The primary focus of this article will be to evaluate specific diagnostic criteria for iron deficiency anemia (IDA) and describe management strategies to correct IDA. Approaches for differentiating IDA from the anemia of chronic disease (ACD) will only be discussed within the context of identifying IDA. Nevertheless, a working consensus on a pragmatic approach to diagnosis and treatment despite the prevalence of this condition remains paramount.
IDA is the most common nutritional deficiency around the globe, yet universal standards of practice guidelines for diagnostic and treatment modalities are riddled with inconsistencies and disagreements among practitioners. A recent review article [1••] presents evidence-based data on the incidence of IDA associated with a myriad of diseases and medical conditions that complicate the diagnosis of true IDA. It also describes the diverse causes of IDA, diagnostic parameters and management strategies. Table 1 summarizes the physiologic and pathologic causes of IDA, and Table 2 delineates diagnostic tests. There is no sole, reliable biochemical indicator that is consistently diagnostic of iron deficiency except the ‘gold standard’, bone marrow iron aspirates. As iron status changes are sequential, we need to move beyond the current philosophy using a single assay to diagnose IDA but rather take an intentional approach that involves the systematic assessment of the underlying cause and use of multiple parameters.
Diagnostic indicators of iron deficiency anemia
Intuitively, combining several iron status indicators provides the best assessment of iron status. Evaluation of multiple indicators such as soluble transferrin receptors (sTfRs), sTfR–ferritin index (sTfR–F), zinc protoporphyrin/heme ratio (ZPP/H), reticulocyte hemoglobin (Hb) content (CHr) and selective endoscopy will provide better diagnosis and treatment iron status to prevent IDA.
Serum transferrin receptor and serum transferrin receptor log/ferritin index
sTfR reflects erythropoiesis and inversely the amount of iron available for erythropoiesis. Values of sTfR are elevated in IDA due to the upregulation of synthesis of transferrin receptors on the erythrocytes so the cells can compete for iron more efficiently. Unlike serum ferritin, sTfR concentrations are not affected by the presence of inflammation . The ratio between sTfR and serum ferritin concentrations, or sTfR–F index, is also considered a good indicator for evaluation of iron deficiency.
sTfRs can contribute significantly to the detection of IDA; however, some claim it to be not any better than serum ferritin [3–7]. Yang et al. [8•] compared the plasma ferritin concentrations alone with the sTfR–F ratio in infants, school-aged children and pregnant women measuring plasma ferritin, sTfR and C-reactive protein (CRP). They concluded that iron status can be effectively measured using plasma ferritin concentrations alone, provided a biomarker such as CRP is also measured to avoid falsely elevated plasma ferritin secondary to concurrent inflammation.
Chang et al.[9•] compared the utility of serum sTfR levels to bone marrow iron stores in identifying IDA. Bone marrow aspirates were performed in adult patients and hematologic assays: sTfR, serum ferritin, Hb, mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC). Cutoff values consistent with previous studies [10,11] that were used to exclude iron deficiency included ferritin values of at least 100 mcg/l and an sTfR/log ferritin ratio of more than 2.5. Elevated sTfR levels were found to be the most sensitive marker for the detection of absent bone marrow iron (100%), whereas the sTfR–F ratio of more than 2.5 had a lower sensitivity (50%). sTfR–F did have better sensitivity and specificity compared with the serum sTfR value alone when differentiating between IDA from ACD, which has been previously reported [2,10–13].
Goyal et al. [14•] evaluated sTfR–F indices to determine 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 pure ACD (20%). They also determined that sTfR–F index values of less than 2.2 mg/l excludes IDA, whereas values of more than 2.9 mg/l confirmed IDA. A similar study [15•] compared the utility of serum ferritin, serum iron and bone marrow iron stores in diagnosing iron deficiency in RA outpatients. On the basis of the bone marrow iron stores, 36% of patients had IDA and 64% exhibited ACD. Correlation between the serum ferritin and the bone marrow iron stores was poor in the IDA group yet significant in the ACD group. Negative predictive values were highest when cutoff values for serum ferritin were less than 82 mcg/l in contrast to other studies’ cutoff values of 30–70 μg/l [16,17].
Zinc protoporphyrin/heme ratio
Evaluation of iron status using the ZPP/H is another diagnostic indicator of IDA diagnostic of early iron depletion . The ZPP/H ratio reflects iron status in the bone marrow during the formation of Hb . When iron supply is diminished, Zn utilization increases resulting in a high ZPP/H ratio. Das and Philip [20•] compared the utility of ZPP/H ratio as a diagnostic measure of IDA with bone marrow iron store aspirates. In tandem with Hb and red blood cell indices, ZPP was reliable in reflecting the bone marrow iron status except in the prelatent phase of iron deficiency; however, it lacked the ability to distinguish between ACD and IDA. Using ZPP/H ratio to determine iron stores is preferential over the invasiveness of bone marrow aspiration. Others have reported that the ZPP/H ratio increase also compares favorably with serum ferritin concentration decrease, MCV and Hb levels in diagnosing IDA and preanemic iron depletion [19,21]. As zinc is also influenced by inflammation, ZPP interpretation can be challenging [22,23].
