Nutrition in Clinical Practice http://ncp.sagepub.

com/

Iron Deficiency Anemia

Susan F. Clark
Nutr Clin Pract 2008 23: 128
DOI: 10.1177/0884533608314536

The online version of this article can be found at:

http://ncp.sagepub.com/content/23/2/128

Published by:

http://www.sagepublications.com

On behalf of:

The American Society for Parenteral & Enteral Nutrition

Additional services and information for Nutrition in Clinical Practice can be found at:

Email Alerts: http://ncp.sagepub.com/cgi/alerts

Subscriptions: http://ncp.sagepub.com/subscriptions

Reprints: http://www.sagepub.com/journalsReprints.nav

Permissions: http://www.sagepub.com/journalsPermissions.nav

>> Version of Record - Apr 1, 2008

What is This?

Downloaded from ncp.sagepub.com at UNIV OF SOUTHERN CALIFORNIA on April 3, 2014

Invited Review
Iron Deficiency Anemia
Susan F. Clark, PhD, RD
Financial disclosure: none declared.
The most severe consequence of iron depletion is iron deficiency
anemia (IDA), and it is still considered the most common nutri-
tion deficiency worldwide. Although the etiology of IDA is multi-
faceted, it generally results when the iron demands by the body
are not met by iron absorption, regardless of the reason.
Individuals with IDA have inadequate intake, impaired absorp-
tion or transport, physiologic losses associated with chronologi-
cal or reproductive age, or chronic blood loss secondary to
disease. In adults, IDA can result in a wide variety of adverse out-
comes including diminished work or exercise capacity, impaired
thermoregulation, immune dysfunction, GI disturbances, and
neurocognitive impairment. In addition, IDA concomitant with
chronic kidney disease or congestive heart failure can worsen
I
ron is a component of every living cell and has been
recognized for centuries as an essential element for
the maintenance of health. Iron participates in
numerous biochemical reactions primarily involved in
oxygen transport and storage, adenosine triphosphate
production, deoxyribonucleic acid synthesis, and electron
transport.1-4 Although the body’s homeostatic mecha-
nisms conserve iron efficiently, iron deficiencies can still
arise, especially when intake fails to meet physiologic
needs or when stores become depleted. Those at greatest
risk for developing iron deficiency include premenopausal
women and young children, elderly hospitalized patients
requiring diagnostic blood sampling, and individuals with
GI blood losses, malabsorption states, gastric cancer, and
following GI surgery.5-10 Therefore, it is reasonable to
conclude that any clinical condition involving blood loss,
iron malabsorption, or decreased intake can potentially
increase the risk of the development of iron deficiency
anemia (IDA).
Iron deficiency anemia is still considered the most
common nutrition deficiency worldwide.11,12 The most
From Virginia Polytechnic Institute and State University,
Department of Human Nutrition, Foods and Exercise, Blacksburg,
Virginia.
Address correspondence to: Susan F. Clark, PhD, RD, Virginia
Polytechnic Institute and State University, Department of
Human Nutrition, Foods and Exercise, 338C Wallace (0430),
Blacksburg, VA 24061; e-mail: sfclark@vt.edu.
128
Downloaded from ncp.sagepub.com at UNIV OF SOUTHERN CALIFORNIA on April 3, 2014
Nutrition in Clinical Practice
Volume 23 Number 2
April/May 2008 128-141
© 2008 American Society for
Parenteral and Enteral Nutrition
10.1177/0884533608314536
http://ncp.sagepub.com
hosted at
http://online.sagepub.com
the outcome of both conditions. In this review, the prevalence of
IDA related to confounding medical conditions will be described
along with its diverse etiologies. Distinguishing IDA from ane-
mia of chronic disease using hematologic measures is reviewed
as well. In addition, current diagnostic strategies that are inclu-
sive of clinical presentation, biochemical tests, and differential
diagnosis will be outlined, followed by a discussion of treatment
modalities and future research recommendations. (Nutr Clin
Pract. 2008;23:128-141)
Keywords: anemia; iron deficiency anemia; iron metabolism
disorders; iron; ferritins
significant negative consequence of iron deficiency is
anemia; this type of anemia is categorized as microcytic,
hypochromic, although in the early stages of depletion, it
is often normocytic, normochromic. In general, iron defi-
ciency results from extensive negative iron balance, culmi-
nating in decreased or exhausted iron stores. Sequential
changes in iron status occur before the diagnosis of IDA
is verified. In fact, the anemia that occurs is a late mani-
festation of IDA; it evolves over time as iron stores pro-
gressively become depleted. The stages of iron depletion
correspond as follows: negative iron balance, iron depletion,
iron-deficient erythropoiesis, and, finally, IDA. Depleted
iron stores and iron deficiency without anemia are consid-
ered mild to moderate forms of iron deficiency and may
or may not have overt symptoms. Conversely, iron defi-
ciency with anemia falls at the severe end of the spectrum
of iron depletion, with corresponding alterations in hema-
tological laboratory values and observable signs and symp-
toms. When this occurs, erythropoiesis within the bone
marrow is diminished, resulting in low hemoglobin con-
centrations with progression to the status of IDA.
The classic hematological screening test for iron
deficiency is hemoglobin, whereas serum ferritin concen-
tration is used to assess iron stores. Because the life span
of a red blood cell is 120 days, sufficient time must elapse
for iron deficiency to have an impact; therefore, relying
on hemoglobin only for screening delays the detection of
IDA. The lack of a highly sensitive, reliable, minimally
noninvasive, and cost-effective screening marker to detect
 Iron Deficiency Anemia / Clark 129

this condition continues to make eradication of iron defi- Table 1. Prevalence of Iron Deficiency
ciency challenging. Anemia in the United Statesa
In adults, iron deficiency leading to anemia can result
Group/Age 1988-1994, % 1999-2000, %
in a wide variety of adverse health outcomes, including
diminished work capacity, impaired thermoregulation, Children
immune dysfunction, GI disturbances, and Helicobacter 1-2 9 7
pylori infection.3,13-17 Other effects include neurocognitive 3-5 3 5
impairment leading to psychomotor and cognitive abnor- 6-11 2 4
malities in children, which, if left unchecked, impair learn- Women (nonpregnant)
ing.18-22 Iron deficiency anemia during pregnancy has 12-49 11 12
long been associated with an increased risk of low birth 50-69 5 9
70 7 6
weight, preterm delivery, perinatal mortality, and infant and
Men
young child mortality as well as maternal mortality.23-26 12-15 1 5
Anemia is also frequently seen in patients with congestive 16-69 1 2
heart failure and chronic kidney failure, and IDA has 70 4 3
been attributed to exacerbating both conditions.27-30 Iron Women by racial/ethnic group
deficiency with anemia is also a fairly common complica- Non-Hispanic white 8 10
tion in inflammatory conditions such as inflammatory Black 15 19
bowel disease (IBD).31 Mexican living in the 19 22
From a clinical perspective, IDA can be relatively iso- United States
lated, appearing in healthy populations (young children, a
Adapted from the Centers for Disease Control and Prevention.
pregnant women), or it can be a by-product of chronic Iron deficiency—United States, 1999-2000. MMWR Morb Mortal
disease, often referred to as anemia of chronic disease Wkly Rep. 2002;51:897-899.5
(ACD). Because IDA is frequently associated with myriad
clinical conditions and many patients initially present
asymptomatic, the actual diagnosis of IDA can be prob- pregnant women.38,39 African American and Mexican
lematic.32 Furthermore, since anemia is a fairly common American women have a prevalence of 19% to 22% as
reason why elderly patients are hospitalized, it tends to well. Recreational athletes (both men and women) have a
further compromise other coexisting medical condi- higher prevalence of iron deficiency compared with the
tions.33,34 Thus, a thorough diagnostic assessment to iden- less active population.40 It is also well documented that
tify the etiology of IDA and provide the appropriate the incidence of iron deficiency, with and without anemia,
therapy is critical. This article will review the prevalence is greater in female athletes than male athletes. Seemingly,
of IDA; investigate its multifaceted etiologies, diagnostic an increase in the occurrence of anemia simply happens
criteria, and strategies; and outline the various treatment with age, especially in persons older than 65 years.41,42
modalities currently recommended in practice. Determining the prevalence of IDA in select popula-
tions has been difficult because of confounding factors
such as the impact of age, living situation, and the extent
Prevalence of comorbidities found in chronic diseases. In addition, the
differential diagnosis between IDA and ACD further com-
According to the National Health and Nutrition plicates interpretation of prevalence data. What is known
Examination 1999-2000 survey, the prevalence of IDA in about the incidence of anemia is that it increases with age,
the United States varies widely by age, gender, race, and constituting roughly 10% of people aged 65 and older.6,42-44
ethnicity (Table 1).5,35 Although its prevalence has Although ACD is considered more common than IDA in
remained relatively stable over the past decade in the gen- the elderly population, 15% of patients older than 65 years
eral U.S. population, it continues to be highest among admitted to a geriatric hospital were found to have IDA.45
minorities, children from economically challenged fami- In contrast, a much lower incidence (4%-7%) was found in
lies, and low-income pregnant women.36 The estimated a community of relatively healthy men and women older
prevalence of iron deficiency among young toddlers aged than 70 years.46 In the 1999 National Nursing Home
1 to 2 years is 7%, increasing to 9% to 16% among adoles- Survey, IDA was reported in only 1.1% of nursing home res-
cents and adult women of childbearing age, respectively. idents.47 However, a more recent report found a 48% preva-
In addition, the prevalence of IDA in low-income pregnant lence of anemia in chronically ill nursing home residents.48
women has been estimated to be as high as 29%.37 Another This disparity in prevalence may simply reflect an inability
contributing factor to IDA in the female population, aside to distinguish between ACD and IDA.
from menstrual iron losses, is that iron intake is well below Unfortunately, most prevalence data for IDA tend to
the estimated average requirement for approximately 16% be generalized for select populations based on age and
of menstruating women and middle- to upper-income gender rather than various clinical conditions. A logical

