iron deficiencies and iron deficiency (IDA) is a significant health issues in the world particularly in young women. Supplementing with iron is an effective method to prevent and treat IDA However, guidelines differ. Some experts recommend dosages of 150-200 mg iron daily and the dosage is divided over the course of the days. Recent studies suggest that this is not an ideal regimen. The proportion of iron that is that is absorbed by high doses of oral iron is small and iron that is not absorbed can cause intestinal irritation, inflammation and dysbiosis. All of these can reduce the compliance. Recent studies using serum Hepcidin profile and isotopes of stable iron for quantifying the absorption of iron among young women and men, we have discovered that (a) doses of iron in the oral cavity more than 60 mg in women who are iron deficient and doses of >100 mg for women suffering from IDA cause an immediate increase in hepcidin which lasts for 24 hours after the dose, however it decreases after 48 hours; (b) therefore, to increase the efficiency of fractional iron absorption oral doses of greater than 60 mg should be administered every day; (c) the increase that occurs during the day in plasma hepcidin levels is amplified with a morning dose of iron and therefore iron doses should not be administered at night or in the afternoon following a morning dose. If Hb’s response rate is crucial, a pooled analysis of the data we collected for this review has shown that the absorption of total iron is higher when double the daily dose of iron is administered every day. In sum the studies suggest that shifting between alternate-day and daily schedules and switching from morning to divided one dose increase iron absorption, and could reduce the risk of adverse reactions. So, giving daily doses of 60 to 120 mg iron in ferrous salts with ascorbic acid on alternate days might be the ideal oral dose regimen for women suffering from iron deficiency or mild IDA.
The estimated incidence of anemia impacts about one-third of the world’s population, with about 50% of cases stemming due to the deficiency of iron which means that more than 1.2 billion people have iron anemia due to iron deficiencies (IDA) ( Camaschella, 2019,). In the world, IDA is 1 of the top five causes of disability and is the leading cause for women ( Camaschella, 2019). Even though oral iron supplementation is often considered to be the initial method of treating iron deficiency among females ( Brittenham, 2018) There is a lack of consensus regarding the dosage recommended or frequency of dose.
The choice of iron compound
Iron supplements available on the market differ in terms of dosage, compound cost, and bioavailability. Bioavailability for supplements with iron is the percentage of iron in the oral supplement that is absorbed by the body and incorporated into the erythrocytes ( WHO, 2006; BNF, 2017). The terms ‘bioavailability and absorption’ are frequently used interchangeably and we’ll use each in our review. The ferrous form is the most preferred version due to its superior biological permeability ( Table 1). ( Brittenham, 2018; WHO, 2006; BNF, 2017) Commonly used ferrous iron compounds are ferrous fumarate and ferrous sulfate ferrous sulfate and ferrous gluconate and ferrous gluconate, and the amino acid ferrous bisglycinate, a chelate. The biological activity of iron-based compounds from ferrous is comparable ( WHO, 2006; BNF, 2017) and their adverse effects and ability to regenerate hemoglobin (Hb) are similar, provided that enough iron is available ( BNF, 2017). But, they differ in the amount of iron they contain. So, the choice of ferrous iron salts is typically determined by the amount of iron that is present and its cost.
Table 1. Iron content and bioavailability relative (RBV) (RBV) in ferrous sulfurate, a common ingredient in orally administered iron supplements.
Iron saltElemental iron content (%)RBV to ferrous Sulfate (%)
Ferrous sulfate 20 Reference
Ferrous sulfate (dried) 32.5 100
Ferrous fumarate 33 100
Ferrous gluconate 12 89
Amino acid chelates (e.g. ferrous biglycinate) 20 100
Carbonyl iron 99 5-20
Sugars (saccharides) typically contain ferric iron. Variable Variable
It is important to note that bioavailability estimates for iron compounds come mainly from comparisons of their low doses in food fortificants instead of as supplements. ( WHO, 2006) Bioavailability studies of iron fortificants are not fully relevant to oral iron supplements.
Ferric iron is very insufficiency solubility in alkaline or near neutral pH. It must be reduced into ferrous iron prior for uptake into enterocytes ( Sangkhae and Nemeth Sangkhae and Nemeth, 2017,). The iron bioavailability of ferric iron preparations is generally about 3-4 times less than the ferrous sulfate ( Brittenham, 2018; WHO, 2006; BNF, 2017; Santiago, 2012). In addition, when compared with ferrous iron, ferrous iron is more effective at the replenishment of Hb in patients suffering from IDA ( Berber and colleagues. 2013). Carbonyl iron is efficient at higher dosages ( Gordeuk et al. 1987) However, it is not absorbed by H-reduced as well as carbonyl iron (two forms of iron that are elemental) is not high which is why their usage is not advised. A variety of ferric iron-polysaccharide polysaccharide complexe offered and they are advertised as having a better flavor and less adverse side effects, however there isn’t a solid evidence to support the assertions. In a clinical trial with patients suffering from inflammatory bowel disease ferric maltol proved to be effective in treating IDA ( Gasche et and. 2015). A different study showed that supplementation with ferrous sulfate improved Hb levels more effectively than iron polysaccharide complex which was also found to be more effective, as were the instances of diarrhea associated due to the latter compound ( Powers et al. 2017).
