1

Normocytic Anemia
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JOHN R. BRILL, M.D., and DENNIS J. BAUMGARDNER, M.D., University of Wisconsin
Medical School, Milwaukee Clinical Campus, Milwaukee, Wisconsin
Am Fam Physician. 2000 Nov 15;62(10):2255-2263.
See related patient information handout on normocytic anemia, written by the authors of
this article..
ARTICLE SECTIONS
Abstract
Etiology
Decreased Red Blood Cell Production
Increased Red Blood Cell Destruction or Loss
Diagnosis
Treatment
References
Anemia is a common problem that is often discovered on routine laboratory tests. Its
prevalence increases with age, reaching 44 percent in men older than 85 years.
Normocytic anemia is the most frequently encountered type of anemia. Anemia of
chronic disease, the most common normocytic anemia, is found in 6 percent of adult
patients hospitalized by family physicians. The goals of evaluation and management are
to make an accurate and efficient diagnosis, avoid unnecessary testing, correct
underlying treatable causes and ameliorate symptoms when necessary. The evaluation
begins with a thorough history and a careful physical examination. Basic diagnostic
studies include the red blood cell distribution width, corrected reticulocyte index and
peripheral blood smear; further testing is guided by the results of these studies.
Treatment should be directed at correcting the underlying cause of the anemia. A recent
advance in treatment is the use of recombinant human erythropoietin.
Anemia is defined as a decrease in the circulating red blood cell mass to below age-specific
and gender-specific limits. In normocytic anemias, the mean corpuscular volume (MCV) is
within defined normal limits, but the hemoglobin and hematocrit are decreased. The MCV is
also age-specific (Figure 1),
1
with normal values ranging from 70 femtoliter (fL) at one year of
age to 80 fL at seven years and older.
2

2

The rightsholder did not grant rights to reproduce this item in electronic media. For the missing
item, see the original print version of this publication.
FIGURE 1.
Most patients with anemia are asymptomatic. Therefore, the condition is most often discovered
by laboratory evaluation, usually on routine testing as part of the general physical examination
or for reasons other than suspected anemia. Anemia should be considered a sign, not a
disease.
3
It can be caused by a variety of systemic disorders and diseases, as well as primary
hematologic disorders.
Approximately 4.7 million Americans have anemia.
4
Population-based estimates indicate that
this condition affects 6.6 percent of males and 12.4 percent of females. The prevalence of
anemia increases with age and is 44.4 percent in men 85 years and older.
5
Although the
elderly are more prone to develop anemia, older age is not of itself a cause of the condition.
6

Etiology
Normocytic anemias may be thought of as representing any of the following: a decreased
production of normal-sized red blood cells (e.g., anemia of chronic disease, aplastic anemia);
an increased destruction or loss of red blood cells (e.g., hemolysis, posthemorrhagic anemia);
an uncompensated increase in plasma volume (e.g., pregnancy, fluid overload); or a mixture of
conditions producing microcytic and macrocytic anemias.
It should be noted that in the initial stage, nearly all anemias are normocytic. The major primary
causes of normocytic anemia are given in Table 1.
TABLE 1

Primary Causes of Normocytic Anemias*
Increased red blood cell loss or destruction
Acute blood loss
Hypersplenism
Hemolytic disorders

Congenital conditions

Hemoglobinopathies
3


Homozygous sickle cell disease (hemoglobin SS disease)

Heterozygous sickle hemoglobin C disease (hemoglobin SC disease)

Disorders of red blood cell membranes

Hereditary spherocytosis

Hereditary elliptocytosis

Red blood cell enzyme deficiencies

Glucose-6-phosphate dehydrogenase deficiency

Pyruvate kinase deficiency

Acquired conditions

Mechanical hemolysis

Macrovascular disorders

Microangiopathic disorders

Disseminated intravascular coagulopathy

Hemolytic-uremic syndrome

Thrombotic thrombocytopenic purpura

Autoimmune hemolytic anemias

Warm-reactive anemias

Cold-reactive anemias

Drug-induced anemias
4



*Mean corpuscular volume of 81 to 99 fL.
TABLE 1 Primary Causes of Normocytic Anemias*
View Table
Decreased Red Blood Cell Production

Paroxysmal nocturnal hemoglobinuria
Decreased red blood cell production
Primary causes