Downloaded from ncp.sagepub.com at UNIV OF SOUTHERN CALIFORNIA on April 3, 2014

130 Nutrition in Clinical Practice / Vol. 23, No. 2, April/May 2008
breakdown of IDA includes 2 categories; one is based on
physiologic or nutrition need, while the other is patho-
genic iron deficiency secondary to GI disease related to
blood loss or malabsorption of iron.17 Explicitly, IDA is
associated with various chronic diseases or conditions in
which it frequently coexists with ACD; however, the
prevalence of IDA is less defined. Some of these condi-
tions or diseases include IBD, chronic kidney disease
(CKD), congestive heart failure, restless leg syndrome, GI
disorders, and other illnesses.49-55 Iron deficiency anemia
is also a frequent manifestation with liver cirrhosis as a
consequence of GI bleeding from peptic ulcers or
esophageal varices.56 In addition, IDA has also been doc-
umented in surgical patients but varies widely from 5% to
75.8% and is dependent on the type of surgery and degree
of blood loss during or after surgery.10
In general, the occurrence of IDA in various GI dis-
eases with or without bleeding is incomplete.57 It has been
reported in 55.5% patients undergoing an ileal pouch with
anal anastomosis for ulcerative colitits.58 The incidence
rose to 77% in those patients who postoperatively devel-
oped pouchitis. Others have reported that as many as one-
third of patients with IBD suffer from anemia, although
these data did not clearly distinguish between IDA and
ACD.59 A systematic review of the literature found that the
incidence of anemia in patients with Crohn’s disease ranged
from 10.2% to 72.7%, from 8.8% to 66.6% in patients with
ulcerative colitis, and from 17.5% to 73.7% in undifferen-
tiated IBD.49,60 Others have reported that 38% of patients
with Crohn’s disease will develop anemia as a comorbidity
of their condition.50 A more recent study reported similar
rates of IDA in 40% of IBD subjects.31 Overall, the preva-
lence of anemia in IBD is significant. Outcomes data of
IBD patients with anemia reveal diminished quality of life
and greater disease severity. Iron deficiency anemia is also
the most commonly encountered anemia in humans diag-
nosed with celiac disease, with an incidence in adults as
high as 46%.61 Interestingly, in pediatric patients with
celiac disease, the percentage is lower (20%), but it is usu-
ally the sole clinical manifestation in these patients and is
often characterized as refractory.62 Iron deficiency anemia
is also reported in 26% of patients with autoimmune
atrophic gastritis.17
Iron deficiency is a well-documented complication of
gastric resection. Dated statistics indicate that the preva-
lence of IDA in patients undergoing gastric resection
ranges from 10% to 34%.57 However, more recent data
report IDA being present in 94.4% of gastrectomized
patients.63 The large difference may be related more to the
actual type of surgical resection. The number of adults
submitting to bariatric surgery as an effective treatment of
obesity has dramatically increased in this country. Although
outcomes pertaining to long-term nutrition consequences
are dependent on the type of procedure performed, the
incidence of iron deficiency after bariatric surgery has
been reported to range from 20% to 49%.64,65
Downloaded from ncp.sagepub.com at UNIV OF SOUTHERN CALIFORNIA on April 3, 2014
When determining prevalence rates in various condi-
tions, a systematic approach to diagnostic criteria and
data collection is needed to identify and correct the
underlying cause of IDA. This will aid in better manage-
ment and diagnostic strategies, which will subsequently
improve treatment and ultimately patient outcomes and
well-being.
Etiology
Iron deficiency anemia has both physiologic and patho-
logic causes. Physiologic causes relate to the greater iron
demands during periods of growth and development ver-
sus pathologic causes, which refer to iron losses second-
ary to a chronic medical condition. The etiology of IDA is
certainly multifaceted and to some extent lacks conformity.
It depends on a patient’s medical condition, age, comor-
bidities, and concomitant therapies. A single hypothesis
seldom explains the cause of IDA. In general, iron defi-
ciency results when iron demands by the body are not met
by iron absorption. Thus, patients with IDA may have
inadequate intake, impaired absorption, suppressed trans-
port, or physiologic losses secondary to chronological or
reproductive age or chronic blood loss. Despite best diag-
nostic efforts, approximately 29% to 47% of patients with
IDA lack a definitive etiology.55
Normal iron balance is tightly regulated via alterations
in absorption rather than excretion.66 Iron deficiency ane-
mia can be related to inadequate intake or increased iron
needs during physiologic growth periods, but it is usually
secondary to GI occult blood loss.55 Several pharmacologic
agents or conditions can also interfere with iron’s absorp-
tion or transport, leading to iron loss or defective absorption,
which results in IDA in adults. These include H2 blockers,
proton pump inhibitors, aspirin or nonsteroidal anti-
inflammatory drug (NSAID) use, duodenal and gastric
ulcers, carcinoma, adenomatous polyps, IBD, and erosive
gastritis.55 Additional reasons include celiac disease, previ-
ous total or subtotal gastrectomy, and bariatric surgery. An
even more complex etiology involves the patient with
altered hepatic function or compromised protein status.
For example, many cirrhotic patients are malnourished
and malabsorb key micronutrients such as iron, with IDA
becoming commonplace in this population.67 Two physio-
logic functions of the liver are the storage of iron as fer-
ritin and the synthesis of transferrin, iron’s transport
protein. Subsequently, with hepatic disease, iron becomes
trapped in a diseased liver as the liver is unable to synthe-
size transferrin or transport iron to tissues, thereby ulti-
mately contributing to the IDA seen in liver disease.56
Additional contributing factors have been implicated
in the origin of IDA. These include inadequate dietary iron
intake, blood losses of iron, medication usage, GI condi-
tions, GI surgery, celiac disease, older age, and inflamma-
tion and chronic diseases.

