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INTRODUCTION — Anemia is common in the older adult population. Although typically mild, it has been associated with substantial morbidity and mortality.
DEFINING ANEMIA IN THE OLDER ADULT
WHO criteria for anemia — Although average hemoglobin values differ from laboratory to laboratory, a working definition of anemia in the adult is a level less than the normal mean minus two standard deviations. For the values shown in the table this would be a hemoglobin <14.0 g/dL (<140 g/L) in men and <12.3 g/dL (<123 g/L) in women (table 1).
Alternatively, the 1968 World Health Organization (WHO) criteria of a hemoglobin (Hgb) <13 g/dL (<130 g/L) in men and <12 g/dL (<120 g/L) in women have been used to define anemia . However, these criteria were based upon data in populations that did not include individuals >65 years of age [6-9], and may or may not be applicable to the older individual [10,11]. (See "Approach to the adult patient with anemia", section on 'Normal range'.)
Racial and ethnic considerations — There is debate as to whether modifications in the definition of anemia should be made for different racial and ethnic groups. As an example, up to 30 percent of African-Americans carry the 3.7 kb deletion in the alpha thalassemia gene. In the heterozygous state (ie, silent carrier of alpha thalassemia, thalassemia minima) this leads to low-normal and occasionally mildly low hemoglobin and mean corpuscular volume values, whereas homozygotes (ie, alpha thalassemia trait) have a mild, microcytic anemia . Thus, the presence of thalassemia may contribute to lowering of the average hemoglobin level in racial or ethnic groups having a high incidence of these mutations. (See "Clinical manifestations and diagnosis of the thalassemias".)
There may be additional underlying factors that contribute to lowering of average hemoglobin levels in certain ethnic populations. As an example, when subjects with the alpha thalassemia -3.7 kb allele, iron deficiency, renal insufficiency, and sickle cell trait were removed from consideration, African-Americans still had significantly lower hemoglobin values when compared with a corresponding white population . Additional data bolstering this hypothesis is that the prevalence of anemia, using WHO criteria, is three-fold higher in elderly African-Americans relative to elderly Caucasians .
Normal values for a population with a high incidence of chronic disease may be skewed toward anemic levels. Thus, anemia may be difficult to define in countries in which malnutrition, infection (eg, tuberculosis, malaria), and/or congenital hematologic disorders (eg, thalassemia) are common. (See "Community public health issues and the thalassemic syndromes: Lessons from other countries", section on 'Introduction'.)
Proposed definitions — Values for hemoglobin and hematocrit in apparently healthy older adults are generally lower than those in younger adults, and differences between males and females that are seen in younger adults are lessened with aging [14-16]. In an attempt to more accurately determine normal hemoglobin ranges in elderly adults, two large databases, the third US National Health and Nutrition Examination Survey (NHANES III), a nationally representative sampling of community-dwellers, and the Scripps-Kaiser database, collected in the San Diego area between 1998 and 2002 were evaluated . Older subjects (≥59 years in men and ≥49 years in women) with laboratory-based evidence of increased inflammation or renal insufficiency were excluded from consideration, which led to the elimination from the analysis of up to 50 percent of older black men and 40 percent of black women from the NHANES database.
Using the fifth percentile value of hemoglobin concentration, new lower limits of normal were proposed for older patients (table 2). Compared with current WHO criteria, these values were slightly higher for older white men and women (13.2 and 12.2 g/dL, respectively) and slightly lower for older black men and women (12.7 and 11.5, respectively).
Significance of these definitions — While further data are needed to confirm or refute the necessity for more precise age-, race-, and ethnicity-based definitions of anemia in the older adult, setting a lower limit of normal for hemoglobin does not imply that such levels are "optimal" in terms of morbidity and mortality. As an example, one study has suggested that the lower limits of an optimal hemoglobin level, as assessed by all-cause mortality data, are 14.0 and 13.0 g/dL for elderly men and women, respectively .