Marrow hypoplasia or aplasia

Myelopathies

Myeloproliferative diseases

Pure red blood cell aplasia
Secondary causes

Chronic renal failure

Liver disease

Endocrine deficiency states

Anemia of chronic disease

Sideroblastic anemias
Overexpansion of plasma volume
Pregnancy
Overhydration
5

ANEMIA OF CHRONIC DISEASE
Anemia of chronic disease is the most common normocytic anemia and the second most
common form of anemia worldwide (after iron deficiency anemia).
7
The MCV may be low in
some patients with this type of anemia. The pathogenesis of anemia of chronic disease is
multifactorial and is related to hypo-activity of the bone marrow, with relatively inadequate
production of erythropoietin or a poor response to erythropoietin, as well as slightly shortened
red blood cell survival.
Anemia of chronic disease is associated with a wide variety of chronic disorders, including
inflammatory conditions, infections, neoplasms and various systemic diseases. The diagnosis
of anemia of chronic disease is not usually applied to the anemias associated with renal,
hepatic or endocrine disorders. Patients with these disorders may not display the hallmark
ferrokinetic profile of anemia of chronic disease (i.e., decreased serum iron level, decreased
transferrin level, or normal or elevated ferritin levels, all of which result in iron being present but
inaccessible for use).
3,810

ENDOCRINE DEFICIENCY
Endocrine deficiency states, including hypothyroidism, adrenal or pituitary insufficiency, and
hypogonadism, may cause secondary bone marrow failure because of reduced stimulation of
erythropoietin secretion. Hyperthyroidism may also cause normocytic anemia.
3,9

RENAL FAILURE
Anemia occurs in acute and chronic renal failure. The anemia is usually normocytic but may be
microcytic. In renal failure, anemia occurs in part because uremic metabolites decrease the
lifespan of circulating red blood cells and reduce erythropoiesis.
Anemia secondary to uremia is characterized by inappropriately low erythropoietin levels, in
contrast to the normal or high levels that occur with most other causes of anemia. To further
confuse the presentation, serum iron levels and the percentage of iron saturation are often low,
apparently because of negative acute-phase reactions.
10
Furthermore, the serum creatinine
level and the degree of anemia may not correlate well.
3

OTHER CAUSES
Other causes of decreased red blood cell production include bone marrow infiltration, fibrosis,
various myeloproliferative diseases and sideroblastic anemias. These uncommon disorders are
generally diagnosed by bone marrow biopsy.
Increased Red Blood Cell Destruction or Loss
HEMOLYTIC ANEMIAS
Hemolytic anemias other than the alloimmune hemolytic anemias of newborns (e.g., Rh or
ABO incompatibility) can be categorized as congenital or acquired (Table 2).
3,9,1113

TABLE 2
6

Selected Causes of Hemolytic Anemias
DISORDER
MOST COMMON
CLINICAL
FEATURES
FEATURES OF
PERIPHERAL
BLOOD SMEAR
LABORATORY
TESTS
Congenital conditions
Homozygous sickle
cell disease
(hemoglobin SS
disease)
Vaso-occlusive
crises,
splenomegaly,
cerebrovascular
accidents,
priapism, hand-foot
syndrome, acute
chest syndrome
Sickle cells Hemoglobin
electrophoresis
Heterozygous sickle
hemoglobin C
disease (hemoglobin
SC disease)
Generally similar to
homozygous sickle
cell disease, except
associated with
fewer infections,
less hemolysis and
fewer crises, but
more retinopathy
and aseptic
necrosis
Sickle cells, target
cells
Hemoglobin
electrophoresis
Hereditary
spherocytosis
Childhood anemia,
splenomegaly,
jaundice
Spherocytes Osmotic fragility test
Hereditary
elliptocytosis
Variable:
asymptomatic
carrier state to
severe hemolysis
Elliptocytes 25 percent or more of
red blood cells
elliptocytic on
peripheral blood smear
G6PD deficiency Transient
hemolysis following
exposure to
Normal G6PD activity
7

DISORDER
MOST COMMON
CLINICAL
FEATURES
FEATURES OF
PERIPHERAL
BLOOD SMEAR
LABORATORY
TESTS
oxidative drug
Pyruvate kinase
deficiency
Variable: severe
anemias in
newborns to no
symptoms in adults
Normal Red blood cell P-50
level (screening); red
blood cell pyruvate
kinase activity
(confirmatory)
Acquired conditions
Microangiopathic
disorders

Thrombocytopenia,
schistocytes


Disseminated
intravascular
coagulopathy
Bleeding and/or
intravascular
hemolysis

Hypofibrinogenemia;
increases in partial
thromboplastin time,
prothrombin time, fibrin
split products and
thrombin time

Hemolytic-uremic
syndrome
Fever, jaundice,
bleeding, central
nervous system
changes, renal
failure; generally
occurs in children

