Anemia in older persons is common and is often incorrectly attributed to the ravages of normal aging. Hemoglobin levels should not vary due to age in elderly patients who are free of disease with bone marrow that is not stressed. Whether anemia is a marker or mediator of disease is not always clear, but even in centenarians it is usually a signal of pathology and is associated with increased morbidity and mortality.1,2 A simple evaluation will identify the majority of causes and facilitate appropriate treatment.
The World Health Organization (WHO) has identified the lower limits of normal hemoglobin as 13 g/dL in men and 12 g/dL in women. While the WHO criteria was based on a small group of younger patients, anemia as defined by WHO criteria is associated with an increased mortality risk in people older than 85 years, indicating that the thresholds are still appropriate for even the very aged.3,4
The prevalence of anemia increases with advancing age. Under age 75 years, anemia is more common in females, but over age 75 years it is more common in males.5 Anemia increases dramatically after age 85 in both sexes, in some studies present in 17% of women and 28% of men.6
In addition to age, anemia prevalence varies as a reflection of the general health of the patient population. The highest rates occur in hospitals and nursing homes, while the lowest are in patients who live at home or in independent living sites.7
Hematopoiesis and Cytokines in Older Persons
Just as other aging organ systems experience a decline in organ function reserve, the hematopoietic system loses its capacity to respond to stress. While hemoglobin, white blood cell count, and platelets are normal under usual circumstances, older patients may take longer to recover from a bleeding episode, or the white blood cell count may not demonstrate a brisk leukocytosis in the face of sepsis.
There are several potential reasons. Normal hematopoiesis requires the coordinated interaction of stem cells, modulating cytokines, and an intact hematopoietic microenvironment. Disruption of any of these three variables may cause abnormalities in the blood counts. Older people may have an overall reduction in stem cell concentration, hematopoietic growth factor production, and sensitivity to hematopoietic cytokines.8 Pro-inflammatory cytokines such as interleukin (IL)-1, tumor necrosis factor-alpha, and IL-6 regulate the inflammatory process during infection, trauma, and stress. Increased levels of each of these cytokines are associated with a number of diseases that are common in older persons, including atherosclerosis, diabetes mellitus, and cancer. The regulation of these cytokines decreases with age. In one population-based, case-control study of adults age 74 years and older, frail subjects had significantly higher IL-6 and lower hemoglobin levels than non-frail subjects.9 This cytokine is one of the likely mediators in the pathogenesis of the frailty syndrome of decreased bone mineral density, reduced lean body mass, low serum cholesterol and albumen, and anemia.10
In the Baltimore Longitudinal Study of Aging (BLSA), patients examined at 1-2–year intervals for 8-30 years had serum erythropoietin levels that increased significantly with aging, but increased less significantly in those patients with hypertension or diabetes. The increase in serum erythropoietin with aging may indicate compensation for subclinical blood loss, increased red cell turnover, or increased erythropoietin resistance of red cell precursors. The less significant rise in those patients with hypertension and diabetes may reflect an age-acquired renal impairment associated with the underlying disorder. In patients with renal disease, anemia may develop because the compensatory mechanism is inadequate.11
Consequences of Anemia in Older Persons
There appear to be clinical associations, if not consequences, of anemia that are not always related to the hematopoietic system.12 The pathophysiology relating anemia to other nonhematologic organ systems is not always clear.
