In this issue of the Journal of Gerontology: Medical Sciences, Cesari and colleagues report on the association of anemia in older adults with muscle density and muscle strength, as measured by ankle extension (1). This cross-sectional analysis does not imply causality, but the association is strong. In this population, the prevalence of anemia was 10%. Participants who were anemic were older, had a higher prevalence of a stroke and gastric ulcer, used more medications, and had higher creatinine levels. These factors suggest that anemia may result from underlying disease; however, the association held even when these diseases were excluded.
The report by Cesari and colleagues focuses attention on an often-unheralded condition—anemia—that contributes to morbidity in older adults. As clearly recognized in recent issues of the Journal, the development of frailty (5) and mobility impairment is multifactorial (2–4). Anemia has been associated with both frailty and mobility impairment (6). For example, women with a hemoglobin concentration between 13–14 g/dL have better mobility and lower mortality compared with those with a hemoglobin concentration of less than 12 g/dL (6). Anemia has been shown to lead to functional impairment (5,6), and is a risk factor for falls in older persons (7–9). Anemia is strongly associated with an increase in myocardial infarction and poor outcomes following an infarct (10). Prolonged anemia results in left ventricular hypertrophy (11). Quality of life is impaired in persons with anemia (12), which produces a high level of fatigue (13). In addition, anemia is an independent risk factor for increased mortality over 5 years (14). Despite the growing evidence of these poor outcomes associated with anemia in older persons, the diagnosis is often overlooked and, more important, undertreated.
Hemoglobin and hematocrit values differ little between the healthy elderly population and the younger population. Thus, anemia is not a normal finding in older persons and hemoglobin concentration should not be adjusted downward in older persons (15,16). The World Health Organization defines anemia as a hemoglobin concentration of less than 13 g/dL in men and less than 12 g/dL in women.
The prevalence of anemia increases with each decade of life over the age of 70. In the Established Population data for 3946 adults aged 71 years or older, hemoglobin concentration was inversely associated with age. In men and women aged 71–74 years, 9% were anemic. The proportion of anemic persons increased differentially with age, reaching 41% for men and 21% for women, aged 90 years or older, respectively (17). A similar trend was reported in the third National Health and Nutrition Examination Survey, where the prevalence jumps from 11% in males aged 70–79 years to 22% in males aged 80–89 years (18). There is a marked sex difference in the frequency of anemia. In a population-based study, among 618 persons older than 65 years, the corrected annual incidence of anemia was higher in men (90.3 per 1000 participants) than women (69.1 per 1000 participants) (19).
The most common cause of anemia in one prevalence study of older persons was anemia of chronic disease, accounting for 35%–40% of cases. Iron deficiency anemia was responsible for between 8% and 15% of cases. Chronic kidney disease was responsible for 6%–8% of cases. Blood loss accounted for 7% and myelodysplasia for about 5%. Vitamin B12 deficiency was responsible for another 5%. As in most studies of older persons, a large number of anemias were undiagnosed despite evaluation (20).
The management of anemia begins with a careful differential diagnosis. A corrected reticulocyte count is useful to determine bone marrow function. Anemia associated with an increased reticulocyte count occurs when the bone marrow responds to red cell destruction (hemolysis) or hemorrhage. The presence of elevated concentrations of unconjugated bilirubin and lactic dehydrogenase usually accompanies hemolysis. If these concentrations are normal, a source of blood loss should be sought. A stool occult blood should be obtained, as gastrointestinal bleeding is the most common cause of occult blood loss.
A low or normal corrected reticulocyte count in the presence of anemia indicates an inadequate bone marrow response. In the presence of a low corrected reticulocyte count, determination of red cell morphology indices is useful.
An elevated mean corpuscular volume (macrocytosis) suggests vitamin B12 or folate deficiency, hepatic disease, myelodysplasia, hypothyroidism, or alcoholism. Measurement of vitamin B12 and folate concentrations will determine anemia due to these causes in the majority of cases. Confirmation of vitamin B12 deficiency in those patients who have values in the lower normal range should be obtained, since about 50% of patients with subclinical disease may have normal B12 levels. A more sensitive method of screening for vitamin B12 deficiency is measurement of serum methylmalonic acid and homocysteine levels, which are increased early in vitamin B12 deficiency. A homocysteine level will be elevated in both vitamin B12 and folate deficiencies, but a methylmalonic acid level will be elevated only in vitamin B12 deficiency. Renal failure is the only other confounding cause of an elevated methylmalonic acid concentration.
