eMedicine Specialties > Hematology > Red Blood Cells and Disorders
Anemia in Elderly Persons
Updated: Sep 29, 2009
Introduction
Background
Anemia is an important sign that often points to a serious and possibly treatable medical condition. Although defined as a reduction in red blood cell (RBC) mass, other readily available measures that estimate RBC mass such as hemoglobin (Hb) concentration and hematocrit (Hct) are commonly used.
In elderly persons (defined as those older than 65 y for the purpose of this article), the etiology of anemia differs sufficiently from younger adults to warrant considering anemia in elderly persons as a distinct entity.
For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Anemia.
Pathophysiology
Hematopoiesis, the production of blood elements, occurs in an orderly, hierarchical fashion. Blood cell production requires stem cells, a functioning bone marrow microenvironment, nutrients, and cytokines. A pluripotent hematopoietic stem cell gives rise to committed progenitors of myeloid, erythroid, and megakaryocytic lineages.
Erythropoiesis specifically relates to the arm of hematopoiesis that generates erythrocytes. The earliest committed erythroid lineage progenitors include the BFU-E (burst-forming unit-erythroid), which later give rise to CFU-E (colony-forming unit-erythroid). Normal erythropoiesis in adults occurs exclusively in the bone marrow and is generally restricted to the pelvis, vertebrae, sternum, ribs, and proximal femurs.
Erythropoietin physiology
Various hematopoietic growth factors support stem cell proliferation, differentiation, and survival. Erythropoietin (EPO), a glycoprotein hematopoietic growth factor, serves as a primary regulation of RBC production.1,2 Synthesis and EPO regulation occurs primarily in the kidney with a smaller contribution by liver hepatocytes.3,4,5,6,7 As a consequence, renal failure inexorably leads to anemia from impaired EPO production.
Reduced tissue oxygenation (rather than diminished RBC production), typically from anemia or hypoxia, potently stimulates a logarithmic enhancement of EPO synthesis.8 Elevated serum EPO levels enhance erythrocyte production primarily by inhibiting apoptosis of erythroid progenitor cells and to a lesser degree by enhancing erythroid progenitor proliferation and differentiation.9
The reticulocyte, an early RBC that has lost the nucleus but retained the polyribosomal reticular network, eventually emerges into the blood. After 1-4 days, reticulocytes lose this ribosomal network and mature into RBCs. Mature RBCS have an average life span in the blood of 100-120 days. Macrophages engulf senescent RBCs in the spleen, liver, and marrow.
Erythropoiesis with aging
Basal erythropoiesis and RBC mass in aged mice appears similar to younger mice, although the measured Hct may be slightly lower secondary to dilution.10,11 In response to stress, such as hypoxia, bleeding, or environmental perturbation, aged mice have an impaired erythropoietic response compared with younger mice.10,12,13
Estimates of RBC mass
RBCs are largely composed of Hb, which is a complex molecule essential in delivering oxygen from the lungs to the tissues. Hb contains a heme-iron complex, and each RBC has hundreds of millions of Hb molecules. Thus, the RBCs serve as the largest storage compartment of iron in the body, and RBC loss often leads to iron deficiency.
Frequency
United States
In the vast majority of patients, Hb represents an excellent and easily reproducible measure of RBC mass. The Hb value below which anemia is defined varies. The World Health Organization (WHO) Hb thresholds of less than 13 g/dL for men and less than 12 g/dL for women are the most common definitions used for anemia in the elderly.14 The threshold has been widely criticized based upon an association of adverse outcomes with higher Hb concentrations.15,16 The WHO criteria remain useful to compare anemia prevalence in different studies.
Hb thresholds for anemia may be defined distinctly for various reasons; thus, different thresholds are considered:
- Prognostic marker: Numerous studies have shown that mildly low Hb values, often 1 - 2 g/dL above the WHO threshold, have been associated with increased mortality, hospitalization, and functional decline in elderly persons.
- Etiologic marker: Clinicians most often define anemia to determine if an etiologic evaluation should be pursued. A wealth of data shows that important causes are uncovered if an evaluation is performed for anemia as defined by the WHO threshold.
- Treatment: A lower Hb threshold is often used when deciding whether to treat with pharmacologic erythropoietin or RBC transfusions.
