is a common condition in older adults and is an increasingly recognized contributor to increased morbidity and mortality. Similar to the younger adult anemic patient, anemia in older adults is most commonly defined according to the 1968 World Health Organization (WHO) criteria of a hemoglobin (Hgb) <13 g/dL in men and <12 g/dL in women. Although anemia has often been considered a normal consequence of aging, its association with adverse clinical outcomes merits a thorough evaluation into the underlying pathophysiology. Recent studies suggest that anemia may arise as a result of accumulated effects of age-related comorbidities acting in concert with poorly understood age-specific changes in early hematopoietic progenitors, that combine to influence erythrocyte production. A greater understanding of the pathogenesis of anemia in older adults will likely have important implications for the prevention, diagnosis, and therapy of this common problem.

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.

Anemia of inflammation—

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.

Associated Conditions

Frailty—

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.

Vitamin D deficiency—

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.

Other nutrients—

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.

HIV disease—

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.

There are presently no recommended or agreed upon strategies for the prevention of anemia in older populations.

It has become increasingly recognized that even mild forms of anemia are associated with increased morbidity, mortality, and frailty in older adults. The relationship between anemia subtypes and mortality was examined in the Women’s Health and Aging Study I, where investigators found that mortality was significantly increased in those with anemia caused by renal disease or AI. Although anemia has been shown to impact physical performance, cognitive function, and mood in older populations, it remains controversial whether the impact of anemia on performance measures is truly independent of concomitant disease co-morbidities.

Symptoms & Signs

Because anemia in older adults is commonly mild in severity, patients will often be asymptomatic. When symptomatic, the clinical presentation of anemia in the older adult is similar to that of younger adult populations. However, because of the increased presence of comorbid disease, it is often difficult to determine whether symptomatic complaints in older adults are directly related to anemia, the underlying cause of anemia, or the presence of comorbidities. Additionally, age-related increases in comorbid disease often make older adults more susceptible to multifactorial anemia.

Clinical symptoms of anemia are dependent on the severity of anemia, on the rate with which anemia develops, and on the patient’s oxygen demand. In older adults, symptomatic anemia typically reflects impaired oxygen delivery to tissues as a consequence of decreased Hgb concentrations, which may lead to increased cardiac output states and increased tissue hypoxia and a progressive decline in organ function. In general, anemia that develops slowly over time tends to present with fewer symptoms than rapid onset anemia, regardless of the underlying etiology. As in younger adults, rapidly developing anemia may additionally cause symptoms because of the effects of hypovolemia. Such symptomatic illness may be more profound and less-well tolerated in older adults, however, because of increased frailty and decreased performance status often related to the presence of multiple chronic comorbidities. The primary symptoms of anemia may include any or all of the following:

1. Varying degrees of fatigue

2. Dyspnea on exertion or dyspnea at rest

3. Some combination of tachycardia, palpitations, sensation of bounding pulses reflecting a hyperdynamic cardiac state

More severe anemia may additionally present with:

1. Lethargy and loss of drive

2. Confusion

3. Severe cardiac symptoms, including congestive heart failure, arrhythmias, angina, or myocardial infarction

Anemia as a result of acute blood loss or severe acute hemolysis may initially present with the following symptoms that reflect physiologic hypovolemia:

1. Lightheadedness

2. Orthostatic hypotension

3. Syncope

4. Symptoms associated with hypovolemic shock, including coma and death

Laboratory Findings

In general, the laboratory evaluation of anemia in older adults is similar to that performed in younger adult populations with a few exceptions. All anemic individuals should receive a complete history and physical examination. Review of the complete blood count and peripheral blood smear is mandatory, as this will help focus on red cell abnormalities, such as unexplained macrocytosis, leucopenia, or leukocytosis, or dysplastic features of white cells or platelets that may provide morphologic evidence suggesting underlying MDS or other diseases. Examining the MCV and red cell indices will help classify anemia as microcytic, normocytic, or macrocytic, and review of the absolute reticulocyte count or reticulocyte index will help determine whether anemia is hyper- or hypoproliferative. Given the increased prevalence of monoclonal gammopathy in older adults, serum and urine protein electrophoresis with immunofixation is warranted in patients with normocytic anemia to evaluate for the presence of an underlying plasma cell dyscrasia.