Anemia due to vitamin B12 or folate deficiency is treated by replacement of the vitamin. Vitamin B12 can be replaced either by injections (1000 μg weekly for 1 month, then monthly thereafter), orally (1000 μg daily, which should not be given with food), or intranasally. Folate 1 mg should be used to treat folate deficiency and should be used during the first few weeks of vitamin B12 deficiency.
Myelodysplasia syndrome (MDS) can be associated with a normal lactic dehydrogenase, normal bilirubin, and low reticulocyte count. An elevated mean corpuscular volume with abnormalities in red cell corpuscular shape suggests myelodysplastic anemia when nutritional deficiency, drugs, and chemotherapy have been excluded. MDS anemia is a bone marrow failure state associated with varying degrees of pancytopenia. About half of these patients will have neutropenia. A blood smear may show hyposegmented nuclei in the neutrophils (pseudo Pelger-Huët phenomenon) or abnormal granular content in the white cells. Approximately one quarter of the patients have thrombocytopenia with megakaryocytes in the peripheral smear. Bone marrow examination confirms the diagnosis with increased cellularity, maturational abnormalities, ringed sideroblasts, and an increase in blasts as well as karyotype abnormalities making the diagnosis. The bone marrow examination may reveal different abnormalities that are useful in classifying the subtype of MDS. Measurements of erythropoietin should be undertaken, as those with concentration below 200 μm/mL often have an excellent response to treatment with erythropoietin together with granulocyte-colony stimulating factor.
In participants with a low or normal mean corpuscular volume, the likely diagnoses include anemia of chronic disease, anemia of renal disease, or iron deficiency anemia. Persons with microcytosis, a low serum iron, and low ferritin concentrations have iron deficiency anemia. If the iron is low and the ferritin is high, this is suggestive of anemia of chronic disease.
Unfortunately, iron deficiency anemia and anemia of chronic disease commonly coexist in older persons. In these cases, soluble transferrin receptor may be useful in determining the diagnosis. Circulating soluble transferrin receptors is a relatively new tool in the diagnosis of anemia. The receptor assay is elevated in iron deficiency anemia even in the presence of chronic disease, but normal or only slightly raised in anemia of chronic disease. As ferritin concentrations are elevated in inflammation, liver disease, renal disease, cancer, and in some elderly women, soluble transferrin receptors can be of use in making the diagnosis of iron deficiency. Soluble transferrin receptor divided by the log of ferritin (<2.55) is the best method of differentiating anemia of chronic disease from anemia of chronic disease associated with iron deficiency anemia (21). There does not appear to be much advantage of these newer, more expensive methods over measuring total iron-binding capacity (22).
In persons with iron deficiency, the recommended treatment is iron sulfate 325 mg three times a day, providing 195 mg of elemental iron per day (23–25). The sulfate moiety can cause gastrointestinal distress, and if this occurs, iron in the form of gluconate or fumerate may be helpful. Some experts suggest that iron sulfate once a day may have a similar effect to three-times-a-day dosing if absorption is normal. The duration of iron therapy may be longer when once-a-day dosing is used. Whatever the chosen dose, a reticulocyte count should be obtained 1 week after starting iron. If there is not a robust reticulocyte response, intravenous iron should be considered.
Anemia may be associated with malnutrition or hypogonadism. Nutritional anemia may occur with protein energy undernutrition as a result of protein deficiency, in addition to iron and vitamin deficiency (26). Protein energy undernutrition, in addition to contributing to anemia, produces a decline in quality of life (27). Guidelines for the evaluation and management of undernutrition have been developed and should be followed (28).
Numerous articles have shown that hypogonadism in men is associated with a decline in hemoglobin levels (29–31). Testosterone replacement increases the hemoglobin levels in these men (32,33). One of the mechanism by which testosterone does this may be by suppressing the production of interleukin-6 (34). Also, as pointed out in the Journal by Bhasin, testosterone enhances the production of stem cells for muscle satellite cells and the hemopoietic system. In addition, testosterone falls with aging in women and can play a role in the pathogenesis of anemia in some older women (35).
Anemia of chronic disease is associated with the presence of renal insufficiency, cancer, congestive heart failure, hepatitis C, inflammation, diabetes, rheumatoid arthritis, osteoarthritis, hypertension, stroke, and chronic obstructive lung disease. In studies of anemia of chronic disease, renal insufficiency accounts for approximately 27% of cases. Most of these patients have an erythropoietin deficiency.