In addition to the varying thresholds for anemia, the highly heterogeneous nature of the elderly population has lead to multiple estimates of anemia prevalence in the elderly. One estimate suggests that more than 3 million elderly Americans are anemic.17
Table 1. Anemia Prevalence in the Elderly Based on WHO Criteria
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Table
Study | Age | Population | Prevalence |
| Guralnik et al, 2004 17 | ≥65 y | Community-dwelling elderly, American | 10.6% |
| Ferrucci et al, 2007 18 | ≥65 y | Community-dwelling elderly, Italian | 11% |
| Denny et al, 2007 19 | ≥71 y | Community-dwelling | 24% |
| Joosten et al, 1992 20 | ≥65 y | Hospitalized | 24% (defined as Hb <11.5 g/dL) |
| Artz et al, 2004 21 | Most ≥65 y | Nursing home | 48% |
Study | Age | Population | Prevalence |
| Guralnik et al, 2004 17 | ≥65 y | Community-dwelling elderly, American | 10.6% |
| Ferrucci et al, 2007 18 | ≥65 y | Community-dwelling elderly, Italian | 11% |
| Denny et al, 2007 19 | ≥71 y | Community-dwelling | 24% |
| Joosten et al, 1992 20 | ≥65 y | Hospitalized | 24% (defined as Hb <11.5 g/dL) |
| Artz et al, 2004 21 | Most ≥65 y | Nursing home | 48% |
International
Studies from Europe and Japan22 indicate a fairly similar prevalence of anemia in elderly adults as in the United States. Prevalence estimates of anemia in elderly persons living in developing countries are lacking.
Mortality/Morbidity
Morbidity and mortality related to anemia in the elderly can occur both from the underlying disease related to the anemia and the adverse effects of anemia itself. Multiple epidemiologic studies show an association between anemia or even mildly low Hb above the WHO threshold for anemia (ie, <14 g/dL) and a worse outcome, including the following:
- Increased mortality16,19,23,24,25,26,27
- Increased hospitalization16,25,28
- Increased difficulty with mobility26,29
- Falls30,31
- Decreased activities of daily living and instrumental activities of daily living19
- The presence of other conditions (cardiovascular disease) appears to increase the negative prognostic impact on survival
Although these differences disappeared after adjustment for comorbidity, a greater increase in disability in instrumental activities of daily living remained; also, incident anemia during follow-up was associated with an additional increase in disability in basic activities of daily living.32 Prevalent and incident anemia were both associated with an increased risk of death (hazard ratio [HR] for prevalent anemia 1.41, 95% confidence interval [CI] 1.13-1.76; HR for incident anemia 2.08, 95% CI 1.60-2.70).
Race
- Anemia is approximately 3 times more prevalent in elderly blacks than among non-Hispanic whites.
- Older Mexican Americans have a fairly similar prevalence to that of elderly whites.
- The median Hb for elderly blacks is approximately 0.8 g/dL lower than for whites.19,26
- The cause for the higher prevalence in blacks has not been established. However, some of the disparity is likely related to biologic differences. Anemia is more common in black children,33 and Hb appears to decline similarly with advancing age in blacks and whites.19 In younger adults, part of the increased anemia prevalence relates to an alpha-thalassemia trait.34
- Whether anemia has different adverse consequences in blacks is unclear.19,26
Sex
Anemia in elderly persons is more common in men than in women. Some of the difference stems from employing a lower Hb threshold (eg, Hb <12 g/dL) for women than for men (ie, <13 g/dL).
Age
- Hb declines slightly, and anemia prevalence rises in both men and women with advancing age.8 This change is more pronounced in men.
- Among community-dwelling adults aged 65 years and older, one study showed anemia prevalence was 8% among those aged 65-74 years, 13% for those aged 75-84 years, and 23% for those aged 85 years and older.17
- The reason for increased anemia prevalence with advancing age has not been established.
Clinical
History
A comprehensive history, physical examination, and laboratory evaluation are required for an elderly person found to have anemia. As a laboratory finding, anemia is often recognized incidentally after the initial evaluation. The multiple causes for anemia in elderly persons and the influence of anemia and anemia treatment on the pathogenesis of associated conditions justify a complete anemia evaluation rather then a piecemeal approach.