Reticulocyte hemoglobin content
CHr assesses the amount of Hb in reticulocytes [24–27]. Measurement of CHr provides a snapshot of iron immediately available for erythropoiesis over the previous 3–4 days, making it functional as an early indicator of iron stores. Blood CHr has been found to be comparable to the traditional parameters for iron deficiency (serum iron, serum ferritin and Hb) for confirming the diagnosis of iron-deficient states [25–27,28•]. Blood CHr has also been identified as an early indicator of the response to parenteral iron therapy, increasing within 2–4 days if sequential measurements are observed [28•].
Diagnostic endoscopic procedures
Current recommendations for adults with unexplained IDA include endoscopy. Capruso et al.  identified risk factors that would predict the presence of abnormalities in patients with IDA that would indicate whether colonoscopy or esophagogastroduodenoscopy (EGD) should be performed first. Serum ferritin, routine blood counts and fecal occult blood test (FOBT) were measured. Endoscopic findings revealed at least one likely cause for unexplained IDA in 86.7% of patients; causes included: bleeding, colon cancer, peptic ulcer, nonbleeding related, atrophic gastritis, Helicobacter pylori and celiac disease. Significant risk factors identified were older age (>50 years), lower MCV and male sex. They concluded that a diagnostic endoscopy in patients with IDA should be based on age with colonoscopy performed first in older patients (>50 years of age) with low MCV and Hb below 12 g/dl, and EGD with biopsy should be done first in younger patients with unexplained IDA. However, the disproportion of women (76%) to men calls into question the conclusions drawn.
Vannella et al. [30•] also evaluated the cause of unexplained IDA in premenopausal women between the ages of 20 and 56 years using endoscopy. IDA was defined as Hb below 12 g/dl with serum ferritin less than 30 μg/dl, and iron deficiency as serum ferritin less than 30 μg/dl. All patients underwent a gastroscopy including biopsies and FOBTs. Patients (≥50 years of age), with positive FOBT or positive family history for colonic cancer were invited to undergo a colonoscopy. Endoscopic evaluation revealed a likely cause of IDA in 68.5% of patients. The cause was due to iron malabsorption in 65.2% of patients, secondary to H. pylori pangastritis, celiac disease and atrophic gastritis. Only 3.7% of iron deficiency anemic patients exhibited bleeding lesions, whereas 67.4% were diagnosed with menorrhagia. This study produced a high diagnostic yield for the cause of IDA.
Another study by Ioannou et al. [31•] identified diagnostic tests and clinical features that were predictive for endoscopic evaluation in patients with anemia (<13 g/dl women, <12 g/dl men) using serum ferritin (<45 ng/dl) and transferrin saturation (<15%) as outcome measures. Anemia was found in 35.4% of the 1798 hospitalized patients; 74% were men, 26% women, mean age is equal to 62 years, 51% white and 49% nonwhite. Those diagnosed with IDA, 39% had either low serum ferritin or low transferrin saturation and underwent endoscopic evaluation. The only significant predictor for endoscopic evaluation was a positive FOBT.
Newer diagnostic biomarkers: hepcidin
Hepcidin is considered a key regulator of iron metabolism; it regulates iron concentrations and tissue iron distribution via inhibition of intestinal iron absorption, iron reclamation by macrophages and iron mobilization from hepatic stores . Its production is decreased in IDA and increased during inflammation and iron overloading. The overproduction of hepcidin during an acute phase response results in reduced iron absorption, mobilization, or both, contributing to the disease of anemia.
Kemna et al. [33••] developed the algorithm [transferrin saturation (%) − sTfR (mg/l) + CRP (mg/l) = hepcidin] to predict hepcidin levels. A strong correlation between the predicted hepcidin values and the actual measured hepcidin levels was found. Despite the selected parameters used in this algorithm, each has shortcomings; the lab indices are readily available and less expensive than serum hepcidin. Hepcidin levels have the potential to improve accuracy when differentiating between IDA and ACD.
Management of iron deficiency anemia
The treatment modalities for managing IDA will depend on the underlying cause. Once the cause of IDA has been ascertained, either oral or parenteral iron therapy is commonly prescribed to correct the deficiency.
Oral iron therapy
Oral iron therapy is usually adequate for most patients; it 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 treat IDA because it is better absorbed by the gastrointestinal tract and causes fewer side effects (heartburn, abdominal pain, nausea, diarrhea and constipation). When complexes or chelated forms of iron are used the gastrointestinal symptoms are minimal.
