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Anemia in Elderly Persons

Overview
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 age 65 y for the purpose of this article), the etiology of anemia differs
sufficiently from the etiology in younger adults to warrant considering anemia in elderly persons as a distinct entity. [1, 2]
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.
Consult a hematologist for bone marrow aspiration and biopsy.
Consult a gastroenterologist for colonoscopy, esophagogastroduodenoscopy, or small bowel evaluation.
Low Hb is a powerful prognostic marker for multiple adverse outcomes in the elderly. Clinicians should be alerted to the
increased risk of morbidity, hospitalization, and mortality in cases of anemia in the elderly.
The critical element in treating anemia is to identify reversible etiologies for the anemia (eg, iron deficiency, infection) and
treat these appropriately. Iron deficiency, vitamin B-12 deficiency, and folate deficiency should be evaluated and treated
in cases of anemia in elderly persons.
Aside from addressing underlying etiologies or comorbid conditions, intervention to correct anemia remains experimental.
Medications in patients with anemia are used based on the cause of the anemia in an elderly person. For unexplained
anemia, no treatment has been well studied. Medications include erythropoiesis-stimulating agents, oral mineral
supplements (used in mineral deficiencies), and colony-stimulating factors (used to enhance erythropoiesis when
endogenous erythropoietin [EPO] levels are low).
Unless a deficiency has been identified as a cause of anemia in an elderly person, no specific dietary intervention will be
fruitful.
Activity restrictions may be considered for symptomatic anemia in elderly patients who may have active cardiac symptoms
until an appropriate cardiac evaluation has been performed.
Go to Anemia, Iron Deficiency Anemia, and Chronic Anemia for complete information on these topics.
Patient Education
It is invaluable for elderly patients with anemia to have documentation of their Hb concentration if it is low. Thus, if
hospitalization occurs, their baseline Hb will be available.
For patient education information, see Anemia.
Hematopoiesis
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 gives rise to the 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. EPO, a glycoprotein
that is a hematopoietic growth factor, serves as a primary regulator of RBC production. [3, 4] Synthesis and EPO regulation
occurs primarily in the kidney, with a smaller contribution by liver hepatocytes. [5, 6, 7, 8, 9] 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. [10] 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. [11]
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.
Estimates of RBC mass
RBCs are largely composed of Hb, which is a complex molecule that is essential to 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.
Anemia Thresholds
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. [12] The threshold has
been widely criticized based upon an association of adverse outcomes with higher Hb concentrations. [13, 14] However, 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.

Etiology
Multiple conditions can lead to anemia in elderly persons. (See Table 1, below.) 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. [15, 16, 17, 18]
Other 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). [16, 17]

Iron deficiency anemia


Identifying iron deficiency anemia in elderly persons is essential, and the condition can be corrected. More importantly,
iron deficiency, particularly in elderly persons, often points to an underlying gastrointestinal pathology, including
malignancy. [19, 20]Despite the importance of establishing a diagnosis, iron deficiency anemia represents only 15-23% of
cases of anemia among the elderly. [15, 16, 17]
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. [21] Anemia of chronic inflammation is a hypoproliferative anemia characterized by low serum iron and
adequate to increased iron stores. [22] Inflammatory markers implicated in anemia of chronic inflammation include tumor
necrosis factor alpha (TNF-alpha), [23, 24]interleukin-1 (IL-1), [25, 26] interferon gamma (IFN-gamma), [27] and IL-
6. [28, 29]Inflammation inhibits erythropoiesis through a variety of mechanisms. [30]
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. [31, 32] 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, has been used. [15]
An alternative method is to consider anemia of chronic inflammation to exist when the patient has an inflammatory
comorbid condition. [17] 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. [22] 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. [33] This entity, known as primary defective iron-reutilization syndrome, may respond to hormonal therapy. [34]
Renal insufficiency

Chronic kidney disease is an important cause of anemia in elderly persons, especially considering that renal function
declines with aging. [35, 36] 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. [37, 38] 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. [39, 40]
A study among community-dwelling elderly persons suggested anemia and low EPO levels are independent of age and
other factors at a creatinine clearance of less than 30 mL/min. [41] Renal function in older residents in a skilled nursing
facility was also examined, [42] and 43% had chronic kidney disease (defined as a creatinine clearance of 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. [43] Folate deficiency is also uncommon, in part related to widespread vitamin
supplementation. [44] To the extent that 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. [45, 46]
Alternatively, myelodysplastic syndrome is an unlikely cause of idiopathic normocytic anemia in elderly
persons. [47, 48, 49] 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 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) count, 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 count (CBC).
Chronic lymphocytic leukemia (CLL) is common in elderly persons. Although most patients will have either an elevated
WBC count 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
count; 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 a lactate dehydrogenase (LDH) level is essential.
Thyroid disease
Hypothyroidism reduces RBC mass and may lead to a normocytic anemia. [50]Occasionally, hypothyroidism may lead to
macrocytosis without anemia. [51]Hypothyroidism and hyperthyroidism may be associated with pernicious anemia,[52] and
both conditions may also lead to a correctable anemia, but most patients with thyroid abnormalities are not
anemic. [52, 53] 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 elderly persons
The traditional notion has been that anemia in elderly persons always reflects a serious underlying condition. [54] 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 approximately 15-45%. [7, 15, 16, 17, 18, 55, 56, 57] Even with the advent of better tests, such as serum ferritin, methylmalonic
acid, and soluble transferrin receptor, a significant portion of elderly persons with anemia will be diagnosed as having
unexplained anemia. [17]
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.[58] In a longitudinal study in healthy elderly subjects, Hb slowly, but
predictably, declined with aging. [10] In elderly patients who reside in nursing homes, a very high prevalence of unexplained
anemia has been found (45%). [17]
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. [15] 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. [15, 59] 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. [15] These included an MCV
greater than 100 fL, a leukocyte count less than 3 K/uL, or a 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). [17]
Relative EPO deficiency

In the prototypical model of complete renal failure, inadequate endogenous EPO secretion rather than a primary marrow
problem leads to anemia. [38] 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. [60] A
similar blunted EPO response occurs in patients with diabetes independent of reduced glomerular filtration. [61] Finally,
administration of angiotensin-converting enzyme (ACE) medication may suppress EPO secretion and precipitate
anemia. [62, 63]
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. [10] A decline in renal function may
be a feature of aging that is accentuated by hypertension and diabetes. [64] Thus, a relative EPO deficiency, potentially from
early renal damage, likely contributes to unexplained anemia. [10, 17, 41]
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. [65, 66]
Testosterone declines with aging in men. [67] The greater rate of Hb decline in men than in women with advancing age
raises the suspicion that falling testosterone may cause unexplained anemia. [10, 68] Further, testosterone replacement
raises Hb in older men. [69]
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, [47] and the proportion
of unexplained anemia appeared similar in men and women. [15]