Feature Anemia

Common Forms
of Anemia
Diagnosis and management in clinical practice.
By Jonathan Prousky, BPHE, BSc, MSc, ND

L ike any relevant clinical finding, the presence

of anemia demands a thorough investigation to
determine its underlying etiology. This article will
review common anemias as they pertain to adults and
elderly individuals (i.e., older than 65 years of age), and
will outline an efficient method of diagnosis as well as
current information on their appropriate management.
Prevalence
Population-based estimates indicate that anemia affects
6.6% of males and 12.4% of females in the United States,
with a prevalence of around 29-30 cases per 1,000 females
of all ages and 6 cases per 1,000 males younger than 45
years of age (Adams 1995). Although anemia occurs more
frequently among elderly men and women, age by itself
is not a cause of anemia (Izaks 1999). In Canada and
Northern Europe, the prevalence of anemia is believed to
be similar to that of the United States (Conrad 2009).
that other factors in the patient evaluation, such as
ethnic background, altitude of residence, smoking status
and physiological fluctuations of plasma volume, need
to be considered in the context of the subnormal result
(Steensma 2007). Another report suggested that anemia
be defined as a decrease in circulating red blood cell mass
to below age-specific and gender-specific limits, with an
anemia evaluation based on the presence of subnormal
hemoglobin and hematocrit levels (Brill 2000).
continued on page 49 >
Jonathan E. Prousky, BPHE, BSc, MSc, ND
Chief Naturopathic Medical Officer
Professor, Clinical Nutrition
The Canadian College of Naturopathic Medicine

Definition 1255 Sheppard Avenue East

Anemia has been defined as a subnormal hemoglobin Toronto, Ontario, Canada M2K 1E2
level adjusted for age and sex, with an understanding jprousky@ccnm.edu