- Previous blood counts: Previous blood counts represent one of the most underused and invaluable tools to help clinicians determine the acuity of the anemia. The causes for an acute fall in Hb are narrow (eg, bleeding, hemolysis) as opposed to the more common slow decline over time. Elderly persons have frequently had previous blood counts that are easily retrievable.
- Transfusion history: One should inquire whether RBC transfusions have previously been administered. A history of transfusions will alert the clinician to a chronic problem.
- Medical history: Recent hospitalization often results in anemia, particularly in elderly persons. The anemia is often the consequence of multiple phlebotomies as well as the acute illness itself. Thus, the prehospitalization Hb can be invaluable.
- Recent surgery suggests blood loss and necessitates comparison to preoperative Hb values. When surgery requires RBC transfusion, the patient has often had a preexisting low Hb before the surgery, had another condition preventing an appropriate response to blood loss, or both.
- Diseases that frequently cause anemia should be noted, including myelodysplasia, cancer, and cancer chemotherapy (especially myelosuppressive chemotherapy), chronic kidney disease, and rheumatologic disorders.
- End-stage renal disease (ESRD) uniformly causes anemia, unless an erythropoietin-stimulating agent is administered.
- Conditions that are associated with specific types of anemia should be clearly identified.
- Lymphoproliferative and autoimmune disease may cause autoimmune hemolytic anemia.
- Previous chemotherapy or radiotherapy raises the possibility of therapy-related myelodysplastic syndrome.
- Alcohol overuse may go unrecognized in the elderly and leads to deficiencies of vitamin B-12, folate, marrow hypoproliferation, and gastrointestinal bleeding.
- Racial background
- Family history can be useful for considering a coexistent thalassemia trait or other hemoglobinopathy.
- Ancestry should be considered, with recognition that blacks may have an approximately 0.8 g/dL lower Hb than whites.
- Symptoms: Symptoms relate to the rapidity of the anemia, the depth of the Hb fall, and concomitant medical conditions. The nonspecific nature of anemia-related symptoms poses a major challenge. Nevertheless, a detailed history often identifies the presence of anemia-related symptoms. Inquiring about specific tasks, such as walking up stairs, that lend additional objective information is often useful. Patients may mistakenly attribute decreased energy to aging or other medications.
- Special attention should be paid to elements that indicate a cause for the anemia (eg, presence or symptoms of cancer, gastrointestinal blood loss, infection, arthritis) and symptoms related to anemia (fatigue, shortness of breath, tinnitus).
- Most symptoms of anemia are nonspecific; however, a temporal relation between falling Hb and symptom exacerbation is very useful. Blood loss should be directly inquired about (eg, melena, hematuria, hemoptysis, hematemesis).
- General symptoms
- Fatigue
- Weakness
- Dyspnea on exertion
- Tinnitus
- Presyncope
- Palpitations
- Headache
- Poor concentration
- Pale skin
- Specific causes and associated signs and symptoms of anemia
- Iron deficiency
- Blood loss (tarry stools, red blood in the stools, hematuria)
- Pica (desire to consume unusual substances such as ice or dirt)
- Koilonychia (spoon-shaped changes in the nail beds)
- Dysphagia (from esophageal webs)
- Mouth and tongue soreness (from atrophy)
- Vitamin B-12 deficiency
- Neuropathy
- Ataxia
- Dementia
- Hemolysis
- Jaundice
- Dark urine (if intravascular hemolysis)
- Iron deficiency
Physical
The physical examination may uncover an anemia etiology, signs related to the anemia, or both. Thus, the examination must be comprehensive. Special attention should be paid to the following:
- Pallor
- Icterus
- Lymphadenopathy
- Tachycardia
- Cardiac murmurs
- Hepatomegaly
- Splenomegaly
- Edema
- Stool for color
- Stool test for blood
Causes
Multiple conditions can lead to anemia in elderly persons. Moreover, the anemia may be multifactorial. Nevertheless, in the majority of cases of anemia in elderly persons, an etiology can be found. The most common causes include iron deficiency (with or without blood loss), chronic disease/inflammation and chronic kidney disease.17 20,21,35Other etiologies of anemia in the elderly include deficiencies of folate or vitamin B-12, diseases of the bone marrow (eg, myelodysplastic syndromes, aplastic anemia, paroxysmal nocturnal hemoglobinuria, myeloproliferative syndromes, acute or chronic leukemia, lymphoma), hypothyroidism, hypersplenism, and hemolytic anemia. Despite a complete evaluation, a significant minority of cases have no etiology uncovered (ie, unexplained anemia).20,21
