Iron deficiency anemia: diagnosis and management

Susan F. Clark
Department of Human Nutrition, Foods and Exercise, Purpose of review
Virginia Polytechnic Institute and State University,
Blacksburg, Virginia, USA
Iron deficiency anemia (IDA) still remains universally problematic worldwide. The primary
focus of this review is to critique articles published over the past 18 months that
Correspondence to Susan F. Clark, RD, PhD,
Department of Human Nutrition, Foods and Exercise, describe strategies for the diagnosis and management of this prevalent condition.
Virginia Polytechnic Institute and State University, 223 Recent findings
Wallace (0430), Blacksburg, VA 24061, USA
Tel: +1 540 231 8768; fax: +1 540 231 3916; The medical community continues to lack consensus when identifying the optimal
e-mail: sfclark@vt.edu approach for the diagnosis and management of IDA. Current diagnostic
Current Opinion in Gastroenterology 2009,
recommendations revolve around the validity and practicality of current biomarkers such
25:122–128 as soluble transferrin-receptor concentrations and others, and cause-based diagnostics
that potentially include endoscopy. Management of IDA is based on supplementation
combined with effective etiological treatment. Advances in oral and parenteral low-
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molecular-weight iron preparations has expanded and improved treatment modalities for
IDA. Since the introduction of low versus high-molecular-weight intravenous iron
administration, there have been fewer serious adverse events associated with
parenteral iron preparations.
Summary
Best practice guidelines for diagnosing and managing IDA should include the
design of an algorithm that is inclusive of multiple biomarkers and cause-based
diagnostics, which will provide direction in managing IDA, and distinguish
between IDA from the anemia of chronic disease.

Keywords
iron deficiency anemia, transferrin-receptor/ferritin ratio, zinc protoporphyrin/heme

Curr Opin Gastroenterol 25:122–128

ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
0267-1379

There is no sole, reliable biochemical indicator that is

Introduction consistently diagnostic of iron deficiency except the ‘gold
The primary focus of this article will be to evaluate standard’, bone marrow iron aspirates. As iron status
specific diagnostic criteria for iron deficiency anemia changes are sequential, we need to move beyond the
(IDA) and describe management strategies to correct current philosophy using a single assay to diagnose IDA
IDA. Approaches for differentiating IDA from the ane- but rather take an intentional approach that involves the
mia of chronic disease (ACD) will only be discussed systematic assessment of the underlying cause and use of
within the context of identifying IDA. Nevertheless, a multiple parameters.
working consensus on a pragmatic approach to diagnosis
and treatment despite the prevalence of this condition
Diagnostic indicators of iron deficiency anemia
remains paramount.
Intuitively, combining several iron status indicators pro-
vides the best assessment of iron status. Evaluation of
Background multiple indicators such as soluble transferrin receptors
IDA is the most common nutritional deficiency around (sTfRs), sTfR–ferritin index (sTfR–F), zinc protoporphy-
the globe, yet universal standards of practice guidelines rin/heme ratio (ZPP/H), reticulocyte hemoglobin (Hb)
for diagnostic and treatment modalities are riddled with content (CHr) and selective endoscopy will provide better
inconsistencies and disagreements among practitioners. diagnosis and treatment iron status to prevent IDA.
A recent review article [1

] presents evidence-based data
on the incidence of IDA associated with a myriad of Serum transferrin receptor and serum transferrin
diseases and medical conditions that complicate the receptor log/ferritin index
diagnosis of true IDA. It also describes the diverse causes sTfR reflects erythropoiesis and inversely the amount of
of IDA, diagnostic parameters and management strat- iron available for erythropoiesis. Values of sTfR are elev-
egies. Table 1 summarizes the physiologic and pathologic ated in IDA due to the upregulation of synthesis of
causes of IDA, and Table 2 delineates diagnostic tests. transferrin receptors on the erythrocytes so the cells can
0267-1379 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MOG.0b013e32831ef1cd

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 Iron deficiency anemia: diagnosis and management Clark 123