It has been suggested that older adults should not be presumed to have a lower "normal" range for hemoglobin [13,19-24]. There are two major reasons for this position:
PREVALENCE AND CLINICAL IMPORTANCE — Given the absence of a uniform definition of anemia, it is not surprising that the reported prevalence of anemia in the older adult has wide variability in the literature. In a systematic literature review, prevalence rates of anemia in older adults were found to vary between 2.9 and 51 percent in men and 3.3 and 41 percent in women [13,25]. While nursing home residents were found to be at high risk for anemia [15,16], the highest prevalence rates were noted in hospitalized older adults [13,14].
Anemia is also very prevalent in non-institutionalized older adults.
The public health importance of this finding is particularly relevant in light of the aging global population. In 2008, the estimated world population was 6.7 billion with 98 million people ≥80 years of age [16,30]. By 2030 this is estimated to grow to 8.4 billion total population, with 216 million ≥80 years of age , leading to an estimated 49 million anemic elderly adults in this age bracket alone, extrapolating from data obtained in the industrialized world.
This number is likely to be substantially increased, however, if one takes into account the much higher prevalence rates of anemia found in areas of the developing world .
Degree of severity — The anemia reported in studies of the older adult tends to be mild, with hemoglobin values generally >10 g/dL.
Functional outcomes — Many of the studies showing an association between anemia and morbidity and/or mortality replicate a reversed J-shaped curve, with worse outcomes at both the lower (Hgb <12 g/dL) and upper (Hgb >15 g/dL) extremes of hemoglobin [11,17,29,32-35].
Importantly, available studies investigating anemia in the older adult and poor outcomes have not been designed to establish causality. Accordingly, it is unknown whether anemia itself leads to increased morbidity and/or mortality, or whether it is the underlying etiology of the anemia or associated co-morbidities that do so. Nonetheless, it is plausible to suggest that anemia, potentially leading to increased cardiac output and/or local tissue hypoxia, could aggravate functional decline in the older adult population.
Decreased physical and mental functioning, if present, can radically affect an older person's life and ultimately lead to loss of independent living in the community .
Physical function — Measures of physical function are important both in assessing current status and in predicting more severe disability, such as decreased mobility leading to subsequent nursing home admission [36,37]. The following observations are important in this regard:
Mental function — Anemia in the elderly is also associated with impaired cognitive performance, depressive symptoms, and reduced quality of life [40,42-45].
Increased mortality — Multiple studies have shown an association between anemia and increased mortality [11,20,29,33,46-48]. As examples:
Effect of race — The impact of anemia on morbidity and/or mortality may also be influenced by race, although data are conflicting.
These discrepant results may be due to different sampling strategies  or disproportionately missing follow-up data among the different races . However, these studies further the debate regarding the validity of using race-specific normal values, and the potential disparate impact of anemia within different racial and ethnic groups.
Other factors — The risk of mortality may be related to the etiology of the anemia; in one study, elderly female subjects with anemia due to renal insufficiency or the anemia of inflammation had an increased risk of death compared with non-anemic controls, whereas those with anemia due to nutrient deficiencies or unexplained anemia did not .
NAHANES III Study — The causes of anemia in the older adult were evaluated in a study of the noninstitutionalized United States population in the third National Health and Nutrition Examination Survey (NHANES III) . Overall, 10 to 11 percent of men and women ≥65 years of age were anemic, with a higher rate (28 percent) in non-Hispanic blacks. The anemia was generally mild, with only 2 to 3 percent of men and women having a hemoglobin level <11.0 g/dL. The causes for anemia were estimated as follows:
These determinations concerning etiology were based upon laboratory data alone. However, reliance on biochemical data alone, without an accompanying clinical evaluation, may lead to the faulty presumption that a subclinical biochemical abnormality has caused the anemia. This is particularly important for the "nutrient" deficiency category. Two examples are described below:
Stanford study — Our own study of subjects ≥65 years of age was comprised of non-anemic community-living control subjects and 190 community-living subjects with anemia according to the WHO criteria, referred to us from outpatient hematology clinics. All anemic participants underwent a clinical hematologic evaluation, including history and physical examination, complete blood count with red cell indices, iron indices (serum iron, transferrin, ferritin), levels of B12 and folate, and a review of the peripheral blood smear. Laboratory data in these older anemic outpatients were as follows (mean values, ranges in parentheses) :
The etiology of anemia in these subjects was as follows:
Of interest were the following observations in this group of subjects:
Initial approach — In general, diagnostic algorithms for determining the cause of anemia in older adults are similar to those for anemia found in any adult patient (algorithm 1). (See "Approach to the adult patient with anemia".)