A lot of multivitamin and mineral preparations contain iron in low amounts that are insufficient to address the deficiency in iron and could contain different mineral substances (such such as zinc) that can interfere the process of the absorption of iron ( Olivares et al.. 2012). Some oral iron preparations contain ascorbic acid, which is a potent enhancer of iron absorption (Teucher et al., 2004) and prebiotic galacto-oligosaccharides given with ferrous fumarate can increase iron absorption (Paganini et al., 2017). However, there isn’t any convincing evidence that the addition in other nutrients including vitamin A, B-vitamins, or vitamin B which improves the bioavailability of iron ( BNF, 2017). Antacids and proton pump inhibitors should not take alongside iron, as an increase in acidity of the stomach lowers the rate of dissolution and absorption. Slow-release or controlled-release formulations of iron offer no benefits for patients, they are generally ineffective and are not recommended for use. They can cause less stomach negative effects but this is most likely due to the fact that the majority of the iron is carried over the distal duodenum (where the majority of iron is absorption) into the distal stomach in which absorption is low ( UpToDate, 2020).
Influence of food factors on bioavailability
Oral iron should usually be consumed on an empty stomach at least an hour prior to meals, since a lot of beverages and foods contain inhibitors for the absorption of iron. The amount of iron absorbed from supplements ranges between 2% to 13% when consumed in conjunction with food, and 5% to 28 percent when consumed during when fasting ( Cook, 2005). For women who are not anemic, the mean absorption of iron from 50 mg of iron intake during not fasting, was 10% but it was 33% when consumed in conjunction in conjunction with foods ( Cook and Reddy 1995). Iron released from supplements may form complexes that are not absorbable with a variety of food ingredients in the gut lumen. For instance the whole grain and pulses in particular are abundant in phytic acid which is a potent inhibiter of the absorption process even at very low concentrations (a Molar ratio for phytate to iron greater than) ( Lynch et al. 2018, 2018). Black tea, coffee herb teas and red wine, and hot chocolate are all rich in polyphenols, that can also hinder iron absorption ( Lynch et al. 2018). Consuming food or drinks with a high content of ascorbic acid and iron oralally will dramatically increase absorption. ascorbic acid exhibits an effect of enhancing dose-dependent iron absorption when the 2:1 ratio (e.g. 60 mg of ascorbic acid versus 10 mg iron) ( Teucher et al. (2004)). The enhancement occurs by the reduction in luminal ferrous iron from ferrous as well as due to the potential of it to chelate iron and prevent its binding from phytates and polyphenols ( Teucher et al. (2004); Siegenberg et and. 1990). For the majority of women, iron supplements taken with empty stomachs can trigger nausea and epigastric pain ( Tolkien et al. (2015)). If this happens, supplements may be taken along with meals, which could minimize side effects, but could decrease absorption. When supplements are taken in conjunction in conjunction with meals, including drink or food item along with the meal that is rich in ascorbic acid (e.g. an US cup (240 milliliters) from orange juice usually has 100 mg) can counteract the effects of food-related inhibitors and permit iron supplements to be fully absorbed ( Lynch et al. in 2018,).
Iron-related side effects that can be a result of oral supplements
An analysis of a recent meta-analysis twenty trials found an increased risk of digestive side effects when compared to placebo when ferrous sulfate orally was administered (OR 2.32, 95% CI 1.74-3.08 2.32, 95 percent range of 1.74-3.08, p 0.0001) ( Tolkien and co. 2015). Iron in equal doses as ferrous sulfurate, ferrous fumarate or ferrous gluconate for healthy adults did not result in significant differences in the severity of side consequences ( Hallberg et al. 1996). The most frequent adverse reactions include nausea, epigastric pain constipation, and epigastric pain. These decrease the effectiveness of treatment in 30 to 70 percent of patients ( Tolkien et al. 2015). It is not clear if iron-related side effects are dose dependent and if they are dose-dependent. However, side effects can be less frequent when iron doses are less than 20 mg per day ( Tolkien et al. in 2015.). Another study suggests that oral doses 50 mg or less iron/day produce fewer adverse consequences as compared to higher dosages. ( Pena-Rosas and Viteri, 2006). The absorption of fractional iron is greater when iron is consumed in lower amounts than larger doses, resulting in less iron unabsorbed within the intestinal lumen ( Moretti et al. 2015; Stoffel et and. 2017.a.). Iron that is not absorbed can cause intestinal inflammation and dysbiosis and increase the development of enteropathogens ( Paganini and Zimmermann in Zimmermann and Paganini,). Numerous studies have suggested that the use of intermittent doses results in less adverse gastrointestinal adverse effects than daily dosing ( Pena-Rosas et al. (2015)).