Nutritional anemia—

Although the diagnostic approach to nutritional anemia is similar to that in younger adults, there are some special circumstances to consider in older adults. For example, iron deficiency typically presents with microcytic and hypochromic red cells. However, when found in combination with macrocytic causes of anemia, such as MDS or vitamin B₁₂ deficiency, the MCV may be in the normocytic range. Such multifactorial anemia common in older adults may be further elucidated by the presence of an increased red cell distribution width. The diagnostic evaluation of vitamin B₁₂ and folate deficiencies in older adults is similar to that in younger adults.

Iron-deficiency anemia is commonly diagnosed by the presence of low serum iron, increased total iron-binding capacity, and decreased serum ferritin, with serum ferritin <12 μg/L being the most sensitive peripheral blood laboratory measure of reduced iron stores. However, ferritin also functions as an acute phase reactant, and serum levels may be falsely elevated in the presence of chronic inflammatory conditions, making it difficult to identify iron deficiency in the backdrop of underlying AI. Ferritin levels may also increase with age, but it remains to be determined whether this occurs in healthy older adults or whether it reflects increases in age-related inflammatory comorbidities.

In an attempt to better delineate iron deficiency in the setting of chronic inflammation, some have examined the utility of measuring the soluble transferrin receptor (sTfR)/log ferritin index, which is calculated by dividing sTfR by the log ferritin. In a prospective analysis of 145 anemic patients diagnosed with iron deficiency and AI, the sTfR index more than doubled the detection of iron-deficiency anemia (92%) compared with ferritin alone (41%). A second prospective controlled study of 49 patients age 80 years or older compared the sTfR index to bone marrow examination for the detection of marrow iron stores and found that the sTfR index diagnosed iron deficiency in 43 of 49 subjects (88%), nearly approaching the sensitivity of bone marrow examination (100%). However, because of a lack of standardization of sTfR/log ferritin testing, data interpretation may prove challenging, and ferritin remains the most important first-line measure of total-body iron stores, with the sTfR/log ferritin index serving as an adjunctive test. Bone marrow examination to evaluate the presence or absence of iron in erythroid progenitors remains the gold standard for measuring total-body iron stores.

A thorough diagnostic evaluation of iron deficiency in older adults is warranted to determine the source of iron deficiency. As it is highly uncommon in the industrialized world for iron deficiency to be caused by inadequate dietary intake of iron, gastrointestinal (GI) blood loss remains the most likely cause for iron deficiency in older adults. Because of the increased incidence of GI malignancies in older adults, a thorough upper and lower GI evaluation in patients diagnosed with iron-deficiency anemia is recommended in patients deemed clinically well enough to tolerate diagnostic evaluation and who may be candidates for therapeutic interventions.

Anemia of chronic renal disease—

Renal disease leads to a blunted EPO response, with lower serum EPO levels seen in patients with declining renal function. The body’s oxygen sensing mechanism in the kidney responds to increased hypoxia associated with decreased Hgb concentrations and results in a logarithmic increase in EPO levels that corresponds to anemia severity.

As aging is associated with a decline in renal function, anemia associated with chronic renal disease is an important consideration in older adults. However, the required degree of renal disease to promote the development of anemia remains in question. In the InCHIANTI Study, a creatinine clearance (CrCl) of <30 mL/min was significantly associated with an increased risk of anemia, as well as age- and Hgb-adjusted serum EPO levels in 1005 participants age 65 years or older. In contrast, a cross-sectional study involving 3222 subjects with a mean age of 65 years found that estimated CrCl levels of <50 mL/min were associated with 3-fold and 5-fold increased risks of anemia in women and men, respectively. These differences highlight the fact that the overall impact of moderate degrees of renal disease on the risk of anemia and decline in EPO synthesis requires more rigorous determination. Furthermore, measurement of serum EPO levels is often unhelpful in diagnosing anemia in older adults because serum EPO levels typically increase significantly only at Hgb levels <10 g/dL, a more severe degree of anemia than typically seen in the majority of older adults regardless of the degree of severity of renal dysfunction.

Unexplained anemia—

During the evaluation of UA in the older adult, a diagnostic work-up of MDS may be justified. Formal diagnosis of MDS typically requires a bone marrow biopsy with morphologic and cytogenetic analyses. However, given the limited treatment options for patients with mild MDS, the necessity of a bone marrow evaluation should be judged in the context of whether information garnered will help inform therapeutic decisions.