Oral iron therapy using iron complexes-chelates
Pitarresi et al. [34•] described the utility of an inulin–iron complex. Inulin is a naturally occurring fructose polymer with fermentation products that enhance iron absorption within the colon. Two derivatives were used, a carboxylated inulin–iron complex formed with succinic anhydride and a thiolated inulin–iron complex formed using a reaction with cysteine. The iron source was ferric chloride, a more bioavailable iron form. Iron release studies were conducted with both complexes simulating intestinal condition; iron was released from the complexes at a rate of 60–70%. They concluded that the delivery of iron into the intestinal tract using an inulin–ferric chloride iron complex might be superior to the commonly used ferrous form.
Mimura et al. [35••] compared the use of another iron complex, ferrous glycinate chelate to ferrous sulfate for the treatment of IDA in postgastrectomized patients. Standard indices were determined (Hb, MCH, MCHC, serum iron, serum ferritin, transferrin and transferrin saturation) and an EGD. Patients received either 400 mg/day ferrous sulfate or 250 mg/day ferrous glycinate chelate. After 2 months, transferrin levels were significantly decreased in patients receiving ferrous sulfate. Results favored ferrous sulfate as more effective in improving iron status over ferrous glycinate chelate, contrary to previous studies [36–38]. Some of the unfavorable results observed were attributed to decreased iron absorption in patients with alkaline gastritis. Another contributing factor could have been presence of H. pylori 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]. Identifying the presence of H. pylori or alkaline gastritis was not verified in this current study.
Response to oral iron therapy
The treatment of IDA should include a strategy for measuring response to iron therapy. Historically, a 2 g/dl improvement in Hb levels has been considered an appropriate response to iron supplementation; yet, other 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 IDA or iron deficiency erythropoiesis (IDE). Iron status was assessed in women (18–45 years) using the serum ferritin, ZPP and Hb levels at weeks 0, 3, 6 and 12. The IDE and IDA group received ferrous L-threonate supplements for 12 weeks (14 and 28 mg/day, respectively). Significant changes occurred in sTfR levels at all measurement intervals in both groups; sTfR levels were normal at week 12. A correlation between sTfR concentrations was found with other iron-related indices sampled, but ZPP was the best indicator. Another beneficial finding regarding the response to iron supplementation was that the sTfR–F ratios decreased more significantly during iron therapy.
When refractory IDA is nonresponsive to oral iron 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 parameters in H. pylori gastritis patients with IDA. Patients received ferrous succinate and treatment for H. pylori or only the iron supplement. Changes in Hb, MCH, serum iron and serum ferritin were compared between groups. Ferrous succinate (200 mg) and ascorbic acid (100 mg) was administered three times per day. Treatment for H. pylori included three medications: deuteron–bismuth citrate, amoxicillin and metronidazole for 2 weeks. After H. pylori was eradicated, Hb, serum iron and serum ferritin values significantly increased to normal. The eradication of H. pylori is warranted to maximize oral iron therapy in the recovery from IDA.
Parenteral iron therapy
Parenteral iron therapy is necessary for patients intolerant or unresponsive to oral iron supplementation [1••]. Historically, parenteral iron therapy has been used with caution because of its anaphylactic potential. Despite the introduction of newer intravenous (i.v.) iron preparations with improved safety profiles, practitioners seem hesitant to administer i.v. iron [47•]. Four parenteral iron preparations are available (Table 4). Two are iron dextrans that differ in molecular weight and the other two preparations are iron salt preparations, ferric gluconate and iron sucrose. An investigational i.v. iron preparation, ferric carboxymaltose complex (i.v.-FeCarb), is a nondextran-containing i.v. iron only approved for use outside the USA.
Parenteral iron versus oral iron therapy
Van Wyck et al. [48••] compared the use of i.v.-FeCarb with oral iron in the treatment of anemic postpartum women. Patients were stratified by Hb levels, need for cesarean section, transferrin saturation more than 20% and serum ferritin values at least 50 ng/ml and randomized to receive i.v.-FeCarb, 1000 mg or less over 15 min, weekly until iron replacement was complete, or oral ferrous sulfate, 325 mg (65 mg elemental iron) three times a day, 1 h prior to meals 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 among the i.v.-FeCarb group, and the median time to achieve the endpoint was shorter than the oral iron group (7 vs. 14 days). The proportion of patients who experienced correction of anemia was higher in the i.v. iron group. Serum ferritin and transferrin saturation increased significantly in the i.v.-FeCarb compared with the oral iron group after 1 week. No serious adverse events occurred, yet gastrointestinal complaints were reported in 20% of patients receiving oral iron. Early intervention with iron therapy was well tolerated, and regardless of the administration route improved the health-related quality of life (QoL) in women with postpartum anemia.