Inadequate Dietary Iron Intake
Inadequate iron intake is a contributing factor in the devel-
opment of iron deficiency and IDA. The typical American
diet is estimated to contain about 5 to 7 mg of iron per
1000 kcal, yet the U.S. recommended dietary allowance for
iron in men 19 to 50 years of age is 8 mg/d and 18 mg/d in
women.66,68 The estimated average requirement for iron
intake increases significantly from 8.1 mg/d in nonpregnant
women to 22 mg/d during pregnancy. Key factors con-
tributing to IDA in the female population stem from a
combination of menstrual blood losses and poor iron
intake. As discussed previously, iron intake in the United
States is well below the estimated average requirement for
menstruating women.38 Other countries have reported sim-
ilar findings.69 Because iron depletion, iron deficiency, and
the subsequent development of IDA occur in several
stages, the question remains whether pregnant women
are at increased risk of developing IDA. Turner and col-
leagues39 evaluated iron from food sources in middle- to
upper-income pregnant women and found similar results
regarding inadequate iron intake. They also confirmed that
pregnant women have difficulty obtaining adequate iron to
meet the iron demands of pregnancy. Therefore, the current
recommendation for iron supplementation during preg-
nancy stands. It is prudent to ensure proper iron status and
intake in this population to especially prevent the adverse
health outcomes of increased perinatal risks to both the
mother and newborn.
Blood Losses of Iron
Typically, iron is lost only via blood loss or loss of cells as
they slough. The amount of iron present in an individual
varies based on age, gender, weight, and nutrition status.
Total body stores contain about 2 to 4 g, with substantial
differences between the sexes.66 Menstruating women
average 40 mg/kg, while men average 50 mg/kg of body
weight.66 Men and nonmenstruating women average a 1-mg
loss of iron per day. A typical 60-kg woman may lose an
additional 10 mg of iron per day during menstruation. Iron
loss of 42 mg per menstrual cycle has been reported in
women with heavy blood flow, and a pregnancy uses about
700 mg of iron.66
Blood loss from donating blood, excessive blood
sampling, excessive GI blood loss, or surgical losses also
contributes to iron loss; a unit of blood (500 mL) con-
tains about 250 mg of iron.8 In a study in critically ill
patients, blood draws were considerable and averaged
41 mL per day.70
Excessive menstrual blood losses, a history of hemor-
rhage, or occult GI bleeding all contribute to iron loss.
Regardless of the reason, blood loss from any source sig-
nificantly increases the risks for iron depletion and IDA.
Downloaded from ncp.sagepub.com at UNIV OF SOUTHERN CALIFORNIA on April 3, 2014
Iron Deficiency Anemia / Clark 131
Medications
Prolonged pharmacological treatment of peptic ulcer and
acid reflux can cause defective iron absorption. Any med-
ications that reduce stomach acidity such as antacids, H2
antagonists, or proton pump inhibitors can impair iron
absorption since the low pH of gastric juice is imperative
for the absorption of iron.17,55,71 Individuals with reduced
gastric acid production caused by aging are also in jeop-
ardy of having impaired iron absorption. Chronic use of
such medications that alter the normal low pH of the
stomach provide an environment that allows bacterial
overgrowth, specifically H pylori, a known bacterium that
has been attributed to causing IDA.17,72,73 Furthermore,
attenuation of gastric mucosal inflammation induced by
prolonged aspirin or NSAID use can also contribute to
altered iron absorption and ultimately H pylori gastritis.73
Iron absorption can be competitively impaired when zinc
or manganese supplements are taken as well.
GI Conditions
Evaluation of the GI tract in adults with IDA is always a
critical clinical diagnostic strategy. Either acute or chronic
blood losses from the GI tract are instrumental in causing
IDA; the most common cause is GI occult blood loss. Both
upper and lower GI lesions can be sites for potential blood
loss and often are the culprit of iron depletion.34,56,74-76 In
1 outpatient clinic, 111 women with a mean age of 63
years were prospectively evaluated for investigation of
IDA.75 Assessment of IDA included standard hematologic
criteria (serum iron, total iron-binding capacity, or ferritin
or both) plus sigmoidoscopy, barium enema, and upper GI
endoscopy. In 20 patients, cessation of NSAID therapy
resolved the IDA. Of interest, there were 64 patients who
received iron therapy 2 weeks prior to the GI evaluation
but were still iron deficient per abnormal ferritin values.
The investigation revealed that 39% of participants were
diagnosed with upper GI conditions (gastric ulcer, duode-
nal ulcer, carcinoma, esophagititis, erosive gastritis, and
celiac disease) compared with 28% diagnosed with lower
GI findings (colonic adenoma, carcinoma, and ulcerative
colitis). Unquestionably, endoscopy produced the great-
est yield in the diagnosis of the cause of IDA compared
with the traditional hematological labs. Consequently,
endoscopy contributed greatly to the diagnosis of IDA vs
the reliance on laboratory data in this study. Similar con-
clusions have been reported by others.55,58,74
Nonbleeding sources within the GI tract are often
overlooked in the differential diagnosis of IDA because
they are too often considered synonymous with occult GI
blood loss. Nonbleeding GI conditions can also result in
compromised iron absorption leading to IDA. Key causes
include celiac disease, H pylori infection, and chronic
132 Nutrition in Clinical Practice / Vol. 23, No. 2, April/May 2008
atrophic gastritis.16,72,77 Body-predominant atrophic gas-
tritis (primarily involving the body and fundus of the
stomach) is associated with hypochlorhydria or achlorhy-
dria, while antrum-predominant atrophic gastritis (involving
the antrum, fundus, and body of the stomach) is related
to hypogastrinemia secondary to the destruction of gas-
trin-producing cells. Hence, any condition that alters the
acidic environment within the stomach also impairs the
absorption of iron, thereby potentially leading to IDA if
left unchecked.
A growing body of evidence is beginning to emerge
linking H pylori infection and chronic gastritis, which can
then lead to IDA.16,73,78-81 In fact, H pylori–associated
chronic gastritis resulting in iron malabsorption has been
suggested as an etiology in about 35% of IDA cases.73 The
precise etiology of how H pylori infection causes IDA is
unclear. Several mechanisms have been proposed and
range from a competitive binding of iron by H pylori to a
reduction in intragastric acidity secondary to chronic dis-
ease.16,78 Many bacteria rely on iron as a key fuel for
growth. Some investigators agree that H pylori competes
with the host for iron absorption, while others disagree.82,83
Still other researchers hypothesized that IDA would
resolve when the invading organism in patients with gas-
tritis was eradicated. Explicitly, there are data to support
this hypothesis. One study reported full recovery from
IDA in 92% of patients 12 months after antibiotic treat-
ment of H pylori plus iron supplementation.84 Another
study revealed improvements in hemoglobin values after
only 8 weeks of iron therapy when patients were concur-
rently treated for H pylori infection.85 It has also been
suggested that age is a factor: specifically, that pre-
menopausal women and children are susceptible to devel-
oping iron deficiency secondary to H pylori infection.73,80
There seems to be consensus that treatment of the H
pylori infection in conjunction with iron supplementation
helps to alleviate IDA.
GI Surgery
Anemia as a common hematologic complication following
total or subtotal gastrectomy surgery, and, more recently,
after bariatric surgery, has been well documented.86-88 In
fact, Beyan et al63 found that 94.4% of patients undergoing
a partial gastrectomy exhibited IDA after 5 years. Another
study evaluated the cause of IDA in patients undergoing
subtotal gastrectomy for gastric cancer.87 The study investi-
gators concluded that IDA could be attributed to chronic
atrophic gastritis, and the IDA remained problematic 2 years
after the surgery. Again, the probable mechanism for IDA in
postgastrectomy patients is related to iron malabsorption.
Contributing reasons for this malabsorption are directly
related to postsurgical anatomical and physiologic changes.
Common consequences of the surgery include achlorhydria
Downloaded from ncp.sagepub.com at UNIV OF SOUTHERN CALIFORNIA on April 3, 2014
and increased transit time through the jejunum since the
duodenum is bypassed, which leaves less opportunity for
iron absorption. Of course, the degree of iron malabsorption
can vary depending on the specific surgical procedure per-
formed. Theoretically, all gastroectomized patients should
be carefully monitored for the development of IDA and, if
indicated, prophylactically treated.
The popularity and demand for bariatric surgery for
the treatment of obesity continue to grow. Although this
procedure can produce effective weight loss and reduce
comorbidities, there are a variety of nutrition complica-
tions associated with the surgery.89,90 Micronutrient defi-
ciencies including iron are commonplace and correlate to
the type of procedure performed. Bariatric surgeries are
classified as restrictive, malabsorptive, or some combina-
tion of the two. They include stapled gastroplasty, gastric
banding, and roux-en-Y gastric bypass or biliopancreatic
diversion.65 The potential for early nutrition complica-
tions is greatest with the malabsorptive procedure, yet
iron absorption declines over time with the restrictive
procedures as well. Several factors contribute to a defi-
ciency of iron after these surgical interventions. One rea-
son is merely the reduction in food intake secondary to
reduced gastric capacity. Another aspect relates to poor
iron absorption due to less food exposed to the stomach’s
acidic environment, which is responsible for converting
ferric iron to the more absorbable ferrous form. Deficiencies
are most substantial in the malabsorptive, biliopancreatic
diversion procedure.91,92 Iron deficiency anemia and other
nutrition deficiencies have been well documented after
bariatric surgery. Because it is well known, there is a clear
advantage in its prevention and any treatment in the pop-
ulation. Therefore, the evaluation of both preoperative
and postoperative iron status is recommended in those
undergoing bariatric surgery.
Celiac Disease
Iron status is also compromised in malabsorptive states
such as celiac disease. Iron deficiency anemia is a com-
mon presentation in individuals diagnosed with celiac dis-
ease secondary to iron malabsorption and in some cases
occult GI bleeding.61,77,93 Intolerance to the food protein
gluten causes villous atrophy in the proximal duodenum,
leading to malabsorption of nutrients such as iron. In fact,
IDA is often the first clinical manifestation and often the
only extraintestinal symptom in celiac disease patients.94
In one study, 190 adult patients with IDA were screened
for celiac disease through duodenal biopsies; subse-
quently, 13.7% of the patients were diagnosed with celiac
disease.94 The study investigators concluded that screen-
ing for celiac disease should be done in any adult patient
presenting with IDA. Interestingly, after 12 months of a
gluten-free diet, they found that IDA resolved in 94.4% of

