Anemia is a significant health problem in the elderly because

of both a high prevalence and significant associated morbidity

(Table 93-1).1 Although there is a long-established perspective
that anemia in the elderly is of little consequence,
studies have shown that even mild decreases in hemoglobin
levels are associated with reduced quality of life, clinical
depression, falls, functional impairment, slower walking
speed, reduced grip strength, loss of mobility, worsening
comorbidities, and mortality and have called for a greater
focus on this problem.2 Currently, screening for anemia is
not generally practiced, and thus it is typically discovered
during a workup for other conditions, at a time when many
of its deleterious effects may have already occurred.
The World Health Organization (WHO) defines anemia
as a hemoglobin level of less than 13g/dL in adult males and
less than 12g/dL in adult females.3 In older men and women,
anemia by this definition is associated with an increase in
mortality.49 It has been pointed out the WHO criteria do
not take into account inherent racial variations, particularly
with respect to African Americans who may have lower levels
of hemoglobin without significant adverse outcomes.10,11
In a study that analyzed 1018 black and 1583 white adults
aged 71 to 82 years, anemia was associated with increased
mortality in whites but not blacks.10,11 The issue of defining
criteria for the diagnosis of anemia is quite relevant in
the context of age as well. Older women, for example, have
better physical performance and function at hemoglobin values
between 13 and 15 g/dL than between 12 and 12.9 g/
dL,12 suggesting perhaps that a cutoff level of 12 g/dL is too
low. Nevertheless, the WHO definition remains the current
standard utilized in most current epidemiologic surveys and
many clinical laboratories.
Prevalence of Anemia
Guralnik and colleagues examined the third National Health
and Nutrition Examination Survey (NHANES III) database,
a nationally representative sample of community-dwelling
persons and determined age- and sex-specific prevalence
rates of anemia in the total U.S. population.13 For those over
the age of 65 years, by WHO criteria, approximately 11%
were anemic (see Table 93-1). The prevalence of anemia was
lowest (1.5%) among males between 17 and 49 years of age
and highest (26.1%) in males over 85 years. Among those
65 years and older, the prevalence rate was notably higher
in African Americans as compared to whites and Hispanics.
Prevalence rates of anemia in the elderly vary in communitydwelling
and institutionalized populations. It is also quite

clear that anemia is more common among frail elderly. In the nursing home, for
example, anemia prevalence approaches
50% or higher.1417

Pathogenesis

In younger adults with anemia, the cause is usually readily

apparent. In older patients, however, discerning the cause of
anemia can oftentimes be challenging (Table 93-2). Inflammation,
nutritional deficiencies, and renal insufficiency are
commonly observed, but for as many as one third of elderly
anemic individuals (and almost 50% for those residing in
nursing homes), the anemia cannot be attributed to conventional
causes, a condition now termed unexplained anemia.18
ANEMIA OF INFLAMMATION

Chronic diseases, such as atherosclerosis, diabetes, arthritis,

infection, and malignancy, increase in prevalence with
age and each is characterized by inflammatory processes.
Although there are several ways in which inflammation can
negatively influence erythropoiesis, disordered iron kinetics
is a common feature.19 During inflammation, there is reduced
iron absorption from the gastrointestinal tract and defective
reutilization of iron sequestered in reticuloendothelial cells.
Hepcidin, a 25 amino acid polypeptide produced in the liver
in response to inflammatory stimuli, down-regulates intestinal
iron absorption as well as macrophage and monocyte
iron release, thereby creating functional iron deficiency and
resultant hypoproliferative anemia.2024 Reduced secretion
of erythropoietin due to the action of inflammatory cytokines
is also known to play a role in the anemia of chronic
inflammation.
25

IRON DEFICIENCY ANEMIA

The prevalence of iron deficiency in the elderly may range

from 2.5% to as high as 30% in some studies. Iron deficiency
is usually secondary to iron loss rather than inadequate
intake and is important to identify because it may be a
manifestation of an occult malignancy. For example, in one
study, of 114 outpatients referred to a gastroenterologist for
investigation of iron deficiency, 45 had upper gastrointestinal
and 18 had colonic sources of bleeding.26 In an older
study of 100 patients in whom the site of bleeding could
not be established by any means other than laparotomy, a
malignancy was found to be the cause in 10%.27 In a survey
of 1388 patients over 65 years of age, 25% were anemic
and approximately one third were iron deficient. Of those
with iron deficiency, gastrointestinal endoscopy found 57%
to have an upper gastrointestinal
lesion and 27% to have
colonic lesions. In total, gastrointestinal malignancy was
found in 15% of those with iron deficiency anemia. 28
Iron deficiency may be the result of gastrointestinal malabsorption,
particularly in patients who have had bowel resection,
inflammatory bowel disease, or who are on chronic
antacid therapy. Furthermore, malabsorption of iron may be
an early manifestation of celiac disease.29,30
For patients who present with anemia and microcytic red