48 IHP February/January 2010


Steps to Diagnosis
The first step involves looking at the hemoglobin
and the hematocrit level of the complete blood count
(CBC). If the hemoglobin and hematocrit levels are
subnormal, or if the hemoglobin level is subnormal,
then the patient has anemia; however, the type of
anemia remains to be elucidated. It is not uncommon
for the red blood cell count to be below normal when
the hemoglobin and hematocrit are also subnormal.
The next step is to review the mean corpuscular volume
(MCV), which simply represents the average red blood
cell size. When the MCV is below normal, the anemia is
referred to as “microcytic.” When the MCV is elevated,
the anemia is referred to as “macrocytic,” and when
normal, it is referred to as “normocytic.” All of these
different types of anemia demand specific laboratory
evaluations in order to identify their underlying etiologies.
Microcytic Anemia
The most important step in evaluating a microcytic anemia
is to assess a patient’s iron status. Iron deficiency is the
most common cause of anemia globally (Brown 1994).
Table 1 outlines common causes of iron deficiency anemia.
The easiest and most cost-effective method of assessment
involves a serum ferritin test. Ferritin represents iron stores
within the body and is a very good measure of a patient’s
iron status. Most medical laboratories consider a ferritin
result below 12ug/L as diagnostic of iron deficiency.
Once you have identified iron deficiency per the subnormal
ferritin result, the evaluation needs to continue. If the
Table 1. Common Causes of Iron Deficiency Anemia
(Adapted from Little 1999)
Blood Loss Malabsorption
Menstruation Celiac disease
Bleeding hemorrhoids Crohn’s disease
Occult malignancy (usually Pernicious anemia
gastrointestinal) Gastric surgery
Gastrointestinal bleeding Acid suppression therapy
NSAID use (including hypochlorhydria)
Intestinal parasites
Feature Anemia
patient is a woman of childbearing age and reports
unusually heavy menstruation in the past six to 12
months, you can stop your evaluation process and treat
empirically with iron replacement therapy. If, however,
you are concerned about the presence of gynecologic
disease, the patient would need to be referred to a
gynecologist to undergo a thorough evaluation. If the
patient eats a diet with very little meat or no meat
(e.g., is a vegetarian or some variation thereof), then
undernutrition would be the cause and the patient would
need iron replacement therapy in addition to appropriate
dietary advice. There is always the possibility that
such a patient has an eating disorder (e.g., anorexia
nervosa or bulimia nervosa), which requires a thorough
psychiatric assessment and physical examination.
If there is a concern about an occult (hidden)
gastrointestinal malignancy, it is imperative that your
patient completes a fecal occult blood test prior to
prescribing iron replacement therapy. Another common
cause of gastrointestinal bleeding that needs to be
considered is nonsteroidal anti-inflammatory drug (NSAID)
use. Even among healthy people, NSAID use can be
associated with significant gastrointestinal bleeding (Bowen
2005). Even hemorrhoids can sometimes be the source of a
patient’s iron deficiency anemia, which must be effectively
managed so that ferritin levels can return to normal.
As for the correct dose of elemental iron that is needed in
adults, a daily dose equivalent to 150 to 200mg of elemental
iron is sufficient (Little 1999). Within one to two months
of treatment, hematocrit levels improve; most patients
need only four to six months of treatment to bring their
ferritin results to an acceptable level (Little 1999). Iron
supplementation should be given once daily (about 30 to 45
minutes before eating) with some orange juice or vitamin
C to increase absorption. Some patients have trouble
tolerating iron supplementation because of gastrointestinal
side effects (i.e., nausea, constipation, diarrhea, and/or
abdominal pain) and should be instructed to take iron with
food, but this can decrease its absorption by 40% to 66%
(Little 1999). When a patient’s response to iron replacement
therapy is less than adequate despite their insistence about
being complaint, it is imperative that malabsorption
(e.g., celiac disease, Crohn’s disease and pernicious
anemia) and even hypochlorhydria are considered.
February/March 2010 IHP 49
Feature Anemia
Table 2. Common Causes of Vitamin B-12 Deficiency and Associated Clinical Manifestations
(Adapted from: OH 2003)
Common Causes of Deficiency
Nutritional deficiency - poor intake
(alcoholics, elderly, vegetarians)
Malabsorption - food-bound B-12 malabsorption (proton
pump inhibitors, histamine-type 2 receptor blockers,
hypochlorhydria), lack of intrinsic factor or parietal cells
(pernicious anemia, atrophic gastritis, post-gastrectomy)
Other gastrointestinal - ileal malabsorption (enteritis from
Crohn’s disease, ileal resection), biologic competition (small
intestinal bacterial overgrowth, tapeworm infection)
Defective transport - transcobalamin II deficiency
Macrocytic Anemia
When you have identified a macrocytic anemia, the
next step is to perform serum cobalamin (vitamin B-12)
testing (Barkin 1998). Table 2 highlights common causes
of vitamin B-12 deficiency and its associated clinical
manifestations. In terms of interpreting serum cobalamin
results, I have adapted a published approach to working
up patients with vitamin B-12 deficiency (OH 2003) to
current vitamin B-12 deficiency values obtained from
several medical laboratories in Ontario. If the serum
cobalamin result is below 110pmol/L (150pg/ml), then
the patient has vitamin B-12 deficiency and the diagnosis
would need to be changed to megaloblastic anemia. If the
serum cobalamin result is between 110 and 295pmol/L
(150-400pg/ml), further testing is still required to rule out
vitamin B-12 deficiency. At this point, urine methylmalonic
acid testing should be done since it can identify metabolic
(or tissue) vitamin B-12 deficiency when serum levels
are considered normal or in the possible deficient range
(Donaldson 1987, Matchar 2000). If serum cobalamin
levels come back above 295pmol/L (>400pg/ml), the
patient should not be considered as having vitamin B-12
deficiency in the classical sense. This can be debated since
there is published evidence of vitamin B-12 deficiency
in the cerebrospinal fluid among patients with normal
vitamin B-12 values as high as 593pmol/L (800pg/ml) in
their serum (van Tiggelen 1983, van Tiggelen 1984).
In the absence of vitamin B-12 deficiency, a less common
cause of megaloblastic anemia is folic acid deficiency.
Common causes of folic acid deficiency include
alcoholism, severe hemolysis, chronic hemodialysis,
tropical sprue, celiac disease, Crohn’s disease, diabetic
enteropathy and drug interference (Barkin 1998). While
several authorities recommend testing folate status
50 IHP February/January 2010
Clinical Manifestations of Deficiency
Hematologic - megaloblastic anemia, pancytopenia
(leucopenia, thrombocytopenia)
Neurologic - parethesias, peripheral neuropathy,
combined system disease (demyelination of
dorsal columns and corticospinal tract)
Psychiatric - irritability, personality change, memory
impairment, dementia, depression, psychosis
Cardiovascular - possible increased risk of cardiovascular
even (myocardial infarction and stroke)
in the serum and/or red blood cells when evaluating
macrocytic anemia (Barkin 1998, OH 2003), this appears
to be unnecessary. Folate deficiency is rarely found
when evaluating macrocytosis with or without anemia
(Robinson 2001). Empiric folic acid supplementation
is recommended to replace laboratory testing to
effectively treat undiagnosed cases (Robinson 2001).
Once vitamin B-12 deficiency has been identified or
when deficiency of folic acid is suspected, it is essential
to thoroughly investigate all potential underlying causes.
Begin by excluding inadequate intake due to vegetarianism,
alcoholism or some other factor. Autoimmune gastritis and
pernicious anemia should be considered as well. According
to “Consensus Guidelines on Anti-Intrinsic Factor
Antibody Testing” (2007), clinicians need to requisition
both anti-parietal cell antibody and anti-intrinsic factor
antibody testing when evaluating for these conditions.
If both tests are positive or if only the anti-intrins ic
factor antibody test is positive, the patient’s diagnosis
would be pernicious anemia. If only the anti-parietal cell
antibody test is positive, the patient’s diagnosis would be
autoimmune gastritis. Another important rule-out would be
tissue transglutaminase antibodies as a first-line screening
test for celiac disease (Presutti 2007). If positive, the patient
should be promptly referred for small intestinal biopsy to
confirm a presumptive diagnosis of celiac disease. If small
intestinal bacterial overgrowth is suspected a urinary
indican can be requisitioned, but it can also be indicative of
other problems, such as hypochlorhydria, gastric cancer and
malabsorption (Brummer 1956, Powell 1999).Patients with
vitamin B-12 deficiency should be given daily intramuscular
(IM) injections consisting of 1,000 mcg of cyanocobalamin
(or other forms of vitamin B-12) for five days, followed by
weekly IM injections for 4 weeks, and then IM injections