Table 2. Prevalence of Various Etiologies of Anemia in Elderly Persons
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Table
| Cause | Prevalence |
| Iron deficiency | 15-23% |
| Chronic disease/inflammation | 15-35% |
| Chronic kidney disease | 8% |
| Endocrinopathies | <5% |
| Vitamin B-12 or folate deficiency | 0-14% |
| Myelodysplastic syndromes | 0-5% |
| Unexplained | 17-45% |
| Cause | Prevalence |
| Iron deficiency | 15-23% |
| Chronic disease/inflammation | 15-35% |
| Chronic kidney disease | 8% |
| Endocrinopathies | <5% |
| Vitamin B-12 or folate deficiency | 0-14% |
| Myelodysplastic syndromes | 0-5% |
| Unexplained | 17-45% |
Iron-deficiency anemia
Identifying iron-deficiency anemia in elderly persons is essential and can be corrected. More importantly, iron deficiency, particularly in elderly persons, often points to an underlying gastrointestinal pathology, including malignancy.36,37 Despite the importance of establishing a diagnosis, iron-deficiency anemia represents only 15-23% of cases of anemia among the elderly.17,20,21
Anemia of chronic disease and inflammation
Anemia of chronic disease appears to be primarily related to inflammation, thus leading to the term anemia of chronic inflammation.38 Anemia of chronic inflammation is a hypoproliferative anemia characterized by low serum iron and adequate to increased iron stores.39 Inflammatory markers implicated in anemia of chronic inflammation include tumor necrosis factor alpha (TNF-alpha),40,41 interleukin-1 (IL-1),42,43 interferon gamma (IFN-gamma),44 and IL-6.45,46 Inflammation inhibits erythropoiesis through a variety of mechanisms.47
The discovery of hepcidin has considerably clarified the pathophysiology of anemia of chronic inflammation. Hepcidin is a hepatically synthesized 25 amino acid peptide that serves as a primary regulator of iron homeostasis. Hepcidin directly inhibits ferroportin, a protein that transports iron out of cells that store it. Inflammation, particularly with IL-6, increases hepcidin expression.
Anemia of chronic inflammation and the disordered iron homeostasis that is typically found may be explained by increased hepcidin expression.48,49 Hepcidin testing is not clinically available and has not been validated as a diagnostic test for anemia of chronic inflammation. No established diagnostic criteria for anemia of chronic inflammation exist. In epidemiologic studies, low serum iron (eg, <60 μg/dL) with or without low to normal transferrin have been used.17
An alternative method is to consider anemia of chronic inflammation to exist when the patient has an inflammatory comorbid condition.21 Not all conditions or even conditions leading to anemia warrant a diagnosis of anemia of chronic inflammation. For example, anemia due to renal insufficiency or endocrine dysfunction is not considered anemia of chronic inflammation.39 Thus, diseases such as hypertension and osteoarthritis should not lead directly to anemia.
Comorbid diseases often contribute indirectly to anemia of chronic inflammation. Nonsteroidal drugs for osteoarthritis may lead to gastrointestinal bleeding and iron deficiency, whereas hypertension may cause anemia from chronic kidney disease. Case reports have proposed that anemia of chronic inflammation may exist in elderly persons absent a chronic condition.50 This entity, known as “primary defective iron-reutilization syndrome” may respond to hormonal therapy.51
Renal insufficiency
Chronic kidney disease is an important cause of anemia in elderly persons, especially considering that renal function declines with aging.52,53 Reduced renal EPO production is the primary factor leading to anemia in chronic kidney disease. Serum EPO levels have been shown to be inappropriately low at a creatinine clearance of less than 40 mL/min.54,55 The precise degree of renal dysfunction sufficient to cause anemia remains controversial. Mild Hb decreases in adults may be detected at a creatinine clearance of 40-60 mL/min.56,57
A study among community-dwelling elderly persons suggested anemia and low EPO levels are independent of age and other factors at a creatinine clearance less than 30 mL/min.58 We also examined renal function in older residents in a skilled nursing facility.59 Forty-three percent had chronic kidney disease (defined as a creatinine clearance less than 60 mL/min). Chronic kidney disease increased the risk of anemia.