blood cell indices, serum levels of iron, ferritin, and transferrin

saturation are typically low and total iron-binding
capacity is elevated. The coexistence of chronic inflammatory
disease may complicate analysis. To determine whether
patients with chronic inflammation and anemia are iron
deficient, measurement of the soluble transferrin receptor is
frequently useful. Under conditions of iron deficiency, transferrin
receptor is upregulated and increased levels are found
in the serum. An index, derived by dividing the serum level
of soluble transferrin receptor by the log of the ferritin level,
has been shown to be helpful.31 A ratio of less than 2 denotes
anemia of chronic inflammation, whereas values greater than
2 identify patients with either uncomplicated iron deficiency
anemia or a combination of both iron deficiency and inflammation.
B12 AND FOLATE

Since the implementation of the Food and Drug Administrations

policy of folic acid fortification of cereal grain products in
1998, there has been a dramatic reduction in measurable folate
deficiency. Just 2 years after implementation, examination of
the NHANES cohort IV (19992000) compared with cohort
III (19881994) revealed the prevalence of low-serum folate
concentrations (<6.8 nmol/L) decreased from 16% before to
0.5% after fortification.32 Thus, folic acid deficiency is currently
an uncommon cause of anemia. Vitamin B12 deficiency,
however, remains a problem, particularly in geriatric populations.
33 The great majority of B12 deficiency in the elderly is
due to food cobalamin malabsorption with true dietary deficiency
or pernicious anemia being significantly less common.
An age-associated atrophic gastritis with or without antacid
therapy is a frequent antecedent. Macrocytic indices, the
hallmark of B12 deficiency, may not be apparent because of
concomitant inflammatory disease or iron deficiency. In addition
to red cell changes, patients with B12 deficiency may also
present with a myriad of hematologic abnormalities including
leukcopenia, thrombocytopenia,
and pancytopenia occasionally requiring
the diagnosis of myelodysplasia
or
aplastic anemia. B12 deficiency is usually suspected by the
finding of an elevated mean corpuscular volume (MCV)
either on routine screening or for evaluation of the cause for
anemia. However, other causes for macrocytosis are more
common, and these include excessive alcohol intake, drug
intake (particularly antineoplastic agents), reticulocytosis,
myelodysplasia, and hypothyroidism. Levels of B12 below
200 pg/mL quite reliably indicate vitamin B12 deficiency; however,
measurement of methylmalonic acid levels and homocysteine
(which are elevated) may be necessary to establish the diagnosis
for those with higher serum B12 levels. Treatment with both
intramuscular B12 and crystalline oral B12 are effective in the
elderly, even in patients with cobalamin food malabsorption Increasingly, it has become
recognized that approximately
one third of older adults with anemia do not have an obviously
discernible cause upon routine evaluation (Table 93-3).
Typically, this anemia is generally mild (hemoglobin concentration

in the 10 to 12 g/dL range), normocytic, and

hypoproliferative (low reticulocyte count). It has been postulated
that the cause relates to a number of factors including
testosterone,40 occult inflammation,41 reduced hematopoietic
reserve with advancing age,42 inappropriately low-serum
erythropoietin level,43 and myelodysplastic syndromes (discussed
later). It is clear that this anemia is associated with
a low-serum erythropoietin level for the degree of anemia.
The EPO level usually falls within the normal reference
range. However, this is abnormal because serum EPO should
rise with falling hemoglobin concentration. The diagnosis
of unexplained anemia assumes the clinician has excluded
Hemoglobin 10.5 to 12 g/dL
Reticulocyte index Low
MCV 80 to 95 fL
Serum iron Mildly low normal
TIBC Normal
% Iron saturation Mildly low normal
B12, folate, ESR, TSH Normal
Platelet and white blood counts Normal
Creatinine clearance <90 to >30 mL/min

serious causes. The threshold to pursue a bone marrow

examination to exclude myelodysplastic syndromes remains
unknown. However, we advocate considering a bone marrow
examination in all patients requiring red cell transfusion
who otherwise have an unexplained anemia. Macrocytosis,
thrombocytopenia, neutropenia, splenomegaly or unexplained
constitutional symptoms of fever, chills, early satiety,
bone pain, or weight loss should prompt consideration
of a bone marrow examination.