Table 1 Physiologic and pathologic conditions associated with compete for iron more efficiently. Unlike serum ferritin,
iron deficiency anemia sTfR concentrations are not affected by the presence of
Physiologic conditions inflammation [2]. The ratio between sTfR and serum
(growth and development) Pathologic conditions
ferritin concentrations, or sTfR–F index, is also con-
Increased iron demands Chronic inflammatory states sidered a good indicator for evaluation of iron deficiency.
Pregnancy Chronic renal disease
Lactation Congestive heart failure
Infants Obesity
sTfRs can contribute significantly to the detection of
Children and adolescents Blood loss IDA; however, some claim it to be not any better than
Increased dietary demands Inflammatory bowel diseasea serum ferritin [3–7]. Yang et al. [8
] compared the plasma
Pregnancy Blood donations
Lactation Excessive blood sampling
ferritin concentrations alone with the sTfR–F ratio in
Infants Excessive surgical blood loss infants, school-aged children and pregnant women
without replacement measuring plasma ferritin, sTfR and C-reactive protein
Children and adolescents Excessive menstrual losses
Menstrual losses Medicationsb
(CRP). They concluded that iron status can be effectively
Inadequate dietary intake Aspirin measured using plasma ferritin concentrations alone,
NSAIDS provided a biomarker such as CRP is also measured
Antacids
H2 antagonist
to avoid falsely elevated plasma ferritin secondary to
Proton-pump inhibitors concurrent inflammation.
Gastrointestinal conditionsc
Upper gastrointestinal conditions
Gastric ulcer
Chang et al. [9
] compared the utility of serum sTfR
Duodenal ulcer levels to bone marrow iron stores in identifying IDA.
Carcinoma Bone marrow aspirates were performed in adult patients
Esophagititis
Erosive gastritis
and hematologic assays: sTfR, serum ferritin, Hb, mean
Celiac disease corpuscular volume (MCV) and mean corpuscular hemo-
Peptic ulcer disease globin concentration (MCHC). Cutoff values consistent
H. pylori gastritis
Crohn’s disease
with previous studies [10,11] that were used to exclude
Malabsorptive states iron deficiency included ferritin values of at least
(surgical or medical) 100 mcg/l and an sTfR/log ferritin ratio of more than
Gastrectomy
Chronic atrophic gastritis
2.5. Elevated sTfR levels were found to be the most
Lower gastrointestinal conditions sensitive marker for the detection of absent bone marrow
Colonic adenoma iron (100%), whereas the sTfR–F ratio of more than 2.5
Carcinoma
Ulcerative colitis
had a lower sensitivity (50%). sTfR–F did have better
Malabsorptive states sensitivity and specificity compared with the serum sTfR
Other value alone when differentiating between IDA from
Restless leg syndrome
ACD, which has been previously reported [2,10–13].
a
Active Crohn’s disease and ulcerative colitis.
b
Defective iron absorption. Goyal et al. [14
] evaluated sTfR–F indices to determine
c
Defective iron absorption or iron loss secondary to blood loss.
the prevalence of ACD, and ACD with coexistent IDA in
rheumatoid arthritis (RA) patients. The sTfR–F index
was found to be a useful measure in classifying patients
with ACD and coexistent IDA (80%) versus patients with

Table 2 Diagnostic test related to sequential changes in iron status

Early negative-iron Iron-deficient
Measure Normal balance Iron depletion erythropoiesis IDA
a þ þ þ
Bone marrow iron 2–3 1 0–1 0 0
TIBCb (mg/dl) 330  30 330–360 360 390 410
Ferritin (mg/l) 100  60 <25 20 10 <10
Iron absorption (%) 5–10 10–15 10–15 10–20 10–20
Plasma iron (mg/dl) 115  50 <120 115 <60 <40
Transferrin saturation (%) 35  15 30 30 <15 <15
Erythrocyte protoporphyrin (mg/dl) 30 30 30 100 200
Erythrocytes Normal Normal Normal Normal Microcytic hypochromic
Serum transferrin receptors Normal Normal–high High Very high Very High
IDA, iron deficiency anemia.
a
Estimates of iron stored in bone marrow according to a six-point scale: 0 ¼ iron absent, 1 ¼ iron decreased, 2–3 ¼ normal amount of iron, 4 ¼ iron
markedly increased and 5 ¼ iron massively increased.
b
Transferrin iron-binding capacity. Adapted with permission [1

].