Essential components of the initial evaluation include the following:
The following issues are especially important when evaluating anemia in an older adult:
Older adult patients can have multiple causes of their anemia. As an example, underlying renal insufficiency, myelodysplasia, or a nutritional deficiency may blunt the ability of the patient's bone marrow to respond to hemolysis or blood loss. Accordingly, full evaluation of the anemic elderly patient may take several visits, including, for example, monitoring for response to nutrient supplementation or hormone replacement. Bone marrow examination may be indicated at a subsequent visit if initial studies are unrewarding. (See "Approach to the adult patient with anemia", section on 'Multiple causes of anemia'.)
The following disorders are common in the older adult population and warrant particular attention:
Iron deficiency anemia
Making the diagnosis — While iron deficiency anemia is typically associated with the presence of microcytic, hypochromic red cells, iron deficiency anemia may be normocytic in its early stages  or when iron deficiency is found in combination with other disorders [21,61]. While this subject is discussed in depth separately, several issues are of importance in determining the presence or absence of anemia in the older adult. (See "Causes and diagnosis of iron deficiency anemia in the adult", section on 'Estimation of iron stores'.)
Serum ferritin levels — The serum ferritin is perhaps the most frequently used peripheral blood measurement to assess iron deficiency anemia. Iron stores are reliably depleted when ferritin is <12 mcg/L [53,62]. Whereas a low serum ferritin dependably indicates iron deficiency irrespective of patient age , a normal ferritin level in an elderly patient does not necessarily rule out iron deficiency, as serum ferritin rises with aging .
Accordingly, a higher serum ferritin cutoff may more accurately diagnose iron deficiency in the older adult. This was shown in a study in hospitalized older adult patients, in which the optimal cutoff point for serum ferritin in predicting an iron-deficiency state was 50 mcg/L .
Transferrin receptor - ferritin index — Iron indices may also be influenced by the presence of inflammation or malignancy (eg, the anemia of inflammation), in which condition the transferrin level is normal or low, and the ferritin level is normal or elevated [65,66]. The serum soluble transferrin receptor (sTfR) divided by the log of the ferritin can be particularly useful to diagnose iron deficiency anemia in the setting of concomitant inflammation [67,68]. (See "Causes and diagnosis of iron deficiency anemia in the adult", section on 'TfR-ferritin index' and "Anemia of chronic disease (anemia of chronic inflammation)", section on 'ACD with coexisting iron deficiency'.)
As an example, in one study in the older adult, the sTfR/log ferritin was found to be more sensitive than standard iron indices in diagnosing iron deficiency anemia (88 versus 16 percent, respectively) . The authors suggested that while the serum ferritin is the most cost-effective measurement for diagnosing iron deficiency, the sTfR/log ferritin may be useful in more complex settings . However, the lack of standardized reagents for the sTfR assay [70,71] complicates interpretation of the sTfR/ferritin ratio.
Trial of oral iron therapy — If the above tests are still inconclusive, a carefully monitored, time-limited trial of iron supplementation may be needed to confirm the diagnosis of iron deficiency when complicated by the anemia of inflammation. (See "Anemia of chronic disease (anemia of chronic inflammation)", section on 'ACD with coexisting iron deficiency'.)
Determining the site of blood loss — Making a diagnosis of iron deficiency anemia requires, in addition to the need for iron repletion, a search for the source(s) of blood loss. In the industrialized world where iron deficiency is less likely due to decreased available iron in the diet, this generally leads to evaluation of the gastrointestinal tract due to the high frequency of occult upper and lower gastrointestinal lesions found in these patients [72,73].