the patients. Other studies support these findings and
consider hematologic screening integral to any diagnostic
celiac disease protocol for early diagnosis and prevention
of potential associated complications such as IDA.77,95
Another common complication of celiac disease is
dermatitis herpetiformis (DH), an intensely pruritic
immunologic skin disorder that is characterized by gluten
sensitivity treatment, primarily the drug dapsone. Two
side effects of this pharmaceutical agent are hemolysis
and methemoglobinemia, which have been shown to con-
tribute to iron deficiency.96 Another mechanism for the
development of iron deficiency in patients with DH on
dapsone therapy is that the drug itself reportedly causes
iron malabsorption.97 However, a gluten-free diet still
remains the first choice of treatment for those exhibiting
DH.98 Most agree that iron deficiency in celiac disease is
primarily the result of impaired iron absorption in tandem
with occult blood loss from the GI tract rather than from
the use of dapsone.99
Elderly Patients
Anemia is common among the hospitalized or institution-
alized elderly population, with the etiology of the anemia
generally multifactorial.36,100-102 In the absence of any his-
tory of hemorrhage, IDA in older people is sometimes
related to diet but is usually a result of occult GI bleeding.44
Common causes in this population include malnutrition,
chronic NSAID use or aspirin therapy, malignant condi-
tions (colonic cancer or polyp, gastric cancer), and IBD. In
a study of 100 patients with IDA, 37% had an upper GI
lesion (half from peptic ulcer) and 26% had a colonic
source of blood loss secondary to colon cancer.55 In these
cases, blood loss was a contributing factor to IDA.
Anemia of chronic disease has been considered a more
common finding in the elderly population than IDA.
Because these 2 conditions can coexist, distinguishing
between them can present a challenge. Current concepts
in the pathophysiology of disease have associated ACD
with cytokine release secondary to inflammatory processes
such that iron is unavailable for transport and incorpora-
tion into hemoglobin. Therefore, IDA can become the
product of unchecked ACD. Increased mortality has been
associated with mild anemic states in elderly patients,
which certainly makes correction a priority.41 Overall, what
makes the causal diagnosis of anemia so difficult in this
population are multiple comorbidities.
Inflammation and Chronic Disease
Although IDA is often associated with chronic disease,
ACD is mediated by different mechanisms and is worth
mentioning. Anemia of chronic disease is related to an
inflammatory response characterized by cytokine release,
Downloaded from ncp.sagepub.com at UNIV OF SOUTHERN CALIFORNIA on April 3, 2014
Iron Deficiency Anemia / Clark 133
resulting in a blunted erythropoietin response to anemia,
abnormal mobilization of reticuloendothelial iron stores,
and reduction in erythrocyte longevity.103 However, it is
not uncommon for patients with conditions such as
IBD to present with both IDA and ACD. In these patients,
the IDA is typically secondary to intestinal blood loss.104
Yet the abnormal laboratory values for iron status that
have been observed might reflect inflammation rather
than poor iron status.105,106 This is related to the fact that
chronic inflammation mediates mechanisms that sequester
iron from the body pool. Upregulation of ferritin and
downregulation of transferrin synthesis are classic host
defense mechanisms that occur during inflammation,
leading to what is referred to as a functional iron defi-
ciency.107 Iron is simply unavailable for delivery to the
bone marrow, and thus, erythropoiesis is compromised,
producing anemia.
Inflammatory processes present an interesting chal-
lenge when evaluating the etiology of IDA associated with
various chronic diseases. The response to inflammation is
physiologically protective to the host and is referred to as
the acute-phase response. Following injury or inflamma-
tion, both iron transport and absorption are suppressed.
Iron is sequestered into the storage form, ferritin, which
then compromises iron availability for incorporation into
hemoglobin. This explains why serum ferritin levels
increase during inflammatory processes.
Inflammation-induced anemia and resistance to ery-
thropoietin are familiar characteristics in patients with
CKD.108 Anemia is a common comorbidity of CKD and is
often ignored or left untreated. It is estimated that more
than 40% of CKD patients are anemic, yet more than
likely, it is much higher, especially in the elderly population,
in part because of age-associated renal impairment.51,101,109
The incidence of anemia in individuals living in skilled
nursing homes has been reported to be 48% and is also
often left untreated.48 A deficiency of erythropoietin pro-
duction and iron deficiency are considered the primary
factors contributing to anemia in CKD.51 The diseased
kidney loses some functional capacity related to iron
metabolism. Causative factors include impaired intestinal
absorption of iron with uremia, limited production of ery-
thropoietin essential to make hemoglobin, and shortened
erythrocyte survival.110,111 Radtke et al112 evaluated the
relationship between hematocrit levels and creatinine
clearance (CrCl). They found that declines in renal func-
tion parallel decreases in hematocrit. More specifically,
they reported that when CrCl falls below 40 mL/min/1.73
m2, anemia is more likely to develop. Others have shown
a correlation between hematocrit and CrCl with a CrCl
range of 41 to 91 mL/min/1.73 m2.113,114
In addition, it has been documented by the Kidney
Early Evaluation Program that the prevalence of chronic
renal disease rises with increasing age, which places the
elderly population at greater risk of CKD and IDA.115 The
134 Nutrition in Clinical Practice / Vol. 23, No. 2, April/May 2008
National Kidney Foundation has established clinical prac-
tice recommendations on how best to treat anemia in
CKD.116 Treatment guidelines include use of both erythro-
poietin-stimulating agents and iron replacement. Specific
iron therapy is predicated on values of serum ferritin con-
centrations. Oral or intravenous iron therapy is recom-
mended for predialysis and peritoneal dialysis when ferritin
levels are between 100 and 500 ng/mL. However, when
ferritin levels are between 200 and 500 ng/mL, intravenous
iron therapy is recommended in hemodialysis. Because
anemia occurs early in CKD, the National Kidney
Foundation recommends a thorough workup for anemia
when hemoglobin levels in adults fall below 12 g/dL.115,117
Early recognition of anemia and subsequent treatment
can improve outcomes in patients with CKD as well as
delay the progression of CKD.
In a patient population with a combination of ane-
mia, heart failure, and CKD, a triad unfolds that has been
called the cardiorenal anemia syndrome.29,52 Anemia is
frequently encountered in patients with congestive heart
failure (CHF), and it is thought to worsen the outcome in
both CKD and CHF.27,52,118 There is now evidence to sup-
port that in renal failure combined with CHF, excessive
cytokine production, an inflammatory marker, is a mech-
anism involved in causing anemia.52 The increased release
of cytokines mediates a decrease in erythropoietin produc-
tion and a resistance of the bone marrow to EPO stimula-
tion. In addition, a cytokine-induced iron deficiency anemia
develops as a result of reduced intestinal absorption of
iron and reduced release of iron from iron stores.30 Early
treatment of anemia in CHF and CKD has been docu-
mented to decrease the length of stay in hospitals and
improve patient outcomes and quality of life.119
The effects of chronic inflammation on intestinal
absorption are just beginning to unfold. Another acute-
phase response includes an increase in hepcidin produc-
tion by the liver, subsequently reducing the intestinal
absorption of iron.120,121 Hepcidin is a small circulating
antimicrobial peptide synthesized by the liver that regu-
lates iron absorption.122 The overproduction of hepcidin
prevents mobilization of iron and contributes to the
pathophysiology of anemia. All of these factors collec-
tively or individually can alter iron status and mediate the
development of anemia.
The etiology of IDA varies greatly. It can be relatively
straightforward because of physiologic demands or losses
associated with pregnancy or menstruation, or conversely
complex when coupled with specific disease states. The
major factor contributing to IDA is still blood loss,
although some conditions not associated with bleeding
result in IDA secondary to some degree of iron malab-
sorption. Whether the etiology of IDA is obvious or com-
plex, astute diagnostic skills are paramount.
Downloaded from ncp.sagepub.com at UNIV OF SOUTHERN CALIFORNIA on April 3, 2014
Diagnosis
Clinical Presentation
In general, the clinical symptoms of IDA are somewhat
nonspecific and are often difficult to attribute directly to
anemia. However, the overt signs or physical manifestations
of iron deficiency are secondary to anemia. Depending on
the severity of anemia, these generic symptoms include
fatigue, lassitude, pallor, and generalized lack of energy.66
Unfortunately, these clinical symptoms are nebulous and
not necessarily good predictors of diagnosing anemia,
particularly in the hospital setting.123
Probably the single most important clinical clue to
anemia is the symptom of chronic fatigue. A hallmark
finding in an iron-deficient patient is microcytic and
hypochromic anemia. The physical examination reveals a
range of symptoms such as tachycardia, shortness of
breath, poor capillary refilling, fatigue, and pallor of the
conjunctiva and skin. Severely anemic patients can display
the symptoms of heart failure as well. Additional clinical
findings include koilonychias, blue sclera, esophageal
webbing, dysphagia, angular stomatitis, and glossitis.66
Behavioral disturbances have also been observed in IDA.
Pica, which is the consumption of nonfood items such as
dirt (pagophagia) and ice (geophagia), has been noted,
especially in children and pregnant women. Restless leg
syndrome has also been casually implicated as a clinical
sign of IDA, although the mechanism is not fully under-
stood.53,54,124 Other physical changes that can influence
quality of life have been reported and include impaired
physical performance and decreased physical activity,
which can result in reduced work capacity, endurance, and
production.13
Background to Diagnostic
Laboratory Tests
Various standard measures of iron status are used to eval-
uate the different stages of iron deficiency (Table 2).
Once normal iron status begins to decline, the stages of
deficiency include negative iron balance, iron depletion,
iron-deficient erythropoiesis, and finally IDA. Each stage
has a corresponding biochemical profile that portrays the
declining iron status. In fact, there are several physiologic
compensatory changes that occur first and are progressive
before IDA manifests.
Many of the adverse effects observed with iron defi-
ciency are often thought to be solely related to low hemo-
globin level. However, when hemoglobin levels initially
fall, the body’s compensatory mechanisms are employed
to supply tissues with oxygen, taking about 2 to 3 days to
become fully operational.2,125 Cardiac output is immedi-
ately increased, which allows more oxygen to be delivered

Table 2. Sequential Changes in Iron Status
Early Negative
Measure Normal Iron Balance
a a
Bone marrow iron 2-3 1 0-1
TIBC, μg/dL 330 ± 30 330-360
Ferritin, μg/L 100 ± 60 <25
Iron absorption, % 5-10 10-15
Plasma iron, μg/dL 115 ± 50 <120
Transferrin saturation, % 35 ± 15 30
Erythrocyte protoporphyrin, μg/dL 30 30
Erythrocytes Normal Normal
Serum transferring receptors Normal Normal-high
IDA, iron deficiency anemia; TIBC, transferrin iron-binding capacity.
a
Represents estimates of iron stored in bone marrow according to a 6-point scale: 0 = iron absent, 1 = iron decreased, 2-3 = normal
amount of iron, 4 = iron markedly increased, and 5 = iron massively increased.
to the tissues. A compensatory metabolic change increases
the concentration of 2, 3–diglycerophosphate in erythro-
cytes, which prompts a right shift of the hemoglobin-
oxygen dissociation curve, resulting in easier release of
oxygen from hemoglobin at the tissues. With protracted
iron deficiency, oxygen delivery is further limited, which
in turn stimulates an increase in erythropoietin production
to subsequently increase the concentration of hemoglo-
bin. However, once iron stores are completely exhausted,
the supply of iron to all tissues is compromised, and
hemoglobin levels begin to decrease. This stage is the
beginning of iron-deficient erythropoiesis, which eventu-
ally advances to IDA. The time line for the development
of IDA, in part, corresponds to the relatively long life span
(120 days) of the red blood cell. Therefore, it takes time
before reticulocytes exhibit the microcytic, hypochromic
state during iron deficiency. This explains the reason why
the evaluation of iron status is done in stages. Identifying
patients at risk during an early stage of iron depletion may
certainly help prevent the progression to IDA.
Diagnostic Laboratory Tests
The diagnosis of anemia varies with age and gender, and
presently, it lacks uniformity. A host of hematological
assays are used to identify the various stages of iron deple-
tion that ultimately lead to IDA. Serum ferritin is a meas-
ure of iron body stores, and a low value unequivocally
identifies IDA. The reference range is still somewhat con-
troversial, but values of 15 to 300 μg/L serum or plasma
are commonly referenced in men and 15 to 150 μg/L in
women. Serum ferritin, which reflects iron stores, remains
one of the best noninvasive tests for the diagnosis of iron
deficiency in patients of all ages.126,127
Most of the diagnostic criteria used in the assessment
of iron status involve measuring shifts in iron status and
initially begin by evaluating red cell indices. One specific
Downloaded from ncp.sagepub.com at UNIV OF SOUTHERN CALIFORNIA on April 3, 2014
Iron Deficiency Anemia / Clark 135
Iron-Deficient
Iron Depletion Erythropoiesis IDA
a
0 0
360 390 410
20 10 <10
10-15 10-20 10-20
115 <60 <40
30 <15 <15
30 100 200
Normal Normal Microcytic
hypochromic
High Very high Very high
strategy begins with the measurement of mean corpuscu-
lar volume (MCV). It has been proposed that any patients
with an MCV <95 fL should have their serum ferritin level
checked.128 When serum ferritin levels are <45 μg/L, a
follow-up endoscopic evaluation should be considered to
assist identifying the cause of IDA.129 Although a serum
ferritin value of 15 to <45 μg/L falls within the reference
range, it introduces a higher sensitivity and earlier identi-
fication of IDA. When serum ferritin levels fall between 46
and 99 μg/L, other markers of iron status such as serum
iron, total iron-binding capacity (TIBC), and transferrin
saturation are warranted. Kis and Carnes130 retrospectively
evaluated the medical charts of 101 veterans with anemia
and a variety of other medical conditions. They concluded
that serum ferritin values ≤100 μg/L maximized sensitivity
and specificity in this population and outperformed other
measures of iron status, including MCV, transferrin satu-
ration, and TIBC. In fact, they found that serum ferritin
values of ≤100 μg/L were 100% accurate when discerning
iron-deficient from iron-sufficient patients.
Another determinant of iron status is the measure-
ment of soluble serum transferrin receptors (sTfR), a
measure that is typically reserved to distinguish between
IDA and ACD.131 Table 3 indicates how various iron mark-
ers are altered in IDA compared with ACD. A decreased
serum ferritin level in combination with decreased trans-
ferrin saturation and microcytic, hypochromic erythro-
cytes definitively confirmed IDA.127 If the diagnosis is still
unclear after an sTfR measurement, a bone marrow biopsy
can be done to determine bone marrow iron content. If
bone marrow values are low, IDA is confirmed; when val-
ues are normal, other causes for the anemia should be
investigated. The use of clinical diagnostic guidelines for
identifying IDA in practice is warranted. The careful inter-
pretation of iron status markers early can lead to more
effective treatment strategies and potentially reduce the
proportion of IDA cases.
136 Nutrition in Clinical Practice / Vol. 23, No. 2, April/May 2008