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 124 Nutrition

pure ACD (20%). They also determined that sTfR–F and fecal occult blood test (FOBT) were measured.
index values of less than 2.2 mg/l excludes IDA, whereas Endoscopic findings revealed at least one likely cause
values of more than 2.9 mg/l confirmed IDA. A similar for unexplained IDA in 86.7% of patients; causes
study [15
] compared the utility of serum ferritin, serum included: bleeding, colon cancer, peptic ulcer, nonbleed-
iron and bone marrow iron stores in diagnosing iron ing related, atrophic gastritis, Helicobacter pylori and celiac
deficiency in RA outpatients. On the basis of the bone disease. Significant risk factors identified were older age
marrow iron stores, 36% of patients had IDA and 64% (>50 years), lower MCV and male sex. They concluded
exhibited ACD. Correlation between the serum ferritin that a diagnostic endoscopy in patients with IDA should
and the bone marrow iron stores was poor in the IDA be based on age with colonoscopy performed first in older
group yet significant in the ACD group. Negative pre- patients (>50 years of age) with low MCV and Hb below
dictive values were highest when cutoff values for serum 12 g/dl, and EGD with biopsy should be done first in
ferritin were less than 82 mcg/l in contrast to other stu- younger patients with unexplained IDA. However, the
dies’ cutoff values of 30–70 mg/l [16,17]. disproportion of women (76%) to men calls into question
the conclusions drawn.
Zinc protoporphyrin/heme ratio
Evaluation of iron status using the ZPP/H is another Vannella et al. [30
] also evaluated the cause of unex-
diagnostic indicator of IDA diagnostic of early iron plained IDA in premenopausal women between the ages
depletion [18]. The ZPP/H ratio reflects iron status in of 20 and 56 years using endoscopy. IDA was defined as
the bone marrow during the formation of Hb [19]. When Hb below 12 g/dl with serum ferritin less than 30 mg/dl,
iron supply is diminished, Zn utilization increases result- and iron deficiency as serum ferritin less than 30 mg/dl. All
ing in a high ZPP/H ratio. Das and Philip [20
] compared patients underwent a gastroscopy including biopsies and
the utility of ZPP/H ratio as a diagnostic measure of IDA FOBTs. Patients (50 years of age), with positive FOBT
with bone marrow iron store aspirates. In tandem with Hb or positive family history for colonic cancer were invited
and red blood cell indices, ZPP was reliable in reflecting to undergo a colonoscopy. Endoscopic evaluation
the bone marrow iron status except in the prelatent phase revealed a likely cause of IDA in 68.5% of patients.
of iron deficiency; however, it lacked the ability to The cause was due to iron malabsorption in 65.2% of
distinguish between ACD and IDA. Using ZPP/H ratio patients, secondary to H. pylori pangastritis, celiac disease
to determine iron stores is preferential over the invasive- and atrophic gastritis. Only 3.7% of iron deficiency ane-
ness of bone marrow aspiration. Others have reported that mic patients exhibited bleeding lesions, whereas 67.4%
the ZPP/H ratio increase also compares favorably with were diagnosed with menorrhagia. This study produced a
serum ferritin concentration decrease, MCV and Hb high diagnostic yield for the cause of IDA.
levels in diagnosing IDA and preanemic iron depletion
[19,21]. As zinc is also influenced by inflammation, ZPP Another study by Ioannou et al. [31
] identified diagnostic
interpretation can be challenging [22,23]. tests and clinical features that were predictive for endo-
scopic evaluation in patients with anemia (<13 g/dl
Reticulocyte hemoglobin content women, <12 g/dl men) using serum ferritin (<45 ng/dl)
CHr assesses the amount of Hb in reticulocytes [24–27]. and transferrin saturation (<15%) as outcome measures.
Measurement of CHr provides a snapshot of iron immedi- Anemia was found in 35.4% of the 1798 hospitalized
ately available for erythropoiesis over the previous 3–4 patients; 74% were men, 26% women, mean age is equal
days, making it functional as an early indicator of iron to 62 years, 51% white and 49% nonwhite. Those diag-
stores. Blood CHr has been found to be comparable to the nosed with IDA, 39% had either low serum ferritin or low
traditional parameters for iron deficiency (serum iron, transferrin saturation and underwent endoscopic evalu-
serum ferritin and Hb) for confirming the diagnosis of ation. The only significant predictor for endoscopic
iron-deficient states [25–27,28
]. Blood CHr has also evaluation was a positive FOBT.
been identified as an early indicator of the response to
parenteral iron therapy, increasing within 2–4 days if
sequential measurements are observed [28
]. Newer diagnostic biomarkers: hepcidin
Hepcidin is considered a key regulator of iron metab-
olism; it regulates iron concentrations and tissue iron
Diagnostic endoscopic procedures distribution via inhibition of intestinal iron absorption,
Current recommendations for adults with unexplained iron reclamation by macrophages and iron mobilization
IDA include endoscopy. Capruso et al. [29] identified risk from hepatic stores [32]. Its production is decreased in
factors that would predict the presence of abnormalities IDA and increased during inflammation and iron over-
in patients with IDA that would indicate whether colo- loading. The overproduction of hepcidin during an acute
noscopy or esophagogastroduodenoscopy (EGD) should phase response results in reduced iron absorption, mobil-
be performed first. Serum ferritin, routine blood counts ization, or both, contributing to the disease of anemia.