every 1 to 3 months thereafter (Little 1999). Even though
hematological improvements begin within five to seven
days, the patient might require treatment for six months or
longer to resolve neurological symptoms, which completely
or partially resolve in some 80% of patients (Little 1999).
In situations of chronic vitamin B-12 deficiency, such as
pernicious anemia or post-surgical malabsorption states,
lifetime vitamin B-12 supplementation is necessary. These
patients can maintain adequate vitamin B-12 levels by
receiving IM injections every one to three months, or by
taking 1,000-2,000mcg of oral vitamin B-12 daily as an
alternative to parenteral therapy (Little 1999). Treatment
of suspected folic acid deficiency usually requires 1mg
daily for three weeks to replenish stores (Davenport
1996). In cases of malabsorption or when patients are
on medications that antagonize folic acid metabolism,
the dose and duration of treatment depend on repletion
of deficient serum folate and/or red blood cell levels. In
these situations, it is probably best to ensure repletion by
measuring a patient’s folate status serially over time.
Normocytic Anemia
When the MCV is normal, the patient might simply be in
the early stages of iron deficiency, vitamin B-12 deficiency
or folic acid deficiency (Barkin 1998). When these nutrient
deficiencies have been properly ruled out, the next step
in the evaluation process is to requisition a reticulocyte
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patient with anemia. Patient Care. 1998;32:70-89.
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and pattern of blood loss with ibuprofen treatment in healthy
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Feature Anemia
count. If it is elevated, hemolysis and blood loss need to
be investigated as potential causes. Fecal occult blood
testing will identify whether blood loss is coming from
the gastrointestinal tract. A serum bilirubin and/or lactate
dehydrogenase can identify hemolysis, but any positive
tests will need to be followed up with a direct Coomb’s
test to confirm immune hemolysis (Barkin 1998). If the
reticulocyte count is low, systemic disease needs to be ruled
out (Brill 2000) and a serum iron should be requisitioned
(Barkin 1998). If the serum iron comes back within normal
limits or is elevated, the patient should be referred for a
bone marrow biopsy (Brill 2000). If the serum iron level
comes back below normal, anemia of chronic disease is
the diagnosis, which happens to be the most common
cause of normocytic anemia (Brill 2000, Weiss 2005).
Common underlying causes of anemia of chronic disease
include chronic infections, cancers, autoimmune diseases,
chronic rejection after solid-organ transplantation, and
chronic kidney disease (Weiss 2005). A serum ferritin
test cannot be used to diagnose anemia of chronic
disease since it is either normal or elevated among
patients with this type of anemia (Weiss 2005). In the
treatment of anemia of chronic disease, hematological
improvement can result when the underlying disease
is treated, but patients might require transfusions
and erythropoietic agents (Weiss 2005).
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February/March 2010 IHP 51