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Iron Deficiency Anemia in the 21st Century: Why is still too prevalent and what we can do as treatment?
Raúl H Morales-Borges1* and Roberto Román-Juliá2
1Department of Internal Medicine, Hematology & Oncology, San Juan Bautista School of Medicine, Puerto Rico, USA
2Department of Biology, National University College, Puerto Rico, USA

Anemia; Iron deficiency; Prevalence; Treatment; 21st century

Anemia due to iron deficiency anemia is the most common anemia in the world and 5% and 2% of American women and men, respectively, have it [1]. Iron deficiency anemia is a form of anemia due to the lack of sufficient iron to create healthy red blood cells. It is caused by inadequate intake of iron, chronic blood loss, or a combination of both. It is quite prevalent in the World for years. We have noticed an increased of patients with this diagnosis in the community based practice as well as in the academic practice. We want to make knowledgeable the importance of prevention, early diagnosis, and management of the anemia in the 21st century despite the advancements of the medicine in particularly using the integrative medicine approach.

Iron has been used by physicians to treat a variety of ills throughout history. According to Nicholas Monarde, a 16th century physician in Seville, the applications of iron as a medicine included in the treatment of diseases are Alopecia, Acne, Vaginal discharges, and Tuberculosis within others [2]. Iron plays a role in anemia and has been used by many physicians, although we can see iron deficiency without anemia. Chlorosis, sometimes known as the “green sickness,” is no longer diagnosed. Clinicians considered it the most common of maladies, and it characterized by a hypochromic anemia that responded to iron therapy; we must conclude that the primary pathogenesis was that of iron deficiency. Hippocrates, Lange, Whipple made history for years about this [2]. There has been greater consensus about the effect of iron deficiency without anemia on deficits and attention spans leading to learning and problem solving difficulties in children [3]. This is critical to let the physicians know about this.

Low iron bioavailability of the diet in developing countries, is the primary cause of iron deficiency anemia [4,5]; however, in advanced countries, decreased iron absorption and blood loss account for the more likely etiologies. Atrophic gastritis and malabsorption syndromes, especially celiac disease, are the responsible for reduced iron absorption [6]. Other causes are post surgical gastrectomy (partial or total), Bariatric Surgery, intra abdominal surgeries, and chronic blood loss from genitourinary, gynecological, or gastrointestinal tracts. Excessive menstruation is the most common etiology of iron deficiency anemia in premenopausal women [1]. It’s quite common seen in my practice. We see women aged from teens until 50’s with excessive regular or irregular menses running with anemia between 7 and 10gm/dL.

A global study [7] performed an evaluation of the change in micronutrient deficiency over time in the form of a composite indicator-the Hidden Hunger Index (HHI). They used an from the Nutrition Impact Model Study for anemia due to iron deficiency, vitamin A deficiency, and stunting (used as a proxy indicator for zinc deficiency). Africa was within the 20 global regions with the lowest HHI in 1995 but was also among the top 20 worst performers regarding a net change in HHI over the 16 year period studied. The reason is due to significant conflict and vulnerability to food insecurity due to climate changes. The impact of micronutrient deficiency holds representative and adverse consequences in the cognitive and physical development of the children as well as adverse effects on productivity and economic potential in later adulthood. So, nutritional deficiency as the cause of iron deficiency anemia is still a major public health issue linked to the socio economic status of the countries in this Century. We don’t see this only in children; we see the elderly population affected too. A study was done at United Kingdom [8] with adults aged 65 years and over revealed that that population’s life expectancy and health status is adversely affected due to nutritional deficiency anemia. The study encouraged to educate health care professionals as to what constitutes a healthy diet for the elderly population and gives practical guidance as to how to try and prevent the ever growing problem of malnutrition within this age group. Definitively, poor nutrition plays a significant role in the pathogenesis of iron deficiency anemia in the World no matter the age and the time.

Another study in Canada with the geriatric population [9] included all anemic patients over 60 years old who had erythropoietin measured between 2005 and 2013 at a single center. A total of 570 patients met the inclusion criteria. Linear regression analysis showed that erythropoietin levels in chronic kidney disease, anemia of chronic illness and anemia of unknown etiology were lower by 48%, 46%, and 27%, respectively, compared to iron deficiency anemia even after adjusting for hemoglobin and other comorbidities. They demonstrated that erythropoietin levels are inappropriately low in anemia of unknown etiology, even after adjusting for confounders. This statement suggests that decreased erythropoietin production may play a fundamental role in the pathogenesis of anemia of unknown etiology. It is imperative when we got that population with anemia to perform the appropiate blood levels of erythropoietin as well as the serum iron levels. It’s important to replace the iron storage if deficient before give epoetin alpha therapy to those patients because it won’t work too.