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 Iron deficiency anemia: diagnosis and management Clark 125

Kemna et al. [33

] developed the algorithm [transferrin Mimura et al. [35

] compared the use of another iron
saturation (%)  sTfR (mg/l) þ CRP (mg/l) ¼ hepcidin] to complex, ferrous glycinate chelate to ferrous sulfate for
predict hepcidin levels. A strong correlation between the the treatment of IDA in postgastrectomized patients.
predicted hepcidin values and the actual measured hep- Standard indices were determined (Hb, MCH, MCHC,
cidin levels was found. Despite the selected parameters serum iron, serum ferritin, transferrin and transferrin
used in this algorithm, each has shortcomings; the lab saturation) and an EGD. Patients received either
indices are readily available and less expensive than serum 400 mg/day ferrous sulfate or 250 mg/day ferrous glyci-
hepcidin. Hepcidin levels have the potential to improve nate chelate. After 2 months, transferrin levels were
accuracy when differentiating between IDA and ACD. significantly decreased in patients receiving ferrous sul-
fate. Results favored ferrous sulfate as more effective in
improving iron status over ferrous glycinate chelate,
Management of iron deficiency anemia contrary to previous studies [36–38]. Some of the unfa-
The treatment modalities for managing IDA will depend vorable results observed were attributed to decreased
on the underlying cause. Once the cause of IDA has been iron absorption in patients with alkaline gastritis. Another
ascertained, either oral or parenteral iron therapy is contributing factor could have been presence of H. pylori
commonly prescribed to correct the deficiency. infection. H. pylori infection is a common comorbidity
found in the gastric remnant of gastrectomized patients,
which is known to decrease iron absorption [1

,39].
Oral iron therapy Identifying the presence of H. pylori or alkaline gastritis
Oral iron therapy is usually adequate for most patients; it was not verified in this current study.
is an efficient, well tolerated and cost-effective way to
replace iron stores. Four common preparations are found
in Table 3. Historically, ferrous sulfate has been used to Response to oral iron therapy
treat IDA because it is better absorbed by the gastroin- The treatment of IDA should include a strategy for
testinal tract and causes fewer side effects (heartburn, measuring response to iron therapy. Historically, a 2 g/
abdominal pain, nausea, diarrhea and constipation). dl improvement in Hb levels has been considered an
When complexes or chelated forms of iron are used appropriate response to iron supplementation; yet, other
the gastrointestinal symptoms are minimal. parameters may be more reliable. Lin et al. [40