Muscle and Bone
Anemia and osteoporosis are both prevalent in the geriatric population.13 Data from the “Invecchiare in Chianti” (Aging in the Chianti Area; InCHIANTI) study demonstrated that there is a negative relationship between low hemoglobin levels and bone mass.14 Another study from the same database demonstrated that lower hemoglobin levels are associated with lower ankle extension strength, lower muscle density, and less muscle mass.15
A study evaluating mobility and anemia using standing balance, a timed 2.4-meter walk, and a timed test of five chair rises as markers found that anemia was associated with greater average decline in physical performance over 4 years, even in participants who were free of diseases that ordinarily cause anemia.16
A cohort of elderly women who lived independently and had participated in the Women’s Health and Aging Studies I and II were evaluated with regard to their ability to walk, rise quickly from a chair, and keep their balance. Women with hemoglobin levels between 13 g/dL and 14 g/dL performed the best, while those with a hemoglobin level under 12 g/dL were consistently worse. Women with levels between 12 g/dL and 13 g/dL performed intermediately. The risk of mobility problems for those with hemoglobin levels of 12 g/dL was more than twice as high as for those with hemoglobin levels of 13 g/dL or greater.17
Thirty percent of people age 65 years and older fall at least once a year. Falls and fractures are significant causes of disability, admission to institutional care, and mortality. In a 3-year study of patients who maintained a calendar of their falls, anemic people appeared to be significantly weaker in terms of muscle strength and had poorer objectively measured physical performance than nonanemic patients, and were more likely to be recurrent fallers.18
A study of claims data for 47,530 patients over the age of 65 years in 30 health plans spanning from January 1999 through April 2004 demonstrated that anemia was significantly and independently associated with an increased risk of injurious falls. Hemoglobin less than 10 g/dL was associated with three times the chance of fall with injury to the hip and almost twice the chance of a head injury as compared to those who were not anemic.19
The role of anemia on cognition, other than that associated with vitamin B12 deficiency, is controversial. In a community-based longitudinal study of subjects age 75-95 years, people with a Mini-Mental State Examination score of 26 or higher who were anemic at the outset had a higher risk of developing dementia when re-examined after 3 years of follow-up.20 In the Women’s Health and Aging Study II, mild anemia appeared to be an independent risk factor for executive function impairment in community-dwelling older adults.21 Anemia has been demonstrated to be a risk for functional and cognitive decline over a 4-year period after accounting for age, body mass index, kidney function, and other indicators of general health.22
Acute and chronic anemia can cause congestive heart failure in patients without heart disease and may precipitate congestive heart failure and angina in patients with underlying heart disease.
In patients age 65 years and older with congestive heart failure, lower hemoglobin levels are associated with an increased risk of death and re-hospitalization at 1 year. Those patients with hematocrit levels less than 27% had 40% greater 1-year mortality than those who were not anemic.23
A study of patients age 75 years and older randomly assigned to an invasive or optimized medical strategy were followed for a median of 4 years with endpoints including death, nonfatal myocardial infarction, or hospitalization for coronary artery disease. Anemia proved to be an independent predictor of major clinical adverse events including death, even in patients with stable but symptomatic coronary artery disease. After adjustment for baseline differences, a decrease of hemoglobin by 1 g/dL increased the risk of all-cause death by 34%.24
Two-year cardiovascular outcomes in a cohort of men with acute coronary syndrome referred for coronary angiography at a Veterans Affairs medical center demonstrated at 24 months an event-free survival of 64% in the group with a hemoglobin level less than 13 g/dL, as compared to 84% in the group with a hemoglobin level more than 13 g/dL. Anemia appeared to be a strong and independent predictor of death or acute myocardial infarction at 2 years in patients with acute coronary syndrome.25
In the Women’s Health and Aging Study I, mortality risk was lowest at normal hemoglobin levels. It increased as the hemoglobin fell, even within the range of low-normal as defined by the WHO criteria.26
In the Established Populations for Epidemiologic Studies of the Elderly (EPESE), anemia maintained a significant association with mortality, and a higher hemoglobin level was significantly associated with lower mortality and hospitalization.27
Apparently stable older residents of a nursing home with hemoglobin levels less than 11 g/dL were observed for 60 months and compared to age/sex-matched controls with hemoglobin levels more than 11 g/dL. The 5-year survival rate of those patients with low hemoglobin concentration was 48%, while that of the controls was significantly higher at 67%.28
Causes of Anemia in Older Persons
Causes of anemia in the population over age 65 years are relatively few. According to an analysis of the Third National Health And Nutrition Examination Survey (NHANES III), 34% of anemia in older adults was due to folate, B12, or iron deficiency alone or in combination. Twenty percent had anemia of chronic disease (ACD), 12% were associated with renal insufficiency, and in this study, the remaining 34% were unexplained.5 While relative percentages vary between studies with the population being examined, the causes of anemia in all older patients are remarkably constant (Table).
