1. Definition

Iron (Fe) is a biochemical microelement important for the health of the population and Fe is necessary for the fetus and all stages of growth individuals. Fe is an essential mineral necessary for delivering oxygen to tissue throughout the body as well as serving important roles in metabolism, respiration, and immune function. Many of functional forms of Fe are essential in processes that affect health such as: oxygen (O₂) supply by hemoglobin (Hb); O₂ storage by myoglobin (Mb); O₂ utilization by cytochrome. Hb synthesis requires an adequate supply of Fe and intact metabolic pathways for the production of heme and globin molecules. The body maintains stores of Fe and carefully sustains a balance between Fe lost, Fe absorbed, and Fe stored. A spectrum ranging from an asymptomatic drop in Fe stores to marked fatigue with depletion of Fe stores and Fe deficiency anemia may occur^[1][2][3][4] [1-4].

Fe is the most abundant trace mineral involved in cell metabolism and the growth of organisms. A smaller fraction (2%) localized in some proteins containing heme and Fe is present as Fe-sulfur (S) groups that contribute to physiological systems such as oxygen (O₂) transport, DNA synthesis, metabolic energy, cellular respiration and electron transport in mitochondria. Approximately 30% and 10% of body Fe is stored as ferritin (Ft) and hemosiderin in the liver, bone marrow, and muscle. In addition, Fe can be used in erythropoiesis according to the demands of the body^[1] [1].

2. Introduction or History

The first step in therapy of iron deficiency (ID) is the correction of the nutritional iron intake. The uptake of heme Fe is much better than the uptake of free Fe. For the latter, uptake of Fe2+ is better than uptake of Fe3+^[5]. In diet, the bioavailability of Fe is very variable and depends much on actual iron stores, ranging from 5 to 15%. with respect to ID, a significant increase in iron bioavailability up to 35% can be observed. Furthermore, iron uptake in the intestinal tract is influenced by different nutritional factors including enhancers and inhibitors. Substances enhancing iron uptake are vitamin C, peptides from partially digested muscle tissue, fermented food, organic acids such as malate or citrate. Substances inhibiting iron uptake are phytates, oxalates, polyphenols (black tea and coffee), peptides from partially digested vegetable proteins and calcium^[6][7].

The Recommended Daily Allowance (RDA), which was 15 mg/day for women and 10 mg/day for men, as the definition of sufficient dietary iron intake. The estimated average requirement (EAR) is the appropriate standard to evaluate nutrients intakes of groups. However, the EAR for physically active healthy individuals may be increased by 30%–70%^[8] because all etiological factors we have reported in another section of this manuscript. A diet of approximately 2500 kcal is suitable for physically active people who would provide 2.3mg Fe/day, this is general recommendations for an optimal dietary Fe intake in sports include an adequate energy intake, especially for athletes with low body mass index as they suffer more frequently from ID^[9].

However, on many occasions the diet is not sufficient and supplementation is necessary. The decisions regarding Fe supplementation are best made on the basis of taking care of personalized care based on the needs of individuals. Thus there are sufficient arguments to support controlled Fe supplementation in all individuals with low serum ferritin levels. Firstly, the development of ID is prevented. Secondly, the nonspecific upregulation of intestinal metal ion absorption is reverted to normal, thus limiting the hyperabsorption of potentially toxic lead and cadmium even in individuals with mild ID or iron deficiency anemia (IDA)^[10] [10].

3. Benefits of Oral Iron Supplementation

The pharmaceutical oral forms of Fe preparations are non-heme (iron salts) and heme (higher bioavailability). Oral supplements with ferrous salts (sulfate, fumarate, and gluconate) are better absorbed (10–15% bioavailability) than ferric salts of Fe complexes that are administered together with amino acids, polysaccharides, and proteins such as ovalbumin. However, high adverse gastrointestinal effects such as constipation, nausea, vomiting, diarrhea, and dark stools have been reported for ferrous Fe salts^[9][11].

The amount of elemental Fe that is available to be absorbed into the body varies depending on the iron salt. Thus, the amount of elemental Fe is 20% for ferrous sulfate (FeSO₄), 33% for ferrous fumarate, and 12% for ferrous gluconate. We must consider that if 100 mg of FeSO₄ is equivalent to 20 mg of elemental Fe, this is approximately the RDA (18 mg/day)^[4][12].