]
measured sTfR levels to assess the response and efficacy
of 12 weeks of oral ferrous L-threonate in patients with
Oral iron therapy using iron complexes- IDA or iron deficiency erythropoiesis (IDE). Iron status
chelates was assessed in women (18–45 years) using the serum
Pitarresi et al. [34
] described the utility of an inulin–iron ferritin, ZPP and Hb levels at weeks 0, 3, 6 and 12. The
complex. Inulin is a naturally occurring fructose polymer IDE and IDA group received ferrous L-threonate supple-
with fermentation products that enhance iron absorption ments for 12 weeks (14 and 28 mg/day, respectively).
within the colon. Two derivatives were used, a carboxy- Significant changes occurred in sTfR levels at all
lated inulin–iron complex formed with succinic anhy- measurement intervals in both groups; sTfR levels were
dride and a thiolated inulin–iron complex formed using a normal at week 12. A correlation between sTfR concen-
reaction with cysteine. The iron source was ferric trations was found with other iron-related indices
chloride, a more bioavailable iron form. Iron release sampled, but ZPP was the best indicator. Another
studies were conducted with both complexes simulating beneficial finding regarding the response to iron supple-
intestinal condition; iron was released from the com- mentation was that the sTfR–F ratios decreased more
plexes at a rate of 60–70%. They concluded that the significantly during iron therapy.
delivery of iron into the intestinal tract using an inulin–
ferric chloride iron complex might be superior to the When refractory IDA is nonresponsive to oral iron
commonly used ferrous form. therapy, H. pylori infection and chronic gastritis are often
to blame [41–45]. Chen and Luo [46
] evaluated the
effects of H. pylori therapy on erythrocytic and iron
Table 3 Common oral iron preparations
parameters in H. pylori gastritis patients with IDA.
Iron salt Elemental Typical dosage Elemental iron/
iron (%) (mg) dose (mg)
Patients received ferrous succinate and treatment for
H. pylori or only the iron supplement. Changes in Hb,
Ferrous sulfate 20 325, t.i.d. 65 MCH, serum iron and serum ferritin were compared
Ferrous sulfate 30 200, t.i.d. 65
exsiccated between groups. Ferrous succinate (200 mg) and ascorbic
Ferrous gluconate 12 325, t.i.d. 36 acid (100 mg) was administered three times per day.
Ferrous fumarate 33 325, b.i.d. 106 Treatment for H. pylori included three medications:
b.i.d., twice daily; t.i.d., three times daily. deuteron–bismuth citrate, amoxicillin and metronidazole

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 126 Nutrition

for 2 weeks. After H. pylori was eradicated, Hb, serum assessing the effects of this iron preparation on Hb
iron and serum ferritin values significantly increased to increase, iron status and its safety and tolerability in
normal. The eradication of H. pylori is warranted to mothers and breast-fed infants. Patients received either
maximize oral iron therapy in the recovery from IDA. i.v.-FeCarb (maximum dose of 1000 mg over 15 min) or
oral ferrous sulfate (100 mg twice a day for 12 weeks).
The primary endpoint to assess efficacy was evaluating
Parenteral iron therapy the change in Hb, serum ferritin and transferrin satur-
Parenteral iron therapy is necessary for patients intolerant ation levels from baseline to week 12. The Hb values in
or unresponsive to oral iron supplementation [1

]. Histori- both groups increased over the 12 weeks. The mean
cally, parenteral iron therapy has been used with caution increase in the i.v.-FeCarb patients was 13.04 g/dl com-
because of its anaphylactic potential. Despite the intro- pared with 12.89 g/dl in the ferrous sulfate group,
duction of newer intravenous (i.v.) iron preparations with although not statistically significant. In contrast, the
improved safety profiles, practitioners seem hesitant to change from baseline for serum ferritin levels was sig-
administer i.v. iron [47
]. Four parenteral iron preparations nificant in the i.v.-FeCarb compared with the ferrous
are available (Table 4). Two are iron dextrans that differ in sulfate group. Transferrin saturation increased in both
molecular weight and the other two preparations are iron groups with maximum mean values reached at week 4,
salt preparations, ferric gluconate and iron sucrose. An yet response rates (RR) for serum ferritin and transferrin
investigational i.v. iron preparation, ferric carboxymaltose saturation were significantly higher in the i.v.-FeCarb
complex (i.v.-FeCarb), is a nondextran-containing i.v. iron group. Both treatment courses were well tolerated and
only approved for use outside the USA. treatment was not associated with any safety concerns.
Breast milk iron content was significantly higher in
mothers receiving the FeCarb at 48 h. Both parenteral
Parenteral iron versus oral iron therapy FeCarb and oral ferrous sulfate treatment were effective
Van Wyck et al. [48