Table 3. Comparison of Laboratory Measures in Treatment

Iron Deficiency Anemia (IDA) and Anemia
of Chronic Disease (ACD) Historically, guidelines for the treatment of IDA were
based more on the perception of safety and efficacy rather
Laboratory Measures IDA ACD than on evidence-based research. Recently, an audit was
Serum ferritin Reduced Normal to conducted that compared published guidelines for cor-
increased rection of iron deficiency with current practice.134 The
Serum iron Reduced Reduced results indicated haphazard treatment modalities for iron
Transferrin Increased Reduced to deficiency and IDA, with a failure to correct the deficiency
normal in 1 of every 4 patients admitted to the hospital. Clearly,
Transferrin saturation Reduced Reduced a need for standard guidelines that correct and prevent
Mean corpuscular volume Reduced Reduced to IDA for all practice settings is still needed.
normal When diet alone cannot restore deficient iron levels
Serum transferrin receptor Increased Normal
to normal within an acceptable time frame, iron supple-
Hemoglobin Reduced Reduced
Ratio of soluble transferrin Ηigh (>2) Low (<1)
mentation is indicated. Foremost, the treatment of IDA
receptor to log ferritin should be always be predicated on a thorough nutrition-
Cytokine levels Normal Increased focused physical assessment, medical history, and nutri-
ent intake analysis. Treatment considerations for patients
with IDA will depend on underlying etiology, and occa-
sionally a blood transfusion may be required. For example,
Differential Diagnosis
if hemoglobin values are <10 g/dL and the patient com-
The diagnosis of IDA in the elderly population can be plains of extreme fatigue or dyspnea upon exertion, a blood
challenging because of the presence of chronic disease.126 transfusion should be considered. Otherwise, oral iron
Standard measures of iron status, such as serum ferritin, therapy still remains the first-line approach to treating
serum iron, and transferrin receptor, are directly affected IDA.135 It is safer, more cost-effective, and convenient
by chronic disease. Although serum ferritin is considered when compared with parenteral iron therapy. Nausea and
the single best measure for diagnosing IDA in this popu- epigastric discomfort are a frequent complaint of oral iron
lation, its reliability is limited because levels increase with but tend to be dose related, and they can be minimized if
age and reference ranges are not definitive in the age supplements are taken with food or the dose is reduced.
group.131 In addition, common maladies found in elderly Other common lower GI complaints include constipation
patients tend to raise serum ferritin levels as well. In fact, or diarrhea. In tandem with oral iron therapy, dietary-rich
up to 50% of elderly patients with IDA have elevated serum sources of iron should be recommended (eg, fortified
ferritin levels or levels within the reference range.126,132,133 breakfast cereals, cream of wheat, red meat, etc).
The interpretation of serum ferritin is further complicated Supplemental iron is available in 2 forms: ferrous and
since it acts as an acute-phase reactant. Consequently, ferric. Ferrous iron salts are the best absorbed forms of iron
the differential diagnosis between IDA and the ACD supplements. Currently, there are many iron preparations
becomes clinically challenging. Although sTfR can be a available including ferrous fumarate, ferrous sulfate, fer-
better alternative to serum ferritin when distinguishing rous gluconate, and 1 ferric form, bisglycinate. Although
IDA from ACD, transferrin receptor–ferritin index has ferrous fumarate has the highest percentage absorption of
been purported to have higher specificity and sensitivity iron, the 2 preferred oral forms of iron used are ferrous
for diagnosing IDA compared with the more traditional sulfate or ferrous gluconate. Both are relatively inexpen-
laboratory assays mentioned earlier.131,133 Although its sive and have good bioavailability. For example, a 300-mg
diagnostic efficiency is much better than standard labs, it dose of ferrous sulfate contains 60 mg of elemental iron,
is quite expensive (5 times that of routine labs). Because whereas a 350-mg dose of the gluconate form provides 36
a serum ferritin level >30 μg/L does not rule out IDA, and mg of elemental iron. The expected goal associated with
because ferritin increases during inflammation independ- oral iron therapy is a 1- to 2-g/dL increase in hemoglobin
ent of iron status, a better approach to differentiate IDA values every couple of weeks. However, restoration of iron
from ACD has been proposed.128 Laboratory evaluations stores and subsequent improvement in hemoglobin and
should include sTfR and C-reactive protein in addition to hematocrit values usually takes longer (about 4 months)
serum ferritin. C-reactive protein values >30 mg/L, together because of the red blood cell’s life span of approximately
with an elevated sTfR level, generally confirm the pres- 120 days. Since iron is better absorbed under acidic condi-
ence of a concurrent iron deficiency as well as ACD. tions, it is recommended that iron supplements be taken
Detection and treatment of presumptive iron deficiency, with a source of ascorbic acid such as orange juice. Any
before it progresses to IDA, is pivotal in the prevention of foods that reduce the absorption of iron should be avoided,
the negative consequences associated with IDA. including tea tannins or phytates, as well as medications