It has described that 50% of patients supplemented with oral Fe have gastrointestinal adverse effects induced by the direct toxicity of ionic Fe due to its caustic action on the intestinal mucosa^[12]. It should also have considered that the excess of Fe, due to the abuse of supplements, makes it difficult for the organism to get rid of Fe micronutrients caused by Ft saturation. The excess of Fe is stored in the form of hemosiderin, which causes hemosiderosis (deposits of Fe in the liver or spleen) and hemochromatosis (deposits of Fe in body tissues)^[1]. As a consequence of these adverse reactions, there is a reduction in tolerance and adherence to the traditional treatment with oral Fe salts^[13].

Furthermore, heme Fe supplements have a lower incidence than non-heme Fe, which could be through different routes in the absorption mechanism. Non-heme Fe by the action of stomach hydrochloric acid passes into its reduced form, Fe²⁺, which is the soluble chemical form capable of passing through the membrane of the intestinal mucosa. Although Fe can be absorbed throughout the entire intestine, its absorption is most efficient in the duodenum and the upper part of the jejunum. The intestinal mucous membrane has the facility to trap the Fe and allow its passage inside the cell, due to the existence of a specific receptor in the layer of the edge in the brush. The apotransferrin of the cytosol contributes to increasing the speed and efficiency of Fe absorption. This type of heme Fe crosses the cell membrane as an intact metalloporphyrin, once the endo-luminal or enterocyte membrane proteases hydrolyze the globin. The products of this degradation are essential for the maintenance of heme in a soluble state, thereby ensuring its availability for absorption^[14].

Generally, 100–200 mg taken once or twice a day is prescribed, which is a high dose of elemental Fe^[15]. The adverse reactions can be minor when a lower, more frequent, dose is dispensed. In this sense, one possibility is to use 100 mg of FeSO₄ taken as 50 mg twice per day [13]. A daily dose of between 50 mg/day and 150 mg/day 1 may be adequate for non-anemic athletes. However, Villanueva et al.^[13] used very high doses of up to 300 mg/day in bleeding patients with severe ID anemia. We have reported^[4] that oral supplementation with 325 mg/day of ferrous sulfate as 105 mg/day of elemental Fe for 11 weeks does not modify Fe reserves and increases the strength of elite volleyball players. In addition, Cordova et al.^[3] prevented the decrease of serum Fe, Ft, Hb and hematocrit, and improved recovery in elite cyclists during the Vuelta a España competition by administering 800 mg Fe protein succinate, which contained 80 mg/day Fe. In this sense, Nielsen et al.^[16] showed that a fasting dose of 100 mg/day Fe ferrous administered for 3 months or more is suitable for non-anemic athletes with low serum Ft or ID only and also in anemic athletes.

An effective treatment for ID is supplementation with a dose of 60–80 mg/day of elemental Fe for 12 weeks, in healthy persons^[16]. In this sense, the use of 80 mg/day of Fe achieved a decrease in fatigue in non-anemic menstruating women with low Ft^[17]. However, another author^[18] recommended an intake of heme Fe including meat, fish, legumes, and vegetables five times a week for healthy non-anaemic people with ID. Mielgo et al.^[19] reported that an intake of 25.8 mg/day of dietary Fe is not sufficient to prevent 30% of female volleyball players from suffering from pre-latent Fe deficit and 20% from latent (pre-anemia) deficit. However, this does not guarantee high levels of Fe. Therefore, these dietary recommendations were supplemented with 28 to 50 mg of elemental Fe daily with mild gastrointestinal adverse effects^[20].

4. Bioavailability of Dietary Iron

One strategy to counteract these adverse effects derived from supplementation and combat Fe ID is to improve the bioavailability of Fe. Bioavailability, defined as the efficiency with which Fe is obtained from the diet, is biologically used, and considered when it is necessary to enhance dietary intake^[21].

Some factors modulate the bioavailability of dietary Fe, such as the content of Fe-hemic and Fe-non-hemic in foods; the original state of Fe, considering that, in an oxidized state and at a pH > 4.0, it is exceedingly insoluble and scarcely absorbed; the metabolic demand of Fe; the substances present in the diet that can be promoters that stimulate the absorption (nutritional enhancers) or that block the absorption of Fe (dietary inhibitors); the interactions between Fe and the components of the digestive tract^[15]; the genetic endowment of the individual associated with the absorption of Fe, which determines the levels of Fe in serum and is determined by genes such as HFE, TMPRSS6, TFR2 and TF^[22] [22].