] compared the use of i.v.-FeCarb with in treating postpartum anemia; the increases in Hb,
oral iron in the treatment of anemic postpartum women. serum ferritin and transferrin saturation were significantly
Patients were stratified by Hb levels, need for cesarean higher in the i.v.-FeCarb group at all time points. The
section, transferrin saturation more than 20% and serum rapid replacement in iron stores after i.v.-FeCarb was an
ferritin values at least 50 ng/ml and randomized to receive advantage as the oral iron therapy did not replenish iron
i.v.-FeCarb, 1000 mg or less over 15 min, weekly until iron stores. Although these findings are promising, we are
replacement was complete, or oral ferrous sulfate, 325 mg reminded that i.v.-FeCarb US Food and Drug Adminis-
(65 mg elemental iron) three times a day, 1 h prior to meals tration (FDA) approval is pending in the USA.
for 42 days. The efficacy endpoint was the proportion of
patients that achieved an Hb increase of at least 2 g/dl after
treatment. Adherence to prescribed therapy was greatest Parenteral iron sucrose
among the i.v.-FeCarb group, and the median time to Intravenous iron sucrose is approved to treat anemia
achieve the endpoint was shorter than the oral iron group (7 related to chronic kidney failure (CKF). However, mini-
vs. 14 days). The proportion of patients who experienced mal data exist on using i.v. iron sucrose infusions in
correction of anemia was higher in the i.v. iron group. patients without CKF. Wall and Pauly [50
] attempted
Serum ferritin and transferrin saturation increased signifi- to determine the efficacy and safety of an i.v. iron sucrose
cantly in the i.v.-FeCarb compared with the oral iron group protocol for patients with IDA not related to erythropoie-
after 1 week. No serious adverse events occurred, yet tin therapy, blood product usage, oral iron supplement-
gastrointestinal complaints were reported in 20% of ation or CKF. Iron necessary for repletion was calculated
patients receiving oral iron. Early intervention with iron and the dose was divided into portions (250 mg, maxi-
therapy was well tolerated, and regardless of the admin- mum of 500 mg) and administered every other day until
istration route improved the health-related quality of life total dose was given. They measured Hb levels as the
(QoL) in women with postpartum anemia. efficacy outcome on days 1, 10, 21 and after last infusion;
and collected transferrin saturation and serum ferritin
Breymann et al. [49

] also compared i.v.-FeCarb to oral between days 10 and 14. Day 13 mean Hb levels after
ferrous sulfate in the treatment of postpartum IDA by last infusion increased (11  1.2 mg/dl) compared with

Table 4 Parenteral iron preparations

Low-molecular-weight High-molecular-weight
iron dextran Iron sucrose Ferric gluconate iron dextran

Test dose required Yes No No Yes

Iron per vial (mg/ml) 50 20 12.5 50
Molecular weight (Da) 165 000 34–60 000 289–440 000 265 000

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 Iron deficiency anemia: diagnosis and management Clark 127

baseline Hb levels (9.45  0.8 mg/dl). Mean transferrin

Conclusion
saturation levels improved from less than 11% to more
In 2008, the prevalence of IDA still remains the most
than 20% but data existed for only three patients.
common nutritional deficiency throughout the world that
Although no adverse events were reported after infusion,
negatively impacts on health and development. We must
definitive efficacy outcomes were lacking in the majority
move beyond current ideology, and learn how to better
of patients.
assess those populations at risk for the development of
iron deficiency regardless of concurrent medical con-
ditions. Evidence-based practice guidelines need to
Management strategies: a simple or
include diagnostic measures that identify changes in iron
sophisticated algorithm
The ultimate goal in anemia management is to maintain status early to avoid progression to IDA, and specific
management goals that include treatment strategies
safety, correct anemia, maintain iron status parameters or
including what constitutes a favorable response to iron
all within recommended limits and improve patient QoL
therapy along with timelines for treatment.
and survival. To help achieve these goals, practitioners
must move beyond the current treatment philosophy and
implement a strategy with a more balanced, systematic References and recommended reading
approach that is applicable in diverse settings. Concrete Papers of particular interest, published within the annual period of review, have
been highlighted as:
clinical practice guidelines for diagnosis and treatment of
of special interest
IDA in at risk populations still lack uniformity partly

of outstanding interest
because of the increasing prevalence of multiple comor- Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 168–169).
bidities among anemic patients. Updated practice stan-
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depletion will ultimately prevent progression to IDA. of iron deficiency in ACD.

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 128 Nutrition

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