Nutrient deficiencies
Low vitamin B-12 levels in elderly persons are not uncommon. However, vitamin B-12 deficiency is a very uncommon cause of anemia in elderly persons.60 Folate deficiency is also uncommon, in part related to widespread vitamin supplementation.61 To the extent such mineral deficiencies are reversible and suggest other conditions (eg, pernicious anemia or hemolysis, respectively), they remain important to identify.
Myelodysplastic syndromes
Myelodysplastic syndromes represent a heterogeneous group of disorders characterized by clonal hematopoiesis and peripheral blood cytopenias. They are more common in older adults and may present as an isolated anemia. In the elderly, anemia in conjunction with macrocytosis, thrombocytopenia, or neutropenia absent another cause raises the suspicion of myelodysplastic syndrome.62,63 Alternatively, Myelodysplastic syndrome is an unlikely cause of idiopathic normocytic anemia in elderly persons.64,65,66 When evaluating mean corpuscular volume (MCV), one must be cognizant that recent RBC transfusions will alter the values. Thus, retrieving hematology values before a transfusion is critical.
Other miscellaneous primary hematologic disorders
A variety of other primary hematologic disorders have anemia as a manifestation. Thrombotic thrombocytopenic purpura (TTP), although rare, should be considered in every patient with anemia, as this a medical emergency requiring prompt intervention. Often (but not always), patients will have other cardinal features of the disease, including thrombocytopenia, altered mental status, and renal insufficiency.
Elderly patients with acute leukemia can have a more smoldering disease course than younger patients. These patients may present with a low, high, or even normal white blood cell (WBC), although in most individuals the WBC differential is abnormal. This fact emphasizes the importance of performing a manual differential in all patients with an abnormal complete blood cell (CBC) count.
Chronic lymphocytic leukemia (CLL) is common in elderly persons. Although most patients will have either an elevated WBC or lymphadenopathy at presentation, some patients will present with autoimmune hemolytic anemia and could have relatively little evidence of CLL. Multiple myeloma should always be considered, particularly in patients with elevated globulin levels. Patients with aplastic anemia will have a low WBC and/or platelet count. Patients with myeloproliferative diseases often have an elevated WBC; however, some patients with myelofibrosis will have anemia as the prominent abnormality.
Finally, anemia can be a sign of bone marrow infiltration from lymphoma. Not uncommonly the patient will not have palpable lymphadenopathy, but computed tomography (CT) scans could reveal extensive internal lymphadenopathy. In these patients, measurement of an lactate dehydrogenase (LDH) level is essential.
Hypothyroidism reduces RBC mass and may lead to a normocytic anemia.67 Occasionally, hypothyroidism may lead to macrocytosis without anemia.68 Hypothyroidism and hyperthyroidism may be associated with pernicious anemia,69 and both conditions may also lead to a correctable anemia, but most patients with thyroid abnormalities are not anemic.69,70 The degree of thyroid dysfunction leading to anemia remains unknown. Generally, the more severe the thyroid dysfunction, the more likely anemia will occur. A therapeutic trial correcting the thyroid abnormalities may be necessary to definitively determine their role in causing lower Hb concentration.
Unexplained anemia in the elderly
The traditional notion has been that anemia in the elderly always reflects a serious underlying condition.71 However, it has long been recognized that a proportion of patients, usually older, have anemia that does not meet diagnostic criteria for a specific etiology (unexplained anemia). Multiple studies of anemia in elderly persons over the past 30 years have confirmed that unexplained anemia represents a considerable proportion of cases of anemia in elderly persons, ranging from 15-45%.5,17,20,21,35,72,73,74 Even with the advent of better tests such as serum ferritin, methylmalonic acid, soluble transferrin receptor, a significant portion of elderly persons with anemia will be diagnosed as having unexplained anemia.21
Unexplained anemia is generally a condition of elderly persons. It appears more commonly with advancing age and is rarely, if ever, encountered in younger adults.75 In a longitudinal study in healthy elderly subjects, Hb slowly but predictably declined with aging.8 In elderly patients who reside in nursing homes, we found a very high prevalence of unexplained anemia (45%).21
Whether unexplained anemia represents a spectrum of undiagnosed etiologies or has a unifying pathogenesis remains unclear. The present data support unexplained anemia as distinct from anemia of chronic inflammation. Guralnik and colleagues evaluated data from community-dwelling elderly and defined anemia of chronic inflammation as a serum iron less than 60 μg/dL but without iron deficiency.17 C-reactive protein (CRP) was elevated in 27% of patients who had anemia of chronic inflammation compared with only 9% in those with unexplained anemia.