Iron deficiency is frequently seen in the elderly and usually is a result of acute or chronic blood loss through the gastrointestinal tract. ACD is associated with several conditions more common in older persons: inflammatory diseases, malignancy, diabetes, heart failure, and stroke.
Normal B12 absorption requires gastric acid, intrinsic factor (IF), and a terminal ileum. Autoimmune destruction of IF-secreting parietal cells, or pernicious anemia, accounts for approximately 2% of the population over age 60 years. Atrophic gastritis and hypochlorhydria may progress with advancing age and may be partly responsible for the 12% of patients over age 75 years who will have a low B12. The majority of older patients with vitamin B12 deficiency are found to malabsorb dietary protein-bound vitamin B12.29 Short-term studies suggest that proton pump inhibitors and H2 blockers also produce malabsorption of protein-bound B12 by suppressing acid production further.30,31 Post-gastrectomy states, pancreatic insufficiency, and disease or resection of the terminal ileum also impair absorption of B12.
In most studies, 15-30% of patients studied will not have an explanation for their anemia. This may be a function of the intensity of the investigation. In nursing home residents, idiopathic anemia may be due to a lower erythropoietin response to a low hemoglobin due to undetected renal dysfunction.32
The reported prevalence of myelodysplastic syndrome (MDS) increases in people age 70 years and older. Anemia is the initial abnormality in more than half of them.33 MDS is almost certainly underdiagnosed since the evaluation of anemia is less likely to include a bone marrow evaluation due to the discomfort of the procedure and the perceived lack of effective treatment.34
A significant percentage of elderly anemic patients have competing causes for their anemia.35,36 Older patients often take several medicines in multiple combinations, and whether or not the drug has a bone marrow suppressive property, the potential for overlapping or synergistic myelosuppressive effects is not measurable.
The appropriate treatment of anemia depends on an accurate diagnosis. When treating iron deficiency, supplemental iron should be given in meaningful doses, yet in such a way that the geriatric stomach can tolerate it. Iron should be given long enough to rebuild the hemoglobin to normal levels and to replenish the iron stores. Smaller doses may require treatment for a longer duration than is necessary in younger iron-deficient patients. Discontinuing iron supplementation prematurely will result in relapse.
Indiscriminate administration of iron to a geriatric patient with an unevaluated anemia is not appropriate. Iron supplementation for patients with ACD or MDS does nothing to relieve the anemia and only contributes to the iron overload.
Anemia caused by B12 deficiency secondary to malabsorption of B12 is adequately and safely replaced using the appropriate dose of oral B12 instead of the monthly injections.37 There are conflicting opinions regarding the use of oral B12 in the patient who is deficient in IF.38 If the oral route is chosen, close follow-up is recommended to document the presence or absence of a response. Anemia of renal insufficiency usually responds to supplemental erythropoietin. While treatment for MDS is still reliant on supportive care, recent advances in chemotherapy provide a menu of well-tolerated treatment options not available only a few years ago.
Since most of the congenital anemias will have been diagnosed before old age, the number of possible causes of anemia in older persons is small when compared to younger patients. A few diseases and a few lab tests will provide a diagnosis more than 60% of the time. When appropriate, a bone marrow aspiration and biopsy may be desirable.
Whether anemia is a marker or a mediator of disease is not always clear, but even in centenarians, anemia is usually accompanied by a pathological condition. It is important to identify these causes and treat them where possible. Anemic elderly patients have increased morbidity and mortality.
The author reports no relevant financial relationships.
Dr. Lands is Associate Professor, Family Medicine-Geriatric Medicine, the University of Tennessee Graduate School of Medicine, Knoxville.