In one study in 111 hospitalized patients ≥75 years of age who were found to have iron deficiency anemia, 92 percent of whom underwent endoscopy and 82 percent of whom underwent colonoscopy, 68 percent were found to have a bleeding source, and 11 percent had synchronous lesions . Of the 43 patients found to have a colorectal source of bleeding, 31 (72 percent) had colon cancer. Of the 44 patient found to have an upper gastrointestinal source of bleeding, six (14 percent) had a malignancy.
The importance of making an accurate and timely diagnosis was shown in follow-up studies of these patients . At two years, those with cancer treated curatively (28/102) had a survival rate (68 percent) similar to those with benign lesions (80 percent) or those in whom no cause of the anemia was found (66 percent).
Iron deficiency in the absence of anemia may or may not require an evaluation for a bleeding source. In one instructive study, 151 elderly hospitalized patients with serum ferritin levels <50 mcg/L on two occasions underwent upper endoscopy and either barium enema or colonoscopy, regardless of their hemoglobin level .
However, the absence of iron deficiency, as defined by a serum ferritin of ≥50 mcg/L, does not exclude the presence of a gastrointestinal malignancy. In one retrospective study of elderly patients undergoing colonoscopy for either anemia or the presence of symptoms, the prevalence of colorectal carcinoma was 16 percent, 20 percent, and 13 percent for those with a serum ferritin <50 mcg/L, between 50 and 100 mcg/L, and >100 mcg/L, respectively .
Treatment — Treatment of iron deficiency is discussed separately. However, constipation can be a major side effect for elderly patients on oral iron supplementation and may require initiation of low oral doses with slow dose escalation over several weeks, or, rarely, the use of parenteral iron. (See "Treatment of the adult with iron deficiency anemia", section on 'Side effects' and "Treatment of the adult with iron deficiency anemia", section on 'Dosing in older adults'.)
Renal disease/hypoxia-sensing abnormalities — In adults, erythropoietin (EPO) is produced primarily by the peritubular interstitial cells in the kidney. The normal response to decreased oxygen tension in the blood is a logarithmic increase in EPO levels corresponding to the severity of the anemia (figure 1) . (See "Regulation of erythropoiesis", section on 'Erythropoietin'.)
The EPO response is blunted in patients with renal disease, and worsening renal excretory function corresponds with lower EPO levels [79,80]. This is of particular importance in the older adult, given the known decline in renal excretory function that occurs with aging [81,82]. However, the degree of renal impairment necessary and sufficient to cause anemia in the older adult, and how to measure it, is a matter of ongoing debate.
Varying degrees of impairment in renal excretory function have been found to correlate with anemia in the older adult [83,84]. In a study of 1005 community-dwelling men and women ≥65 years of age living in Italy, a creatinine clearance, calculated from a 24 hour urine collection, of ≤30 mL/min was associated with a significantly increased risk of anemia, and significantly decreased age- and hemoglobin-adjusted serum EPO levels , suggesting that this might be the inflection point below which anemia is most likely to be due to renal disease in older adult patients.
The measurement of serum EPO is not generally useful in this regard for two reasons:
Although there are data to the contrary [86,87], several studies have shown a rise in serum EPO levels with increasing age [88,89]. This finding suggests the need for relatively more EPO in order to maintain physiologic erythropoiesis in the older adult, possibly secondary to a relative resistance to EPO. Alternatively, elevated EPO levels might reflect decreased utilization by a hypoplastic marrow, increased local hypoxia, or a perturbation in the hypoxia-sensing pathway.
Myelodysplastic syndrome — A percentage of older adults with otherwise unexplained anemia are likely to have myelodysplastic syndrome (MDS), a disease of the older adult with a median age at the time of diagnosis of ≥65 years [90,91]. (See "Clinical manifestations and diagnosis of the myelodysplastic syndromes", section on 'Epidemiology'.)
Several small studies have investigated the prevalence of MDS in elderly patients with otherwise unexplained anemia.