Increased creatinine
level

Thrombotic
thrombocytopenic
purpura
Purpura, fever,
central nervous
system changes;
generally occurs in
adults

Mechanical hemolysis Mild to moderate
anemia; frequently,
Schistocytes None
8

DISORDER
MOST COMMON
CLINICAL
FEATURES
FEATURES OF
PERIPHERAL
BLOOD SMEAR
LABORATORY
TESTS
iron deficiency,
second-degree
chronic urinary
loss; history of
heart valve
replacement or
valvular disease
Paroxysmal nocturnal
hemoglobinuria
Recurrent
abdominal pain,
vomiting,
headache, eye
pain; venous
thromboses; leads
to iron deficiency
anemia
Normal Sucrose hemolysis
(screening); Ham's test
(confirmatory)

G6PD = glucose-6-phosphate dehydrogenase; P-50 = oxygen half-saturation pressure of
oxygen.
Information from references 3, 9 and 11 through 13.
TABLE 2 Selected Causes of Hemolytic Anemias
View Table
Congenital hemolytic anemias include the hemoglobinopathies (homozygous sickle cell
disease [hemoglobin SS disease], heterozygous sickle hemoglobin C disease [hemoglobin SC
disease]), red blood cell membrane disorders and red blood cell enzyme deficiencies.
11,12

Homozygous sickle cell disease is the most common cause of hemolytic normocytic anemias
in children. Because of longevity, this disease is also becoming an increasingly prevalent
cause of these anemias in adults.
1113

Hereditary spherocytosis is the most common red blood cell membrane disorder. It usually
presents in childhood with anemia, jaundice and splenomegaly. Pigment gallstones, delayed
growth and dysmorphic features may occur. Hereditary elliptocytosis ranges from an
asymptomatic carrier state to severe hemolytic anemia.
1113

9

Red blood cell enzyme deficiencies include glucose-6-phosphate dehydrogenase (G6PD) and
pyruvate kinase deficiencies. More than 300 varieties of G6PD deficiency have been identified.
The southern Mediterranean variety, referred to as favism, is best known, but the most
common variant in the United States is a less severe X-linked disorder that affects 10 percent
of black males. Persons with the U.S. variant may experience an acute, self-limited hemolytic
episode after exposure to causes of oxidative stress, including sulfa drugs, nitrofurantoin
(Furadantin), phenazopyridine (Pyridium) and antimalarial drugs.
11,12

Acquired hemolytic anemias include autoimmune hemolytic anemias, mechanical hemolysis
and paroxysmal nocturnal hemoglobinuria.
12
Autoimmune hemolytic anemias primarily occur in
persons older than 40 years. The most common and typically most severe of these anemias
are those caused by warm-reactive antibodies. Autoimmune hemolytic anemias caused by
cold-reactive antibodies most commonly follow Mycoplasma pneumonia or infectious
mononucleosis.
Drugs that induce autoimmune hemolytic anemias include methyldopa (Aldomet), penicillins,
cephalosporins, erythromycin, acetaminophen (e.g., Tylenol) and procainamide (Pronestyl).
Paroxysmal nocturnal hemoglobinuria generally presents as a chronic hemolytic anemia.
Classic nocturnal hemoglobinuria is seldom seen.
12

UNCOMPENSATED BLOOD LOSS
Acute posthemorrhagic anemia occurs with gastrointestinal bleeding, bleeding from an external
wound or, less obviously, retroperitoneal bleeding or bleeding into a hip fracture. A healthy
young person would be expected to tolerate rapid loss of 500 to 1,000 mL of blood (10 to 20
percent of the total blood volume) with few or no symptoms, although about 5 percent of the
general population would have a vasovagal reaction.
14
Indeed, healthy young persons at rest
may tolerate an acute isovolemic reduction of hemoglobin volume to a level of 5 g per dL (50 g
per L) without impairment of critical oxygen delivery.
15

HYPERSPLENISM
Hypersplenism leads to anemia only after the spleen reaches three to four times its normal
size, as may occur in cirrhosis, chronic infections and myeloproliferative diseases. The anemia
is primarily caused by the removal of red blood cells from the circulation, but increased
destruction of red blood cells is usually a contributing factor.
16