Downloaded from ncp.sagepub.com at UNIV OF SOUTHERN CALIFORNIA on April 3, 2014


that raise the gastric pH (antacids, proton pump inhibitors,
H2blockers).136 Despite the efficacy and low cost of the
ferrous preparations, they are associated with side effects
such as nausea, epigastric discomfort, and constipation.
An alterative to the ferrous compounds is ferric bisglyci-
nate, an enteric coated, delayed-release supplement. It
tends to be better tolerated with fewer GI complaints;
however, it has a lower bioavailability compared with fer-
rous salts. It is well accepted that the side effects of iron
are dose dependent and influenced by specific iron salt
preparations. To ensure patient compliance, tolerance to
prescribed supplements should be assessed.
Intravenous iron therapy has been controversial for
centuries, mostly because of report of adverse drug reac-
tions. When oral therapy is unsuccessful, parenteral iron
therapy is then indicated. Three main indicators for par-
enteral iron therapy include (1) high iron requirements
secondary to chronic uncorrectable bleeding or chronic
hemodialysis; (2) iron malabsorption from gastric resec-
tion, atrophic gastritis, or celiac disease; and (3) intolerance
to oral therapy because of GI side effects or poor adher-
ence.137,138 In addition, there may be a reason to provide
parenteral iron when hemoglobin values are <6 g/dL and
there is documented inadequate perfusion, which would
contraindicate a transfusion. The appropriate iron replace-
ment dose is calculated using the following equation:
replacement dose (mg) = 0.3 × weight × (100 – [actual
Hgb × 100/desired Hgb]), where weight is in pounds and
hemoglobin (Hgb) in g/dL.139
Three intravenous iron preparations are available for
use in the United States today: iron dextran injection,
sodium ferric gluconate, and iron sucrose injection.138,140,141
Until recently, only iron dextran was available. In 1999,
the Food and Drug Administration approved a safer form
of parenteral iron, sodium ferric gluconate, for treating
adults with renal failure who are hemodialysis dependent.
However, the efficacy and tolerability of ferric gluconate
has also been shown to be beneficial in treating IDA in
patient populations without renal disease.142 Iron sucrose
is another form that has been approved for use since 2000.
There are some data to suggest that iron sucrose can be
administered safely in individuals who have exhibited
hypersensitivity reactions to ferric gluconate.143 Overall,
ferric gluconate and iron sucrose preparations have been
associated with fewer side effects than iron dextran. A
major advantage to iron dextran is that it can be adminis-
tered in large doses (200-500 mg); however, a significant
drawback is the number of reports indicating anaphylac-
tic reactions that can be fatal. Other adverse reactions
include myalgia, arthralgia, and fever, which are often
delayed but treatable with standard analgesics. Current
product dosing standards limit the first dose of iron dex-
tran to no more than 100 mg per day; it serves as a test
dose to determine patient response.
The newer iron preparations, ferric gluconate or iron
sucrose, have a distinct advantage over iron dextran in
Downloaded from ncp.sagepub.com at UNIV OF SOUTHERN CALIFORNIA on April 3, 2014
Iron Deficiency Anemia / Clark 137
that they do not require a test dose. A typical intravenous
dose for sodium ferric gluconate is 125 mg over a con-
secutive 8-week period, for a total dosage of 1000 mg.
Conversely, iron sucrose is administered intravenously in
doses of 200 mg per day over a 5-week period when IDA
is not associated with hemodialysis. The recommended
dose for hemodialysis patients is usually 100 mg adminis-
tered 1 to 3 times per week to provide a cumulative dose
of 1 g. Both iron gluconate and iron sucrose are effective
and safe for use, and the incidence of adverse drug effects
is considerably lower than with iron dextran.3,137,144 It
should also be noted that if the deficiency is not related
to iron as in ACD, intravenous iron therapy does not cor-
rect the anemia or improve iron status markers.
Summary
As highlighted throughout this review, there are 2 funda-
mental criteria that are essential to ensure the proper
management of iron deficiency. These criteria are not
mutually exclusive; rather, they are interdependent and
should be evaluated concurrently. One criterion relies on
the ability to accurately validate the diagnosis of iron defi-
ciency, while the other requires the identification of the
underlying etiology. Future research is needed to charac-
terize more fully how tissue iron deficiency and its most
severe consequence, anemia, are clinically defined, meas-
ured, and treated, inclusive of preventive strategies. In
the past, we have relied too heavily on anemia prevalence
data as the sole indicator for assessing and monitoring
iron deficiency with little continuity. If we are convinced
that iron deficiency is an important problem for human
health and development, it is reasonable to expect that we
can better assess those populations at risk for the devel-
opment of iron deficiency regardless of concurrent medical
conditions. It will take commitment from all practitioners
in all settings to develop and disseminate appropriate
clinical standards of practice guidelines for diagnostic
and treatment modalities for IDA. These guidelines
should begin with finite methodology to determine appro-
priate criteria for defining anemia since inexplicit defini-
tions remain problematic in correcting IDA. Establishing
a standard definition of anemia and specifically evaluat-
ing its impact on functional outcomes such as physical
work capacity, cognitive and immune function, and
improved health once anemia is corrected warrants future
research. The greatest opportunity for improving care and
outcomes lies in identification and treatment of multiple
underlying causes.
Furthermore, the impact of treating anemia with
respect to hospital length of stay, costs, and mortality in
conjunction with the potential for cost savings and
improved patient outcomes should be considered a com-
ponent of any future research. In addition, the overall
economic consequences of IDA, although difficult to
138 Nutrition in Clinical Practice / Vol. 23, No. 2, April/May 2008
quantify, must not be forgotten. These include reduced
work performance and productivity in adults or the irre-
versible adverse impact on intellectual and psychomotor
development in young children.
References
1. Crichton RR, Wilmet S, Legssyer R, Ward FR. Molecular and cel-
lular mechanisms of iron homeostasis and toxicity in mammalian
cells. J Inorg Biochem. 2001;91:9-18.
2. Halliberg L. Perspectives on nutritional iron deficiency. Annu Rev
Nutr. 2001;21:1-21.
3. Schumann K, Ettle T, Szegner B, Elsenhans B, Sololmons N. On
risks and benefits of iron supplementation recommendations for
iron intake revisited. J Trace Elem Med Biol. 2007;21:147-168.
4. Theil EC. Iron, ferritin, and nutrition. Ann Rev Nutr. 2004;24:
327-343.
5. Looker AD, Cogswell ME, Gunter EW. Iron deficiency—United
States, 1999-2000. Morb Mortal Wkly Rep. 2002;51:897-899.
6. Beghe C, Wilson A, Ershler WB. Prevalence and outcomes of ane-
mia in geriatrics: a systematic review of the literature. Am J Med.
2004;116(suppl 7A):S3-S10.
7. Smith DL. Anemia in the elderly. Am Fam Physician. 2000;62:
1565-1572.
8. Joosten E, Hiele M, Pelemans W, Haesen E. Blood loss from diag-
nostic laboratory tests in elderly patients. J Am Geriatr Soc. 1992;
40:298.
9. Knight K, Wade S, Balducci L. Prevalence and outcomes of anemia
in cancer: a systematic review of the literature. Am J Med. 2004;
116(suppl 7A):S11-S26.
10. Shander A, Knight K, Thruer R, Adamson J, Spence R. Prevalence
and outcomes of anemia in surgery: a systematic review of the lit-
erature. Am J Med. 2004;116(suppl 7A):S58-S69.
11. Denic S, Agarwal MM. Nutritional iron deficiency: an evolutionary
perspective. Nutrition. 2007;23:603-614.
12. Stoltzfus RJ. Defining iron-deficiency anemia in public health
terms: a time for reflection. J Nutr. 2001;131(suppl 2):S565-S567.
13. Haas JD, Brownlie T IV. Iron deficiency and reduced work capac-
ity: a critical review of the research to determine a casual relation-
ship. J Nutr. 2001;131(suppl 2):S676-S690.
14. Oppenheimer SJ. Iron and its relation to immunity and infectious
disease. J Nutr. 2001;131(suppl 2):S616-S635.
15. Beard JL. Iron biology in immune function, muscle metabolism
and neuronal functioning. J Nutr. 2001;131(suppl 2):S568-S580.
16. Franceschi F, Gasbarrini A. Helicobacter pylori and extragastric dis-
eases. Best Pract Res Clin Gastroenterol. 2007;21:325-334.
17. Hershko C, Patz J, Ronson A. The anemia of achylia gastrica revis-
ited. Blood Cell Mol Dis. 2007;39:178-183.
18. Beard J. Iron deficiency alters brain development and functioning.
J Nutr. 2003;133(suppl 1):S1468-S1472.
19. Beard JL, Connor JR. Iron status and neural functioning. Annu
Rev Nutr. 2003;23:41-58.
20. McCann JC, Ames BN. An overview of evidence for a causal rela-
tion between iron deficiency during development and deficits in
cognitive or behavioral function. Am J Clin Nutr. 2007;85:931-945.
21. Lozoff B, Corapci F, Burden MJ, et al. Preschool-aged children
with iron deficiency anemia show altered affect and behavior. J
Nutr. 2007;137:683-689.
22. Grantham-McGregor S, Ani C. A review of studies on the effect of
iron deficiency on cognitive development in children. J Nutr.
2001;131(suppl 2):S649-S668.
23. Rasmussen KM. Is there a causal relationship between iron defi-
ciency anemia and weight at birth, length of gestation and perina-
tal mortality? J Nutr. 2001;131(suppl 2):S649-S668.
Downloaded from ncp.sagepub.com at UNIV OF SOUTHERN CALIFORNIA on April 3, 2014
24. Lozoff B, Kaciroti N, Walter T. Iron deficiency in infancy: applying
a physiologic framework for prediction. Am J Clin Nutr. 2006;84:
1412-1421.
25. Brabin BJ, Hakimi M, Pelletier D. An analysis of anemia and
pregnancy-related maternal mortality. J Nutr. 2001;131(suppl
2):S604-S615.
26. Cook JD. Defining optimal body iron. Proc Nutr Soc. 1999;58:
489-495.
27. Butler J, Forman DE, Abraham WT, et al. Relationship between
heart failure treatment and development of worsening renal func-
tion among hospitalized patients. Am Heart J. 2004;147:331-338.
28. Silverberg DS, Iaina A, Wexler D, Blum M. The pathological con-
sequences of anaemia. Clin Lab Haematol. 2001;23:1-6.
29. Silverberg DS, Wexler D, Iaina A, Steinbruch S, Wollman Y,
Schwartz. Anemia, chronic renal disease and congestive heart
failure—the cardio renal anemia syndrome: the need for cooperation
between cardiologists and nephrologists. Int Urol Nephrol. 2006;
38:295-310.
30. Silverberg DS, Wexler D, Iaina A, Schwartz D. The interaction
between heart failure and other heart diseases, renal failure, and
anemia. Semin Nephrol. 2006;26:296-306.
31. Vagianos K, Bector S, McConnell J, Bernstein CN. Nutrition
assessment of patients with inflammatory bowel disease. JPEN J
Parenter Enteral Nutr. 2007;31:311-319.
32. Willoughby JMT, Laitner SM. Audit of the investigation of iron
deficiency anaemia in a district general hospital, with sample guide-
lines for future practice. Med J. 2000;76:218-222.
33. Ahmad I, Gibson PR. Management of iron deficiency in patients
admitted to hospital: time for a rethink of treatment principles.
Intern Med J. 2006;36:347-354.
34. Jolobe OMP. Medicine in the elderly: does this elderly patient have
iron deficiency anaemia, and what is the underlying cause? Postgrad
Med J. 2000;76:195-198.
35. Centers for Disease Control and Prevention. National Health and
Nutrition Examination Survey, 1999-2002. Hyattsville, MD: National
Center for Health Statistics. http://www.cdc.gov/. Accessed
September 7, 2007.
36. Looker A, Dallman P, Carroll M, Gunter E, Johnson C. Prevalence
of iron deficiency in the United States. JAMA. 1997;277:973-976.
37. Bodnar LM, Cogswell ME, Scanlon KS. Low income postpartum
women are at risk of iron deficiency. J Nutr. 2002;132:2298-2302.
38. Moshfegh A, Goldman J, Cleveland L. What We Eat in America
NHANES 2001-2002: Usual Nutrient Intake Form Food Compared
to Dietary Reference Intakes. Washington, DC: U.S. Department of
Agriculture, Agricultural Research Service; 2005.
39. Turner RE, Langkamp-Henken B, Littell RC, Lukowski MJ, Suarez
MF. Comparing nutrient intake from food to the estimated average
requirements shows middle-to-upper income pregnant women lack
iron and possibly magnesium. J Am Diet Assoc. 2003;103:461-466.
40. Sinclair LM, Hinton PS. Prevalence of iron deficiency with and
without anemia in recreationally active men and women. J Am Diet
Assoc. 2005;105:975-978.
41. Izaks GJ, Westendorp RG, Knook DL. The definition of anemia in
older persons. JAMA. 1999;281:1714-1717.
42. Guralnik JM, Eisenstaedt RS, Ferrucci L, Klein HG, Woodman
RC. Prevalence of anemia in persons 65 years and older in the United
States: evidence for a high rate of unexplained anemia. Blood.
2004;104:2263-2268.
43. Anía BJ, Suman VJ, Fairbanks VF, Rademacher DM, Melton LJ.
Incidence of anemia in older people: an epidemiologic study in a
well defined population. J Am Geriatr Soc. 1997;45:825-831.
44. Mukhopadhyay D, Mohanaruban K. Iron deficiency anaemia in
older people: investigation, management and treatment. Age Ageing.
2002;31:87-91.
45. Joosten E, Pelemans W, Hiele M. Prevalence and causes of anaemia
in a geriatric hospitalized population. Gerontology. 1992;38:111-117.