Thus, approximately 5 to 15 percent of older adult patients with unexplained anemia are likely to have MDS using FAB criteria, and an additional minority may have abnormalities that are suspicious for, but not confirmatory of, MDS. This "pre-MDS" category is particularly intriguing; more data are needed to better categorize these patients and better understand their long-term prognosis. Emerging molecular techniques to detect clonal hematopoiesis and sensitive flow cytometry techniques will likely play an important role in this area [95,96].
Unexplained anemia — Unexplained anemia (also called "idiopathic anemia of aging") occurs in approximately 20 to 30 percent of community-dwelling elderly anemic subjects in cross-sectional epidemiologic studies [13,14,91,97], and in up to one-half of anemic nursing home residents [21,98]. Even after a thorough clinical and laboratory evaluation, 17 percent of elderly hospitalized patients with a hemoglobin <11.5 g/dL had unexplained anemia .
Interest has focused on the importance of this group and potential mechanisms underlying the anemia [13,99,100]. These include hypogonadism , alterations in hematopoietic stem and erythroid progenitor cell number and/or function [102,103], age-related decline in renal function and/or erythropoietin (EPO) secretion [82,85,97], and the presence of "early" myelodysplastic syndrome [92,93].
Impaired bone marrow function — Results from two studies indicate that EPO levels are significantly lower in this group compared with those in whom the etiology of the anemia is found [104,105]. If these reports are confirmed, this would suggest impairment in hypoxia sensing, EPO production, and/or bone marrow response to EPO.
In kinetic terms, the anemia is invariably hypoproliferative, with low absolute reticulocyte counts and a low reticulocyte index. It is customarily assumed that the bone marrow can achieve a compensatory increase in erythropoiesis of approximately eightfold in children and approximately fivefold in adults in response to hemolytic anemia. However, there is little information on this point for the older adult. In any case, most of the potential compensatory increases in erythropoiesis appear to be lost in unexplained anemia of the older adult.
Inflammation — Increased inflammation, or a “proinflammatory state” leading to otherwise unexplained anemia in the older adult is an attractive hypothesis, given the increase in interleukin-6 (IL-6) and C-reactive protein seen with advancing age [106,107], together with the known effects of the IL-6/hepcidin axis on erythropoiesis . However, available studies are conflicting, as shown below.
Although differences in methodology may explain these discordant results, results of the Leiden study suggest that inflammatory processes may contribute to the anemia seen in many older patients, including those with otherwise unexplained anemia. (See "Anemia of chronic disease (anemia of chronic inflammation)", section on 'Pathogenesis'.)
Search for treatable disorders — Effective management of anemia in the older adult requires detection and correction of any treatable underlying etiology . The following is a partial list of the major conditions that should be considered in this regard (table 3). (See "Approach to the adult patient with anemia".)
The patient found to have iron deficiency may have an accompanying bleeding disorder, either exacerbating or causing the condition, which requires additional treatment.
Symptomatic anemia — In the individual with unexplained anemia, treatment requires individual management, and depends upon a multiplicity of factors, including functional status, co-morbidities, and patient wishes. There is no single threshold at which therapy should be initiated. In some patients, a hemoglobin of 8 g/dL may be well tolerated, whereas in others, particularly those with underlying cardio-pulmonary or renal disease, intervening to maintain a hemoglobin >10 g/dL may be of benefit. Given the generally mild nature of anemia in this population, the majority of patients will not require therapy. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Symptomatic patient' and "Anemia of chronic kidney disease: Target hemoglobin/hematocrit for patients treated with erythropoietic agents".)
Current therapeutic interventions for the treatment of symptomatic anemia in the older patient are limited to the use of packed red cell transfusions or erythropoiesis stimulating agents (ESAs) .
Red cell transfusion — Risks of red blood cell transfusion include the more common and less serious febrile or cutaneous reactions, as well as the more rare and more serious risks such as infection, anaphylaxis, transfusion-related acute lung injury and fatal hemolytic reactions . (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Risks and complications of transfusion'.)
The older adult, especially those of small stature, low body weight, and/or known or poor cardiac function, may be susceptible to transfusion-associated volume/circulatory overload (TACO). Suggestions for avoiding this complication are presented separately. (See "Transfusion reactions caused by chemical and physical agents", section on 'Transfusional volume overload (TACO)' and "Use of red blood cells for transfusion", section on 'Administration'.)