In a nursing-home study categorizing anemia of chronic inflammation as the presence of an inflammatory comorbid condition, the mean CRP was 36.9 mg/dL for those with anemia of chronic inflammation compared with 6.0 mg/dL for patients with unexplained anemia. IL-6 levels were significantly higher in cases of anemia of chronic inflammation (44.3 pg/mL +/– 72.4) compared with cases of unexplained anemia (8.5 pg/mL +/– 7.8).
Thus, anemia of chronic inflammation as diagnosed by criteria that differed in 2 studies showed higher markers of inflammation for anemia of chronic inflammation relative to unexplained anemia. Although higher inflammatory markers have not been used as the sole criterion for the diagnosis of anemia of chronic inflammation, the presence of significant inflammation (ie, high CRP) should alert the clinician to a possible inflammatory component. The expected inflammatory profile may be blunted, however, when patients are undergoing treatment for a chronic inflammatory disease.
Another concern has been that unexplained anemia reflects occult myelodysplastic syndrome.17,76 In the National Health and Nutrition Examination Survey III (NHANES III) study of anemia in the elderly, 17% of cases of unexplained anemia had hematologic abnormalities that may have been consistent with myelodysplastic syndrome.17 These included an MCV greater than 100 fL, a leukocyte count less than 3 K/uL, or platelet count less than 150 K/uL. In a nursing home study, 27 patients exhibited a normocytic unexplained anemia, whereas 3 patients had an unexplained macrocytic anemia (ie, 3 of 30 patients or 10% with unexplained anemia).21
Relative EPO deficiency
In the prototypical model of complete renal failure, inadequate endogenous EPO secretion rather than a primary marrow problem leads to anemia.55 Even in renal conditions without overt renal glomerular filtration abnormalities, endocrine function as measured by the endogenous EPO response to anemia may be impaired. For example, children with nephritic syndrome, before significant renal clearance impairment, have a blunted endogenous EPO response to anemia.77 A similar blunted EPO response occurs in patients with diabetes independent of reduced glomerular filtration.78 Finally, administration of angiotensin-converting enzyme (ACE) medication may suppress EPO secretion and precipitate anemia.79,80
In older adults with preserved renal function, the endogenous EPO response in those having renal-damaging conditions (ie, diabetes and hypertension) is blunted relative to those not having such a condition.8 A decline in renal function may be a feature of aging that is accentuated by hypertension and diabetes.81 Thus, a relative EPO deficiency, potentially from early renal damage, likely contributes to unexplained anemia.8,21,58
Sex hormones
The general Hb difference between men and women relates in large part to the erythropoietic effects of testosterone, which can be illustrated by the fact that after orchiectomy or androgen deprivation therapy for prostate cancer, Hb falls by 1.2 g/dL to 1.5 g/dL on average.82,83 Further, testosterone replacement raises Hb in older men.84
Testosterone declines with aging in men.85 The greater rate of Hb decline in men than in women with advancing age raises the suspicion that falling testosterone may cause unexplained anemia.8,86 A large epidemiologic study showed that men with lower testosterone were more likely to have anemia. However, one small study did not show a difference in testosterone between anemic and nonanemic older men,64 and the proportion of unexplained anemia appeared similar in men and women.17
More on Anemia in Elderly Persons |
 Overview: Anemia in Elderly Persons |
| Differential Diagnoses & Workup: Anemia in Elderly Persons |
| Treatment & Medication: Anemia in Elderly Persons |
| Follow-up: Anemia in Elderly Persons |
| References |
| Further Reading |
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Keywords
anemia in elderly persons, anemia, unexplained anemia, idiopathic anemia, anemia of aging, senile anemia, iron-deficiency anemia, erythropoietin, myelodysplastic syndromes, reduction in red blood cell mass, anemia of chronic disease, anemia of chronic inflammation