So, we usually give oral iron preparations and supplementations when we diagnosed iron deficiency anemia, but in many cases, they do not respond well, and we need to use parenteral iron such as iron dextran or iron sucrose. The first parenteral infusions caused severe acute reactions and were unsuitable for use [10]. The development of iron dextran in 1954 caused that IV iron is given more quickly, but severe acute reactions still occurred infrequently. In 1964, the first report of 37 patients receiving a total dose infusion (single replacement dose) published in Blood [11], with one delayed reaction consisting of fever and chills without hypotension or wheezing. It was, however, another 16 years before the findings of the first prospective study in 471 patients published in JAMA [12]. While all patients responded and none died, three developed signs of anaphylaxis, leading the investigators to conclude that IV iron should reserve for those clinical situations in which oral iron could not use.

A study of C.Wang et al., [13] stated that rates of adverse reactions are lower than others. Although other study populations might have contributed to the observed differences, other differences in identifying and reporting anaphylaxis cases during clinical trials and during general clinical practice might also be pertinent. Practicing physicians might not classify less severe or atypical anaphylactic cases as anaphylaxis; thus, the sensitivity of the anaphylaxis algorithm used in their study was probably small. Others did not recommend comparing the crude incidence rates of anaphylaxis from their study with rates of other medications, especially if the following estimates based on different data sources or research methods. Interestingly, 5 of 444 patients identified with anaphylaxis in the study died within two days of anaphylaxis diagnosis (2 in iron dextran group, 1 in iron gluconate group, and 2 in ferumoxytol group).

Few prospective studies report the safety, ease, convenience and efficacy of complete or near complete replacement doses of IV iron administered in a single setting (total dose infusion over 15-60 minutes) [14-17]. One study in chronic heart failure and iron deficiency anemia [18] demonstrated that another parenteral iron formulation such as ferric carboxymaltose IV is very effective compound for total dose single infusions causing better health related quality of life and fewer hospitalizations. For subjects who have losses and absorption problems, a total dose infusion is a more convenient and less expensive method of replacing iron than oral preparations. Compared to the side effects present in the majority of people taking oral preparations, such as constipation, metallic taste, gastric cramping and robust green tenacious stool, the adverse events with IV iron are minor, infrequent and short lasting. So, IV iron is consequently moving rapidly forward in the treatment paradigm in the last decade. Published evidence supports a larger and earlier role for parenteral iron and raises the question of whether it should be frontline therapy in many conditions. It is more important than ever that inferences and conclusions on the relative safety of the available IV iron formulations based on credible data. Based on all prospective and retrospective studies, when iron dextran is avoided the remaining formulations are safe, and probably much safer than most physicians realized.

  1. Johnson-Wimbley TD, Graham DY (2011) Diagnosis and management of iron deficiency anemia in the 21st century. Therap Adv Gastroenterol 4: 177-184.
  2. Beutler E (2002) History of Iron in Medicine. Blood Cells Mol Dis 29: 297-308.
  3. Cook JD, Lynch SR (1986) The liabilities of iron deficiency. Blood 68: 803-809.
  4. Berger J, Dillon JC (2002) Control of iron deficiency in developing countries. Sante 12: 22-30.
  5. Ramakrishnan U, Yip R (2002) Experiences and challenges in industrialized countries: control of iron deficiency in industrialized countries. J Nutr132: 820-824.
  6. Bermejo F, García-López S (2009) A guide to diagnosis of iron deficiency and iron deficiency anemia in digestive diseases. World J Gastroenterol 15: 4638-4643.
  7. Ruel-Bergron JC, Stevens GA, Sugimoto JD, Roos FF, Ezzati M, et al. (2015) Global Update and Trends of Hidden Hunger, 1995-2011: The Hidden Hunger Index. PLoS One 10: 0143497.
  8. Harris RJ (2004) Nutrition in the 21st century: what is going wrong. Arch Dis Child 892: 154-158.
  9. Gowanlock Z, Sriram S, Martin A, Xenocostas A, Lazo-Langner A, et al. (2016) Erythropoietin Levels in Elderly Patients with Anemia of Unknown Etiology. PLoS One 11: 0157279.
  10. Auerbach M, Macdougall IC (2014) Safety of intravenous iron formulations: facts and folklore. Blood Transfus 12: 296-300.
  11. Marchasin S, Wallerstein RO (1964) The treatment of iron deficiency anemia with intravenous iron dextran. Blood 23: 354-358.
  12. Hamstra R, Block M, Schocket AL (1980) Intravenous iron dextran in clinical medicine. JAMA 1726-1731.
  13. Wang C, Graham DJ, Kane RC, Xie D, Wernecke M, et al. (2015) Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products. JAMA 314: 2062-2068.
  14. Auerbach M, Pappadakis JA, Bahrain H, Auerbach SA, Ballard H, et al. (2011) Safety and efficacy of rapidly administered (one hour) one gram of low molecular weight iron dextran (INFeD) for the treatment of iron deficient anemia. Am J Hematol 86: 860-862.
  15. Auerbach M, Strauss W, Auerbach S, Rineer S, Bahrain H, et al. (2013) Safety and efficacy of total dose infusion of 1,020 mg of ferumoxytol administered over 15 min. Am J Hematol 88: 944-947.
  16. Quinibi W, Martinez C, Smith M, Benjamin J, Mangione A, et al. (2011) A randomized controlled trial comparing intravenous ferric carboxymaltose with oral iron for treatment of iron deficiency anaemia of non dialysis-dependent chronic kidney disease patients. Nephrol Dial Transplant 26: 1599-1607.
  17. Onken JE, Bregman DB, Harrington RA, Morris D, Acs P, et al. (2014) A multicenter, randomized, active controlled study to investigate the efficacy and safety of intravenous ferric carboxymaltose in patients with iron deficiency anemia. Transfusion 54: 306-315.
  18. Hofmarcher T, Borg S (2015) Cost effectiveness analysis of ferric carboxymaltose in iron deficienct patients with chronic heart failure in Sweden. J Med Econ 18: 492-501.