NORMOCYTIC ANEMIA IN CHILDREN
The prevalence of anemias caused by iron deficiency or lead toxicity continues to decline in the
United States.
17
As a result, normocytic anemias are constituting a larger proportion of cases in
the pediatric age group.
Iron deficiency, which in its early stages is usually characterized by a normal MCV, is still a
common cause of mild normocytic anemia in children beyond the neonatal period. Other
common childhood normocytic anemias are the result of acute bleeding, sickle cell anemia, red
10

blood cell membrane disorders and current or recent infections (particularly in younger
children).
2,17
Aplastic crises in patients of any age who have chronic hemolytic anemias are
frequently precipitated by human parvovirus B19 infection.
2,12,13,18

Most anemias in children can be diagnosed with a basic work-up that includes a complete
blood cell count (CBC), a corrected reticulocyte index, a peripheral blood smear and targeted
studies of the peripheral blood (e.g., hemoglobin electrophoresis).
Although bone marrow examinations are generally unnecessary, one study found that when
the basic laboratory studies and historical and physical evidence were unrevealing, bone
marrow specimens yielded a specific diagnosis in 92 percent of children.
18
The most frequent
diagnosis in this study was transient erythroblastopenia of childhood, a common, generally
mild, self-limited red blood cell aplasia of unknown etiology. This entity must be distinguished
from Blackfan-Diamond syndrome, a rare, usually macrocytic and probably genetic disorder of
infants. Blackfan-Diamond syndrome is a congenital erythroid hypoplasia that usually does not
spontaneously remit.
3,9

Diagnosis
Physicians are sometimes inefficient in their evaluation of normocytic anemia, either ordering
an excessive battery of tests or foregoing testing entirely in the belief that a cause is not likely
to be found.
19
The first step in the evaluation of anemia is to correlate the finding of anemia with
the information obtained from the patient's history and physical examination. In many
instances, this approach allows a working diagnosis to be made and many disorders to be
eliminated.
Most published algorithms for the diagnosis of normocytic anemia begin with an examination of
the peripheral blood smear
20
or a corrected reticulocyte index.
2,9,21
The red blood cell distribution
width is a measure of the variability of the size (anisocytosis) of the cells and is usually
reported as a component of automated CBCs. Therefore, a practical and useful first step is to
use the red blood cell distribution width to help categorize the normocytic anemia as
heterogeneous (e.g., hemolytic anemia) or homogeneous (e.g., anemia of chronic disease).
2
In
patients with a mild homogeneous normocytic anemia (hematocrit of 30 percent or greater) and
a known chronic disease, anemia of chronic disease is highly likely, and bone marrow biopsy
may not be necessary (Figure 2).
21


11

Evaluation of Normocytic Anemia

FIGURE 2.
Approach to the evaluation of normocytic anemia in adults. (RBC = red blood cell; CRI = corrected reticulocyte
index; ACD = anemia of chronic disease; AIHA = autoimmune hemolytic anemia)
12

Adapted with permission from Brown RG. Normocytic and macrocytic anemias. Postgrad Med 1991;89(8):125
32,1356.
DRAW AND HOLD STRATEGY
Because the diagnosis of normocytic anemia usually proceeds in a step-wise fashion that
begins with the corrected reticulocyte index and examination of the peripheral blood smear, a
patient-friendly, cost-effective and time-efficient strategy is to use a draw and hold order for
possible later testing. Most laboratories do not charge to hold tubes, and tests can usually be
added up to one week after specimens are obtained. The physician should check with the local
laboratory to determine the number and type of specimens that need to be obtained.
PERIPHERAL BLOOD SMEAR
The examination of the peripheral blood smear often yields diagnostic clues or confirmatory
evidence. Easily recognized red blood cell findings related to normocytic anemias include the
following: large polychromatic shift cells, which represent reticulocytosis; target cells, which
may be found in liver disease; basophilic stippling, which may be present in hemolytic anemias;
and mixtures of large and small red blood cells, which may suggest the presence of mixed
microcytic and macrocytic disease processes (a finding that should be suggested by an
elevated red blood cell distribution width).
Other findings include burr cells (uremia), spherocytes (hereditary spherocytosis, autoimmune
hemolysis, G6PD deficiency), elliptocytes (hereditary elliptocytosis), schistocytes
(microangiopathic processes), bite or blister cells (where all of the hemoglobin appears to be
pushed to one side of the cell, G6PD deficiency) and nucleated red blood cells (hemolytic
anemia, acute blood loss). These findings may be present in other anemias and in other
conditions.
3,9,10