46. Nilsson-Ehle H, Jagenburg R, Landahl S, Svanborg A. Blood
haemoglobin declines in the elderly: implications for reference
intervals from age 70 to 88. Eur J Haematol. 2000;65:297-305.
47. The National Nursing Home Survey: 1999 summary. Rockville,
MD: U.S. Dept of Health and Human Services, Centers for Disease
Control and Prevention, National Center for Health Statistics.
Vital Health Stat. 2002;13:1-50.
48. Artz AS, Fergusson D, Drinka PJ, et al. Prevalence of anemia in
skilled nursing home residents. Arch Gerontol Geriatr. 2004;39:
201-206.
49. Wilson A, Reyes E, Ofman J. Prevalence and outcomes of anemia
in inflammatory bowel disease: a systematic review of the litera-
ture. Am J Med. 2004;116(suppl 7A):S44-S49.
50. Semrin G, Fishman DS, Bousvaros A, et al. Impaired intestinal iron
absorption in Crohn’s disease correlates with disease activity and
markers of inflammation. Inflamm Bowel Dis. 2006;12:1101-1106.
51. Agarwal AK. Practical approach to the diagnosis and treatment of
anemia associated with CKD in elderly. J Am Med Dir Assoc.
2006;7:S7-S12.
52. Silverberg DS, Wexler D, Blum M, Iaina A. The cardio renal anemia
syndrome: correcting anemia in patients with resistant congestive
heart failure can improve both cardiac and renal function and
reduce hospitalizations. Clin Nephrol. 2003;60(suppl 1):S93-S102.
53. O’Keeffe ST, Gavin K, Lavan JN. Iron status and restless leg syn-
drome in the elderly. Age Ageing. 1994;23:200-203.
54. Patrick LR. Restless legs syndrome: pathophysiology and the role
of iron and folate. Altern Med Rev. 2007;12:101-112.
55. Rockey DC, Cello JP. Evaluation of the gastro-intestinal tract in
patients with iron deficiency anemia. N Engl J Med. 1993;329:
1691-1695.
56. Intragumtornchai T, Rojnukkarin P, Swasdikul D, Israsena S. The
role of serum ferritin in the diagnosis of iron deficiency anaemia in
patients with liver cirrhosis. J Intern Med. 1998;243:233-241.
57. Annibale B, Capurso G, Chistolini A, et al. Gastrointestinal causes
of refractory iron deficiency anemia in patients without gastroin-
testinal symptoms. Am J Med. 2001;111:439-445.
58. Pastrana RJ, Torres ES, Arroyo JM, Rivera CE, Sanchez CJ,
Morales L. Iron-deficiency anemia as presentation of pouchitis. J
Clin Gastroenterol. 2007;41:41-44.
59. Gasche C. Anemia in IBD: the overlooked villain. Inflamm Bowel
Dis. 2000;6:142-150.
60. Giannini S, Martes C. Anemia in inflammatory bowel disease.
Minerva Gastroenterol Dietol. 2006;52:275-291.
61. Halfdanarson TR, Litzow MR, Murray JA. Hematologic manifesta-
tions of celiac disease. Blood. 2007;109:412-421.
62. Mody RJ, Brown PI, Wechsler DS. Refractory iron deficiency ane-
mia as the primary clinical manifestation of celiac disease. J Pediatr
Hematol Oncol. 2003;25:169-172.
63. Beyan C, Beyan E, Kaptan K, Ifran A, Uzar AI. Post-gastrectomy
anemia: evaluation of 72 cases with post-gastrectomy anemia.
Hematology. 2007;12:81-84.
64. Malinowski SS. Nutritional and metabolic complications of
bariatric surgery. Am J Med Sci. 2006;331:219-225.
65. Brolin RE. Bariatric surgery and long-term control of morbid obe-
sity. JAMA. 2002;288:2793-2796.
66. Wood RJ, Ronnenberg AG. Iron. In: Shils ME, Shike M, Ross AC,
Caballero B, Cousins RJ, eds. Modern Nutrition in Health and
Disease. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins;
2006:248-270.
67. Peng S, Plank LD, McCall JL, Gillanders LK, McIlroy K, Gane EJ.
Body composition, muscle function, and energy expenditure in
patients with liver cirrhosis: a comprehensive study. Am J Clin
Nutr. 2007;85:1257-1266.
68. Food and Nutrition Board, Institute of Medicine. Dietary Reference
Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper,
Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium,
and Zinc. Washington, DC: National Academy Press; 2000.
Downloaded from ncp.sagepub.com at UNIV OF SOUTHERN CALIFORNIA on April 3, 2014
Iron Deficiency Anemia / Clark 139
69. Pynaert I, Delanghe J, Temmerman M, De Henauw S. Iron intake
in relation to diet and iron status of young adult women. Ann Nutr
Metab. 2007;51:172-181.
70. Vincent JL, Baron JF, Reinhart K, et al. Anemia and blood transfu-
sions in critically ill patients. JAMA. 2002;288:1499-1507.
71. Annibale B, Capurso G, Fave GD. The stomach and iron defi-
ciency anaemia: a forgotten link. Dig Liv Dis. 2003;35:288-295.
72. Bini EJ. Helicobacter pylori and iron deficiency anemia: guilty as
charged? Am J Med. 2001;111:495-497.
73. Nahon S, Lahmek P, Massard J, et al. Helicobacter pylori-associ-
ated chronic gastritis and unexplained iron deficiency anemia: a
reliable association? Helicobacter. 2003;8:573-577.
74. Joosten E, Ghesquiere B, Linthoudt H, et al. Upper and lower gas-
trointestinal evaluation of elderly inpatients who are iron deficient.
Am J Med. 1999;107:24-29.
75. McIntyre AS, Long RG. Prospective survey of investigations in out-
patients referred with iron deficiency anaemia. Gut. 1993;34:
1102-1107.
76. Capurso G, Lahner E, Pallotta N, Panzuto F, Delle Fave G,
Annibale B. Iron deficiency anemia caused by nonspecific (idio-
pathic) small bowel ulcerations: an uncommon presentation of an
uncommon disease. Can J Gastroenterol. 2007;16:855-859.
77. Harper JW, Holleran SF, Ramakrishnan R, Bhagat G, Green PH.
Anemia in celiac disease is multifactorial in etiology. Am J
Hematol. 2007;82:996-1000.
78. Annibale B, Capurso G, Lahner E, et al. Concomitant alterations
in intragastric pH and ascorbic acid concentration in patients with
Helicobacter pylori gastritis and associated iron deficiency anaemia.
Gut. 2003;52:496-501.
79. Annibale B, Di Giulio E, Caruana P, et al. The long-term effects of
cure of Helicobacter pylori infection on patients with atrophic body
gastritis. Aliment Pharmacol Ther. 2002;16:1723-1731.
80. DuBois S, Kearney D. Iron-deficiency anemia and Helicobacter
pylori infection: a review of the evidence. Am J Gastroenterol. 2005;
100:453-459.
81. Shuval-Sudai O, Granot E. An association between Helicobacter
pylori infection and serum vitamin B12 levels in healthy adults. J
Clin Gastroenterol. 2003;36:130-133.
82. Blaser MJ. Helicobacter pylori and gastric diseases. BMJ. 1998;
316:1507-1510.
83. Olivares A, Buadze M, Kutubidze T, et al. Prevalence of Helicobacter
pylori in Georgian patients with dyspepsia. Helicobacter. 2006;
11:81-85.
84. Annibale B, Marignani M, Monarca B, et al. Reversal of iron defi-
ciency anemia after Helicobacter pylori eradication in patients with
asymptomatic gastritis. Ann Intern Med. 1999;131:668-672.
85. Choe YH, Kim SK, Son BK, Lee DH, Hong YC, Pai SH.
Randomized placebo-controlled trial of Helicobacter pylori eradi-
cation for iron-deficiency anemia in preadolescent children and
adolescents. Helicobacter. 1999;4:135-139.
86. Hines JD, Hoffbrand AV, Mollin DL. The hematologic complica-
tions following partial gastrectomy: a study of 292 patients. Am J
Med. 1967;43:555-569.
87. Roviello F, Fotia G, Marrelli D, De Stefano A, Macchiarelli R,
Pinto E. Iron deficiency anemia after subtotal gastrectomy for gas-
tric cancer. Hepatogastroenterology. 2004;51:1510-1514.
88. Shah M, Simha V, Garg A. Review: long-term impact of bariatric
surgery on body weight, comorbidities, and nutritional status. J
Clin Endocrinol Metab. 2006;91:4223-4231.
89. Folope V, Coeffier M, Dechelotte P. Nutritional deficiencies
associated with bariatric surgery. Gastroenterol Clin Biol. 2007;31:
369-377.
90. Alvarez-Leite JI. Nutrient deficiencies secondary to bariatric sur-
gery. Curr Opin Clin Nutr Metab Care. 2004;7:569-575.
91. Flancbaum L, Belsley S, Drake V, Colarusso T, Tayler E. Preoperative
nutritional status of patients undergoing Roux-en-Y gastric bypass for
morbid obesity. J Gastrointest Surg. 2006;10:1033-1037.
140 Nutrition in Clinical Practice / Vol. 23, No. 2, April/May 2008
92. Bloomberg RD, Fleishman A, Nalle JE, Herron DM, Kini S.
Nutritional deficiencies following bariatric surgery: what have we
learned? Obes Surg. 2005;15:145-154.
93. Hernandez L, Green PH. Extraintestinal manifestations of celiac