Anemia associated with chronic kidney disease is quite common. Approximately 13.5 million adults have a creatinine clearance of 50 mL/min or less, and about 800,000 adults have chronic renal insufficiency–associated anemia, defined as a hemoglobin concentration of <11 g/dL (18). In persons with chronic kidney disease, a statistically significant decrease in hemoglobin concentration was seen among men starting at a creatinine clearance of 70 mL/min or less and among women starting at 50 mL/min or less. At any given level of creatinine clearance, men had a larger decrease in hemoglobin concentration than women. Compared with participants with a creatinine clearance of greater than 80 mL/min, the decrease in hemoglobin concentration for participants with a creatinine clearance of 20–30 mL/min was 1.0 g/dL in women and 1.4 g/dL in men (18).
Anemia of chronic kidney disease is diagnosed by recognizing renal insufficiency in association with a low erythropoietin level. If the serum creatinine is greater than 2 mg/dL, it is usually unnecessary to measure erythropoietin levels. However, older persons can have a declining glomerular filtration rate in the face of a relatively normal serum creatinine. This results from the loss of lean mass (sarcopenia) associated with aging or disease-related cachexia, reducing the source of serum creatinine. For example, an 85-year-old woman with a hemoglobin concentration of 10 g/dL who weighs 55 kg and has a serum creatinine of 1.3 mg/dL (normal range) will have a creatinine clearance calculated by the Cockcroft-Gault equation of 27.5 mL/min. For this reason, a creatinine clearance should be calculated in all older persons with anemia to determine their renal status. The Cockcroft-Gault equation will demonstrate that the majority of older women with a creatinine of 1.2 mg/dL or greater have severe renal impairment (36).
Since the introduction of human recombinant erythropoietin in 1989, the treatment of anemia due to chronic disease has been revolutionized. A linear relationship between glomerular filtration rate and anemia has been demonstrated. In patients with chronic renal insufficiency, the evaluation of anemia should begin in women with a hemoglobin concentration of 11 g/dL or less, and in men with a hemoglobin concentration of 12 g/dL or less. Anemia can develop relatively early in the course of chronic renal failure, and has been associated with a serum creatinine as low as 2.0 mg/dl (37). Significant anemia has been noted when the calculated glomerular filtration rate is less than 20–35 mL/min (38,39). In patients with impaired renal function and a normochromic, normocytic anemia, it is rare for the serum erythropoietin level to be elevated. Therefore, measurement of erythropoietin levels in such patients is not likely to guide clinical decision-making or therapy. While the majority of persons on dialysis receive erythropoietin, there are many persons who have chronic renal insufficiency who do not receive erythropoietin. This is particularly true among older persons.
Erythropoietin has been shown to increase hemoglobin concentration in patients with anemia associated with surgical blood loss, cancer, chemotherapy, anemia associated with drug therapy for AIDS or hepatitis C virus, myelodysplastic disease, and the anemia of chronic disease, especially when associated with rheumatoid arthritis. Several conditions may result in an inadequate response to erythropoietin therapy, including coexisting iron, vitamin B12, or folate deficiency, acute or chronic infections, inflammatory diseases, chronic blood loss, hemoglobinopathies, multiple myeloma, malnutrition, hemolysis, malignancy, hyperparathyroidism, and hypogonadism. Failure to respond to erythropoietin should trigger an evaluation for these conditions.
Erythropoietin therapy increases hemoglobin concentration, improves quality of life, and may decrease mortality (40,41). Erythropoietin causes a decrease in the left ventricular hypertrophy associated with anemia (11). As may be expected with increased blood volume, erythropoietin therapy increases blood pressure, necessitating close monitoring in patients with known cardiovascular disease. Two forms of erythropoietin are currently marketed, epoetin alfa and darbeopoietin alfa. Both drugs are effective, but differ in half-life. Longer-acting darbeopoietin alfa may be as effective at less frequent dosing intervals.
The report by Cesari and colleagues highlights the need to pay more attention to anemia in older persons. The positive clinical outcomes for treating anemia, such as improved quality of life, decreased hospitalization, and decreased mortality, demand that a hemoglobin concentration of less than 12 g/dL should be investigated and treated whenever possible. Chronic kidney disease and its associated anemia are very likely underdiagnosed in older persons. Erythropoietin should clearly be considered in all anemic older adults with chronic kidney disease whose serum creatinine is greater than 2 mg/dl. A calculated creatinine clearance should be done to identify patients with chronic renal failure whose creatinine may be less than 2 mg/dl. The availability of recombinant erythropoietin makes the goal of correcting anemia and improving patient outcomes a priority.