Breymann et al. [49••] also compared i.v.-FeCarb to oral ferrous sulfate in the treatment of postpartum IDA by assessing the effects of this iron preparation on Hb increase, iron status and its safety and tolerability in mothers and breast-fed infants. Patients received either 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 the change in Hb, serum ferritin and transferrin saturation levels from baseline to week 12. The Hb values in both groups increased over the 12 weeks. The mean increase in the i.v.-FeCarb patients was 13.04 g/dl compared with 12.89 g/dl in the ferrous sulfate group, although not statistically significant. In contrast, the change from baseline for serum ferritin levels was significant in the i.v.-FeCarb compared with the ferrous sulfate group. Transferrin saturation increased in both groups with maximum mean values reached at week 4, yet response rates (RR) for serum ferritin and transferrin saturation were significantly higher in the i.v.-FeCarb group. Both treatment courses were well tolerated and 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 FeCarb and oral ferrous sulfate treatment were effective in treating postpartum anemia; the increases in Hb, serum ferritin and transferrin saturation were significantly higher in the i.v.-FeCarb group at all time points. The rapid replacement in iron stores after i.v.-FeCarb was an advantage as the oral iron therapy did not replenish iron stores. Although these findings are promising, we are reminded that i.v.-FeCarb US Food and Drug Administration (FDA) approval is pending in the USA.
Parenteral iron sucrose
Intravenous iron sucrose is approved to treat anemia related to chronic kidney failure (CKF). However, minimal data exist on using i.v. iron sucrose infusions in patients without CKF. Wall and Pauly [50•] attempted to determine the efficacy and safety of an i.v. iron sucrose protocol for patients with IDA not related to erythropoietin therapy, blood product usage, oral iron supplementation or CKF. Iron necessary for repletion was calculated and the dose was divided into portions (250 mg, maximum of 500 mg) and administered every other day until total dose was given. They measured Hb levels as the efficacy outcome on days 1, 10, 21 and after last infusion; and collected transferrin saturation and serum ferritin between days 10 and 14. Day 13 mean Hb levels after last infusion increased (11 ± 1.2 mg/dl) compared with baseline Hb levels (9.45 ± 0.8 mg/dl). Mean transferrin saturation levels improved from less than 11% to more than 20% but data existed for only three patients. Although no adverse events were reported after infusion, definitive efficacy outcomes were lacking in the majority of patients.
Management strategies: a simple or sophisticated algorithm
The ultimate goal in anemia management is to maintain safety, correct anemia, maintain iron status parameters or all within recommended limits and improve patient QoL and survival. To help achieve these goals, practitioners must move beyond the current treatment philosophy and implement a strategy with a more balanced, systematic approach that is applicable in diverse settings. Concrete clinical practice guidelines for diagnosis and treatment of IDA in at risk populations still lack uniformity partly because of the increasing prevalence of multiple comorbidities among anemic patients. Updated practice standards need to include specific recommendations for diagnosis that also includes management strategies based on the known risks or causes of IDA.
Gasche et al. [51••] used a systematic approach to develop such guidelines for diagnosis and management of iron deficiency and IDA in patients with inflammatory bowel disease (IBD). A panel of gastroenterologists evaluated the literature and addressed: anemia evaluation (definition of anemia, screening parameters, anemia workup, iron deficiency and ACD), triggers for treatment of anemia (initiation of therapy, initiation of iron supplementation, initiation of erythropoietic therapy, initiation of vitamin supplementation and blood transfusions), targets of iron therapy (treatment goals, response to treatment and treatment evaluation), and treatment of anemia (iron supplementation, erythropoietic agents and adjustment of IBD therapy. This article describes recommendations regarding diagnostic tools to screen for IDA; it identifies the triggers for medical intervention, treatment goals and treatment modalities. It could serve as a model for a universal practice guideline in which updated diagnostic and management algorithms are presented . Establishing the cause as the first step in an algorithm would be pivotal to the remaining components of the algorithm such as key parameters with quantified reference limits, follow-up assays such as sTfR, sTfR–/F index, ZPP/H, testing for H. pylori, recommendations for endoscopy and intervention modalities inclusive of expected response rates [30•,53–55]. A more definitive algorithm would also include assessment of chronic inflammation measuring CRP, hepcidin or the possibility of using the predictive formula for hepcidin. Incorporating more diagnostic components into existing algorithms that evaluate early iron depletion will ultimately prevent progression to IDA.
In 2008, the prevalence of IDA still remains the most common nutritional deficiency throughout the world that negatively impacts on health and development. We must move beyond current ideology, and learn how to better assess those populations at risk for the development of iron deficiency regardless of concurrent medical conditions. Evidence-based practice guidelines need to include diagnostic measures that identify changes in iron status early to avoid progression to IDA, and specific management goals that include treatment strategies including what constitutes a favorable response to iron therapy along with timelines for treatment.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 168–169).
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