Complications may arise as a result of the chronic impact of anemia or may be associated with specific therapeutic interventions. Chronic anemia may predispose to symptoms associated with high-output congestive heart failure. Common complications of therapy include the following:

1. Adverse effects of oral iron therapy include abdominal pain, constipation, diarrhea, nausea, and vomiting.

2. Adverse effects of parenteral iron administration include allergic reactions, back pain, generalized muscle aches, dizziness, skin rash or erythema, fever, dizziness, headache, hypotension, or anaphylaxis. Anaphylaxis is rare, especially with newer iron formulations, and typically occurs within several minutes of administration.

3. Folic acid therapy may mask coexisting vitamin B₁₂ deficiency, allowing for progression of unrecognized neurologic symptoms of vitamin B₁₂ deficiency.

4. Erythropoiesis-stimulating agents (ESAs) may worsen underlying hypertension.

In general, effective management of anemia in older adults should be based on identification of treatable causes of anemia, with therapy following similar guidelines as for younger adults. Monitoring of treatment in the older adult with anemia should also follow similar guidelines as established for younger patients and should focus on the individual’s response to therapy and the impact of anemia on clinical status, with therapeutic adjustments made as clinically indicated. Treatable causes of anemia in older adults include the following:

1. Nutritional deficiencies of iron, vitamin B₁₂, and folic acid

2. Underlying disorders related to the development of a chronic proinflammatory state, including infection, rheumatologic disease, and malignancy

3. MDS

4. Hypothyroidism

5. Renal disease

6. Acute blood loss

Nutritional Anemia and AI

Management of anemia caused by nutritional deficiencies in older adults follows the same recommendations as those in younger adults. Similar to younger adults, the use of oral iron therapy is as effective as administration of parenteral iron, provided there is normal enteric iron absorption. As there are no currently proven therapies that directly target inflammatory pathways in patients with AI, management of AI should be targeted to the underlying disorder.

Anemia of Chronic Renal Disease

For treatment of anemia caused by chronic renal disease, the United States Food and Drug Administration (FDA) has approved the use of ESA therapy. Guidelines for use of ESAs in older adults with both hemodialysis-dependent and -independent renal disease are similar to those in younger adults. However, recent studies have highlighted the potential for adverse cardiovascular outcomes, such as thrombosis and stroke, with the use of ESAs in anemic patients with renal disease. The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) evaluated the effect of darbepoetin alfa in 1872 patients with anemia, diabetes and nondialysis dependent chronic kidney disease and found that the risk of stroke was double in those patients receiving darbepoetin alfa compared with placebo. The etiology of these adverse cardiovascular outcomes is unclear but may involve attempts to normalize Hgb levels in resistant subpopulations of patients. For this reason, the FDA recently placed a black-box warning on the use of ESAs in patients with anemia caused by renal disease, with recommendations targeting Hgb levels between 10 g/dL and 12 g/dL.

Unexplained Anemia

The majority of older adults with UA present with mild anemia that does not require initiation of therapy. For those symptomatic patients, currently available therapies are limited to red cell transfusions and ESAs. It should be noted that there is no absolute Hgb level that requires the initiation of therapy, and therapeutic intervention should be based on the individual patient, with consideration placed on the following factors: performance status, clinical impact of disease comorbidities, and quality of life assessment. The benefits of red cell transfusions must be weighed against the associated risks of iron overload, infectious complications, anaphylaxis, and red cell alloimmunization.

The use of ESAs in older adults with UA is not currently FDA-approved and there are few studies that have evaluated their use in this population. In one exploratory, randomized trial examining the impact of epoetin alpha in a cohort of 62 predominantly black older women with AI or UA, 69% receiving epoetin alpha achieved a greater than 2 g/dL increase in Hgb compared with those taking placebo (P <0.001) and demonstrated improvement in their assessment of fatigue. However, the target Hgb in this study was 13.0–13.9 g/dL, which represents a level above current FDA guidelines and one associated with adverse effects in numerous studies. Future randomized, controlled studies are needed to effectively determine the safety and efficacy of ESA therapy in older patients with UA and to determine whether there exists appropriate and safe target Hgb levels.