Figure 1: (a) Chemical structures of PAMPS48-PEG227-PAMPS48 (AEA) and PEG47-PMAPTACm (EMm, m = 27,53, and 106).
[M]0 and [M] represent the concentrations of the monomer at polymerization time = 0 and the corresponding time, respectively.

Figure 2: Time-conversion (?) and the first-order kinetic plots (?) for the polymerization of AMPS in the presence of CPD-PEG-CPD in water at 70oC.
[M]0 and [M] represent the concentrations of the monomer at polymerization time = 0 and the corresponding time, respectively.

Figure 3: GPC elution curves for a sample of HO-PEG-OH (Mn = 9.40 ? 103; Mw/Mn = 1.06) (----) and triblock copolymer of PAMPS48-PEG227-PAMPS48 (AEA, Mn = 2.32 × 104; Mw/Mn = 1.42) (--).
[M]0 and [M] represent the concentrations of the monomer at polymerization time = 0 and the corresponding time, respectively.

Figure 4: 1H NMR spectra for (a) EM53, (b) AEA, and (c) AEA/EM53 micelle in D2O containing 0.1 M NaCl at 20°C. Assignments are indicated for the resonance peaks.
[M]0 and [M] represent the concentrations of the monomer at polymerization time = 0 and the corresponding time, respectively.

Figure 5: (a) Light scattering intensities and (b) Rh for PIC micelles of AEA/EM106 (?), AEA/EM53 (?), and AEA/M27 (?) as a function of fAMPS (= [AMPS]/([AMPS] + [MAPTAC])) in 0.1 M NaCl aqueous solutions. [AMPS] and [MAPTAC] represent the concentrations of the AMPS and MAPTAC units, respectively. The total polymer concentration was kept constant at 1 g/L.
[M]0 and [M] represent the concentrations of the monomer at polymerization time = 0 and the corresponding time, respectively.

Figure 6: (a) Distributions of Rh for the PIC micelles of AEA/EM106 (?), AEA/EM53 (?), and AEA/EM27 (?) in 0.1 M NaCl aqueous solutions. (b) Relationship between relaxation rate (G) and square of the magnitude of the scattering vector (q2). (c) Plots of Rh as a function of Cp.
[M]0 and [M] represent the concentrations of the monomer at polymerization time = 0 and the corresponding time, respectively.

Figure 7: A typical example of Zimm plots for AEA/EM106 micelle in 0.1 M NaCl aqueous solution.
[M]0 and [M] represent the concentrations of the monomer at polymerization time = 0 and the corresponding time, respectively.

Figure 8: TEM images for (a) AEA/EM27, (b) AEA/EM53, and (c) AEA/EM106 micelles.
[M]0 and [M] represent the concentrations of the monomer at polymerization time = 0 and the corresponding time, respectively.

SamplesMn(theo)a × 10-4Mn(NMR)b ×10-4Mn(GPC)c ×10-4Mw/MncRhd (nm)?-potential (mV)
Table 1: Number-average Molecular weight (Mn), Molecular weight distribution (Mw/Mn), hydrodynamic radius (Rh), and ?-potential for the polymers.
aCalculated from Equation (2), bEstimated from 1H NMR, cEstimated from GPC, dEstimated from DLS.

PIC micelles Mwa × 10-5 Rga Rhb Rg/Rh Naggc dPICd


(nm) (nm)
AEA/EM27 8.48 15.1 15.2 0.99 50 0.096 -0.88
AEA/EM53 189 36.6 41.0 0.89 735 0.109 -0.53
AEA/EM106 111 28.6 32.4 0.88 302 0.129 -0.20
Table 2: Dynamic and static light scattering data for PIC micelles in 0.1 M NaCl.
aEstimated by SLS in 0.1 M NaCl, bEstimated by DLS in 0.1 M NaCl, cAggregation number of PIC micelles calculated from Mw(SLS) of PIC micelles determined by SLS and Mw of the corresponding unimers determined by 1H NR and GPC, dDensity calculated from Equation (3).

Citation: Morales-Borges RH, Román-Juliá R (2017) Iron Deficiency Anemia in the 21st Century: Why is still too prevalent and what we can do as treatment. J Hematol Blood Transfus Disord 4: 016