In addition, given the transient beneficial effects of red cell transfusion, committing those with chronic anemia to a chronic transfusion program brings with it the attendant risks of iron overload. Although transfusional iron overload in thalassemia major leads to severe cardiac and hepatic iron overload , there is debate about whether iron overload leads to the same degree of organ toxicity in other settings, including MDS .
However, current guidelines recommend consideration of iron chelation therapy in patients with lower-risk MDS in whom 20 to 30 units of packed red blood cells have been transfused and who have ongoing transfusion requirements and a serum ferritin >2500 ng/mL. (See "Management of the complications of the myelodysplastic syndromes", section on 'Iron overload'.)
It is unknown if similar recommendations are warranted in elderly patients with unexplained anemia who are receiving chronic transfusion therapy.
Erythropoietin and darbepoetin — The currently available alternative to packed red blood cell transfusion is the use of an erythropoiesis-stimulating agent (ESA). Three ESAs are currently in use: epoetin alfa, epoetin beta, and darbepoetin. All are recombinant human erythropoietins and bind to the erythropoietin receptor [111,114]. Most data related to the use of ESAs exist in patients with renal disease (both dialysis-dependent and non-dialysis dependent), myelodysplastic syndrome, and other malignancies. Data from patients with renal disease are most likely to be relevant to elderly patients with unexplained anemia, given the decline in renal function with aging and low erythropoietin levels seen in these patients.
A number of trials suggest that ESAs can be harmful in those with renal disease, particularly when the anemia is aggressively corrected. Based in part on these data, the United States Food and Drug Administration has issued a black box warning related to the use of ESAs in renal disease, and the package inserts recommend maintaining hemoglobin levels between 10 and 12 g/dL. (See "Anemia of chronic kidney disease: Target hemoglobin/hematocrit for patients treated with erythropoietic agents", section on 'Summary and recommendations'.)
Similar warnings have been given concerning the aggressive use of ESAs in cancer patients. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Regulatory and fiscal policies'.)
The value of erythropoietin for the treatment of chronic unexplained (undiagnosed) anemia in the elderly patient is unclear . In one randomized, blinded, placebo-controlled crossover trial in elderly predominately African-American women with unexplained anemia or anemia of inflammation (defined by iron indices), increasing the hemoglobin by 2 g/dL led to improvements in quality of life as measured by the Functional Assessment of Chronic Illness Therapy (FACIT) measurement system . Importantly, the target hemoglobin in this study was 13.0 to 13.9 g/dL, a target higher than that suggested in current guidelines and one that has been associated with an increased incidence of adverse side effects.
No serious adverse events were felt to be treatment related in this study. The one reported thrombotic event was a pulmonary embolism occurring during epoetin alfa administration with a last study hemoglobin of 14.3 g/dL. (See "Erythropoietin for the anemia of chronic kidney disease in hemodialysis patients", section on 'Adverse cardiovascular effects with high hemoglobin levels' and "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Thromboembolic risk'.)
Additional data are needed to determine whether correction of mild unexplained anemia in the elderly patient will lead to improvements in functional outcomes without accompanying toxicity, as well as to determine the optimal therapeutic target.
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SUMMARY AND RECOMMENDATIONS
Who should be considered anemic — At present, there is not a uniformly accepted definition of anemia for the older adult, with proposed definitions differing by sex, age, race, and ethnicity (table 1 and table 2). (See 'Defining anemia in the older adult' above.)
Until such definitions become available, anemia should be considered when the hemoglobin is <13.0 g/dL in elderly men and <12.0 g/dL in elderly women. (See 'WHO criteria for anemia' above and 'Proposed definitions' above.)
Establishing the diagnosis — Elderly anemic patients should undergo a standard evaluation for anemia. (See 'Search for treatable disorders' above and "Approach to the adult patient with anemia", section on 'Summary and recommendations'.)
Testing should include, as a minimum:
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