disease. Curr Gastroenterol Rep. 2006;8:383-389.
94. Annibale B, Severi C, Chistolini A, et al. Efficacy of gluten-free
diet alone on recovery from iron deficiency anemia in adult celiac
patients. Am J Gastroenterol. 2001;96:132-137.
95. Lombardo T, Ximenes B, Ferro G. Hypochromic microcytic anemia
as a clinical presentation of celiac disease. Clin Lab. 2006;52:
231-236.
96. Wolverton SE, Remlinger K. Suggested guidelines for patient
monitoring: hepatic and hematologic toxicity attributable to sys-
temic dermatologic drugs. Dermatol Clin. 2007;25:195-205.
97. Gawkrodger DJ, Ferguson A, Bameton RS. Nutritional status in
patients with dermatitis herpetiformis. Am J Clin Nutr. 1988;48:
355-360.
98. Nino M, Ciacci C, Delfino M. A long-term gluten-free diet as an
alternative treatment in severe forms of dermatitis herpetiformis.
J Dermatol Treat. 2007;18:10-12.
99. Mant MJ, Bain VG, Maguire CG, Murland K, Yacysthyn BR.
Prevalence of occult gastrointestinal bleeding in celiac disease.
Clin Gastroenterol Hepatol. 2006;4:451-454.
100. Ania BJ, Suman VJ, Fairbanks VF. Prevalence of anemia in medical
practice: community versus referral patients. Mayo Clinic Proc.
1994;69:730-735.
101. Artz AS, Fergusson D, Drinka PJ, et al. Mechanisms of unexplained
anemia in the nursing home. J Am Geriatr Soc. 2004;52:423-427.
102. Mitrache C, Passweg JR, Libura J, et al. Anemia: an indicator for
malnutrition in the elderly. Ann Hematol. 2001;80:295-298.
103. Spivak JL. Anemia in the elderly. Arch Intern Med. 2005;165:
2187-2189.
104. Child JA, Brozovi B, Dyer NY, Mollin DL, Dawson AM. The diag-
nosis of iron deficiency in patients with Crohn’s disease. Gut.
1973;14:642-648.
105. Means RT. Advances in the anemia of chronic disease. Int J
Hematol. 1999;70:7-12.
106. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J
Med. 2005;352:1011- 1023.
107. Gasche C, Lomer MC, Cavill I, Weiss G. Iron, anaemia, and
inflammatory bowel diseases. Gut. 2004;53:1190-1197.
108. Balla J, Jeney V, Varga Z, Komodi E, Nagy E, Balla G. Iron
homeostasis in chronic inflammation. Acta Physiol Hung. 2007;
94:95-106.
109. Garg AX, Papaioannou A, Ferko N, Campbell G, Clarke JA, Ray
JG. Estimating the prevalence of renal insufficiency in seniors
requiring long-term care. Kidney Int. 2004;65:649-653.
110. Robinson BE. Epidemiology of chronic kidney disease and ane-
mia. J Am Med Dir Assoc. 2006;7(suppl 9):S3-S6.
111. Schoorl M, Schoori M, Nube MJ, Barteis PC. Erythropoiesis
activity, iron availability and reticulocyte hemoglobinization dur-
ing treatment with hemodialysis and in subjects with uremia. Clin
Lab. 2006;52:621-629.
112. Radtke HW, Claussner A, Erbes PM, Scheuermann EH,
Schoeppe W, Koch KM. Serum erythropoietin concentration in
chronic renal failure: relationship to degree of anemia and excre-
tory renal function. Blood. 1979;54:877-884.
113. Obrador GT, Roberts T, St Peter WL, Frazier E, Pereira BJ,
Collins AJ. Trends in anemia at initiation of dialysis in the United
States. Kidney Int. 2001;60:1875-1884.
114. Kazmi WH, Kausz AT, Khan S, et al. Anemia: an early complication
of chronic renal insufficiency. Am J Kidney Dis. 2001;38:803-812.
115. Ohmit SE, Flack JM, Peters RM, Brown WW, Grimm R.
Longitudinal study of the National Kidney Foundation’s (NKF)
Kidney Early Evaluation Program (KEEP). J Am Soc Nephrol.
2003;14(suppl 2):S117-S121.
Downloaded from ncp.sagepub.com at UNIV OF SOUTHERN CALIFORNIA on April 3, 2014
116. Grabe DW. Update on clinical practice recommendations and
new therapeutic modalities for treating anemia in patients with
chronic kidney disease. Am J Health Syst Pharm. 2007;64(suppl
8):S8-S14.
117. Brown WW, Collins A, Chen SC, et al. Identification of persons
at high risk for kidney disease via targeted screening: the NKF
Kidney Early Evaluation Program. Kidney Int Suppl. 2003;83:
S50-S55.
118. Forman DE, Butler J, Wang Y, et al. Incidence, predictors at admis-
sion, and impact of worsening renal function among patients hos-
pitalized with heart failure. J Am Coll Cardiol. 2004;43:61-67.
119. Wexler D, Silverberg D, Sheps D, et al. Prevalence of anemia in
patients admitted to hospital with a primary diagnosis of conges-
tive heart failure. Int J Cardiol. 2004;96:79-87.
120. Gantz T. Molecular control of iron transport. J Am Soc Nephrol.
2007;18:394-400.
121. Malyszko J, Mysliwiec M. Hepcidin in anemia and inflammation
in chronic kidney disease. Kidney Blood Press Res. 2007;30:15-30.
122. Andrews NC, Schmidt PJ. Iron homeostasis. Annu Rev Physiol.
2007;69:69-85.
123. Elnicki DM, Shockcor WT, Brick JE, Beynon D. Evaluating the
complaint of fatigue in primary care: diagnoses and outcomes.
Am J Med. 1992;93:303-306.
124. O’Keeffe ST. Secondary causes of restless legs syndrome in older
people. Age Ageing. 2005;34:349-352.
125. Beard JL, Murray-Kolb LE, Rosales FJ, Solomons NW, Angelilli
ML. Interpretation of serum ferritin concentrations as indicators
of total-body iron stores in survey populations: the role of bio-
markers for the acute phase response. Am J Clin Nutr. 2006;84:
1498-1505.
126. Guyatt GH, Oxman AD, Ali M, Willan A, Mcllory W, Patterson C.
Laboratory diagnosis of iron-deficiency anemia: an overview. J Gen
Intern Med. 1992;7:145-153.
127. Tefferi A. Anemia in adults: a contemporary approach to diagnosis.
Mayo Clin Proc. 2003;78:1274-1280.
128. Killip S, Bennett JM, Chambers MD. Iron deficiency anemia. Am
Fam Physician. 2007;75:671-678.
129. Ioannou GN, Spector J, Scott K, Rockey DC. Prospective evalua-
tion of a clinical guideline for the diagnosis and management of
iron deficiency anemia. Am J Med. 2002;113:281-287.
130. Kis AM, Carnes M. Detecting iron deficiency in anemic patients
with concomitant medical problems. J Gen Intern Med.
1998;13:455-461.
131. Rimon E, Levy S, Sapir A, et al. Diagnosis of iron deficiency ane-
mia in the elderly by transferrin receptor-ferritin index. Arch
Intern Med. 2002;162:445-449.
132. Loria A, Hershko C, Konijn AM. Serum ferritin in an elderly pop-
ulation. J Gerontol. 1979;34:521-524.
133. Joosten E, VanLoon R, Billen J, Blanckaert N, Gabri R,
Pelemmans W. Serum transferring receptor in the evaluation of
the iron status in elderly hospitalized patients with anemia. Am J
Hematol. 2002;69:1-6.
134. Ahmad I, Gibson PR. Management of iron deficiency in patients
admitted to hospital: time for a rethink of treatment principles.
Intern Med J. 2006;36:347-354.
135. Croby WH. The rationale for treating iron deficiency anemia.
Arch Intern Med. 1984;144:471-472.
136. Clark SF. Vitamins and trace elements. In: Gottschlich MM,
DeLegge MH, Mattox T, Mueller C, Worthington P, eds. The
A.S.P.E.N. Nutrition Support Core Curriculum: A Case-Based
Approach—The Adult Patient. Silver Spring, MD: A.S.P.E.N;
2007:129-159.
137. Cook J. Diagnosis and management of iron-deficiency anaemia.
Best Pract Res Clin Haematol. 2005;18:319-332.
138. Maslovsky I. Intravenous iron in a primary-care clinic. Am J
Hematol. 2005;78:261-264.

139. Kumpf VJ. Update on parenteral iron therapy. Nutr Clin Pract.
2003;18:318-326.
140. Auerbach M, Ballard H, Glaspy J. Clinical update: intravenous
iron for anemia. Lancet. 2007;369:1502-1504.
141. Beutler E, Hoffbrand AV, Cook JD. Iron deficiency and overload.
Hematology Am Soc Hematol Educ Program. 2003;40-61.
142. Miller HJ, Hu J, Valentine JK, Gable PS. Efficacy and tolerability
of intravenous ferric gluconate in the treatment of iron deficiency
Downloaded from ncp.sagepub.com at UNIV OF SOUTHERN CALIFORNIA on April 3, 2014
Iron Deficiency Anemia / Clark 141
anemia in patients without kidney disease. Arch Intern Med.
2007;167:1327-1328.
143. Sane R, Baribeault D, Rosenberg CL. Safe administration of iron
sucrose in a patient with a previous hypersensitivity reaction to
ferric gluconate. Pharmacotherapy. 2007;27:613-615.
144. Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. Update on
adverse drug events associated with parenteral iron. Nephrol Dial
Transplant. 2006;21:378-382.