The bioavailability of Fe is also conditioned by some physiological factors such as body reserves of Fe, the speed of erythropoiesis, hypoxia, infections, and the mobilization of Fe and HAMP, which is a hepatic peptide intimately related to the homeostasis of this micronutrient^[1][23]. Thus, there are interactions between exercise-induced factors and the expression of HAMP in humans, which are directly related to an increase or decrease in the absorption and bioavailability of Fe. Factors that negatively regulate exercise-related HAMP levels include anemia, hypoxia that triggers erythropoietin (EPO) secretion, and hemolysis^[24]. On the other hand, inflammation, oxidative stress and interleukin-6 (IL-6) act by positively regulating the levels of HAMP^[25]. These factors are induced during exercise, causing an alarming increase in HAMP, mainly as an acute-phase inflammatory response. Therefore, the origin of a negative iron balance in athletes may be due to factors related to exercise (type, duration, and intensity) and HAMP status. All of these directly affect iron absorption and hematological parameters. HAMP expression decreases metal absorption, increases cytoplasmic concentrations of Fe-saturated Ft, and decreases transport to the blood vessels, whereby Fe accumulates in the enterocyte and is excreted within the desquamated epithelial cells from the intestine. On the other hand, unlike excesses of Fe, deficiencies of Fe, hypoxia, and states of increased erythropoiesis generate a decrease in the expression of HAMP, and therefore, these situations are directly related to an increase in the absorption and bioavailability of Fe^[23][25].

Some studies^{[26][27][28][29]} indicate that the concomitant use of vitamin C (ascorbic acid), vitamin A, vitamin E, vitamin B9 (folic acid), vitamin B12 (cobalamin) and vitamin D3 (cholecalciferol) increases the bioavailability and absorption of Fe in the intestinal tract. These absorption enhancers can be provided by diet or direct supplementation preparations. These compounds could lead to formulations of multi-components associated with Fe that would facilitate its absorption in the digestive tract^[29].

In this way, vitamin C is a promoter of the absorption of non-heme Fe. However, it does not affect heme Fe. Its effects are related to its reducing power, which blocks the synthesis of insoluble ferric hydroxide, and also its the capacity to synthesize soluble complexes with ferric ions, which maintains solubility at an alkaline pH in the duodenum. Similarly, other promoters, such as vitamins A and E, act in a similar pathway^[30].

Mielgo-Ayuso et al.^[28] described a positive relationship between 25(OH)D levels and levels of faith in the body in a group of elite athletes. This study reports that vitamin D3 stimulates erythropoiesis, probably because reticulocytes express receptors for the active form of vitamin D3 that would accelerate their proliferation and maturation into erythrocytes. Thus, supplementation with vitamin D3 would play a vital role in the prevention of ID and/or anemia.

The naive erythrocytes formed recently by erythropoiesis allow senior erythrocytes to be replaced daily by phagocytosis. Koury et at.^[8] described the critical role that Fe, folate, and vitamin B12 play in erythropoiesis. Folate and vitamin B12 stimulate erythrocyte ontogeny from the erythroblast stage. Thus, folate and vitamin B12 deficiency inhibit purine and thymidylate synthesis, impair DNA synthesis and cause erythroblast apoptosis, resulting in ineffective erythropoiesis. The consequences of which produce anemia.

It is necessary to consider in the supplementation that the pharmaceutical form of Fe administered has a decisive influence on bioavailability. Biopharmaceutical bioavailability includes the availability, absorption, retention, and use of Fe, and is the critical factor for Fe to be biologically productive^[31]. Fe preparations with higher bioavailability, which allow one to take lower absolute doses of Fe, may cause less gastrointestinal discomfort and be better tolerated by patients^[11][31]. One way to increase the bioavailability of Fe is through the use of absorption enhancers, which have significant repercussions in terms of the pharmacokinetics and pharmacodynamics of Fe supplements, improving the processes of release, absorption, metabolism, utilization, and excretion^[18].