The corrected reticulocyte index, along with the white blood cell and platelet counts, indicates
whether the bone marrow is functioning appropriately. The corrected reticulocyte index should
be elevated in patients with an acute anemia but a competent bone marrow.
ILLUSTRATIVE CASES
Case 1. A 50-year-old woman who had been taking aspirin for a flare of rheumatoid arthritis
presented with mild epigastric pain. A CBC was ordered, and a guaiac test for occult blood was
performed. The guaiac test was negative.
The CBC revealed a normocytic anemia (hemoglobin count, 11 per mm
3
[11 10
6
per L];
hematocrit, 33 percent [0.33]; MCV, 84 fL), with a red blood cell distribution width of 41 fL
(normal range: 39 to 47 fL). A reticulocyte count and draw and hold specimens were ordered.
The corrected reticulocyte index was 1.0 percent.
Ferritin and serum iron levels were obtained from the stored specimens. These tests revealed
an elevated ferritin level and a low serum iron level, findings consistent with a diagnosis of
anemia of chronic disease related to the patient's rheumatoid arthritis.
13

Case 2. A 44-year-old woman presented with the complaint of fatigue. Her physical
examination was unremarkable.
A CBC revealed normocytic anemia (hemoglobin count, 11 per mm
3
[11 10
6
per L];
hematocrit, 33 percent [0.33]; MCV, 84 fL), with an elevated red blood cell distribution width of
53 fL. A reticulocyte count and draw and hold specimens were ordered. The corrected
reticulocyte index was elevated (3.6 percent).
Examination of a peripheral blood smear from the stored specimens was normal. A direct
antiglobulin test (direct Coombs' test) was positive, and a preliminary diagnosis of autoimmune
hemolytic anemia was made.
Treatment
The treatment of a normocytic anemia begins with timely identification of its cause. In most
patients, therapy is individualized to the underlying disorder. Treatments may include
avoidance of trigger exposure in patients with hemolytic anemia, correction of iron, folate or
vitamin B12 deficiency in patients with mixed disorders, or splenectomy in patients with
hypersplenism.
12,13

Anemia of renal disease is associated with a relative underproduction of erythropoietin, and
inappropriate erythropoietin levels appear to contribute significantly to anemia of chronic
disease. With the development of recombinant human erythropoietin (r-HuEPO; epoetin alfa
[Epogen]), there has been considerable interest in finding out whether exogenous
erythropoietin administration would improve anemia.
The effects of r-HuEPO administration have been studied in a variety of disorders. In a trial
conducted in 1990,
22
all 11 patients with anemia related to rheumatoid arthritis reached a
normal hematocrit after 24 weeks. Since then, r-HuEPO has been tested in patients with
anemia of chronic disease secondary to acquired immunodeficiency syndrome, malignancy,
inflammatory bowel disease, renal disease and other disorders.
23,24
Quality-of-life parameters in
responders improved significantly.
Therapy with r-HuEPO is very expensive and should never replace treatment of the underlying
cause of an anemia. R-HuEPO is an indicated therapy for anemia of renal disease. In this
situation, its use should be based on clinical and quality-of-life issues rather than specific
hemoglobin levels.
10
There are no consistent guidelines for r-HuEPO therapy in patients with
anemia of chronic disease, although response rates of 40 to 80 percent may be achieved.
8

Erythropoietin also appears to be useful prophylactically in patients undergoing autologous
blood donation and certain surgical procedures.
25

In all patients, treatment of anemia should include the provision of optimal nutrition and
supportive care.
The Authors
14

JOHN R. BRILL, M.D., is assistant professor and medical director of Community Health
Programs in the Department of Family Medicine at the Milwaukee Clinical Campus of the
University of Wisconsin Medical School. Dr. Brill graduated from the Medical College of
Wisconsin, Milwaukee, and completed a faculty development fellowship and residency at St.
Luke's Medical Center, also in Milwaukee.
DENNIS J. BAUMGARDNER, M.D., is professor and residency director at St. Luke's Family
Practice Residency Program, which is affiliated with the Department of Family Medicine at the
Milwaukee Clinical Campus of the University of Wisconsin Medical School. Dr. Baumgardner
graduated from the University of Illinois at Chicago College of Medicine and completed a family
medicine residency at the Rockford (Ill.) Medical Education Foundation.
Address correspondence to John R. Brill, M.D., St. Luke's Family Practice Residency, 2801 W.
Kinnickinnic River Pkwy., Suite 175, Milwaukee, WI 53215 (e-mail: jbrill@fammed.wisc.edu).
Reprints are not available from the authors.
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16

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Members of various family practice departments develop articles for Problem-Oriented
Diagnosis. This article is one in a series coordinated by the Department of Family Medicine at
the University of Wisconsin Medical School, Madison. Guest editor of the series is William E.
Scheckler, M.D.