The most reputable guidelines for the use of oral iron supplements
Iron supplements taken orally are considered to be the as the first line treatment option for deficiency in iron and IDA for females ( Camaschella, 2015) however, guidelines differ. The standard daily dosage is 100-200 mg of iron daily, which is administered in three or four equal amounts of ferrous sodium. e.g. three-quarters of a ferrous sulfate tablets contains 65 mg of iron elemental 3 tablets daily will give 195 mg iron ( Brittenham, 2018). Expert groups generally recommend between 80 and 200 mg of iron in the form of elemental supplements per day for the treatment of iron deficiency as well as IDA (Goddard and colleagues. 2011, Gastroenterological Society of Australia, 2015; Pavord et al. 2012) however, recent guidelines suggest that lower doses are as efficient and can cause lesser adverse reactions (Camaschella 2019; UpToDate, 2010) For instance the most recent British guidelines recommend 40 to 80 mg of iron in the morning, as a ferrous iron salt (Pavord 2020). Women in reproductive age in countries with low incomes are more at risk of IDA which is why it is recommended that the World Health Organization (WHO) provides guidelines for the population-based iron dose schedules to avoid anemia in women having menstrual cycles in situations where the prevalence of anemia is at or above 20% ( WHO, 2011) or 40% or greater ( Table 2) ( WHO, 2016). WHO also suggests intermittent iron supplementation for women in their teens in situations where daily supplementation may be ineffective or unattainable ( Fernandez-Gaxiola and De-Regil in 2019,). A systematic review has concluded that, compared to the daily dose intermittent supplementation can provide similar benefits to anemia but could also have lower negative side negative effects ( Fernandez-Gaxiola and De-Regil 2019,). Hb typically responds quickly to a successful oral iron therapy, and an increase in Hb of 2 g/dL or more after three weeks of treatment indicates sufficient treatment reaction ( Brittenham, 2018). However, the repletion of the iron storage and normalization ferritin levels in serum ferritin might require up to 4-6 months to treat ( Brittenham, 2018).
Table 2. WHO recommendations for iron supplementation for women who menstruate and adolescents.
Preventing iron deficiency anemia in women who menstruate by taking daily or weekly iron supplementation
Frequency One supplement per week One supplement daily
Supplement Iron: 60 mg elemental iron
Folic acid 2800 mg 30-60 mg of iron in the form of elemental iron
Duration Three months of supplements and followed by a period of 3 months without supplementation, after which the supply of supplements must be reintroduced. Three consecutive months within the course of a year
Settings Populations where the incidence of anemia among women in reproductive age is at least 20% In the case where the incidence of anemia among menstruating females and adolescents is 40% or more
60 mg of iron elemental is equivalent to 300 mg FeSO 4, Heptahydrate, 150 mg FeFum, or 500 mg ferrous the gluconate. Revisions to WHO Guidelines for 2011 ( WHO, 2011) and 2016 ( WHO, 2016).
The’mucosal block’ as well as intermittent iron dosing versus daily
In 1943, a study on absorption in dogs demonstrated a decrease in iron absorption after iron was administered after the previous iron dose ( Hahn et al. 1943) and the idea of the “mucosal block” was born. The subsequent studies confirmed the blockade effect of high doses of iron in affecting iron absorption following a dosage ( Fairweather-Tait and Wright 1984; Fairweather-Tait et and. 1985). The daily administration of large doses of iron to rats with iron sufficiency resulted in a decrease of iron absorption. However, iron doses administered every 3rd day produced a steady iron absorption ( Viteri et al. 1995). In a radioiron research study on humans, the absorption of iron from a pre-specified 50 mg dose of iron was evaluated to that of one one-time dose or administered after adult recipients had received 50 mg iron per day for six days ( Cook and Reddy 1995). Iron absorption total was 9.8 percent for the single dose (50 mg) in comparison to 8.5 percent for 6 dosages (300 mg) that were administered over a period of six consecutive weeks ( Cook and Reddy 1995). Similar research compared absorption of 60 mg iron given prior to and following daily intake of 60 mg iron for six days. The preceding intake of iron did not influence iron absorption ( Olivares et al. 1999). Furthermore, comparing the average iron absorption from the administration of 240 mg iron in four successive daily dosages of 60 mg with the average iron absorption from 240 mg of iron taken with doses of 120 mg each week revealed no significant differences in absorption rates: 7.7 percent for daily, and 10.9 percent in weekly doses ( Olivares et al. 1999). So, while animal studies have suggested a blocking the effect of an earlier iron dose in the absorption process of the next dose however, human studies have revealed inconsistent outcomes ( Hallberg, 1998).
Circulating hepcidin predicts iron bioavailability
A key determinant of iron supplement absorption will be the state of iron within the person. In order to ensure the iron balance the absorption of iron is controlled within a range of iron intakes from food and the requirements for iron ( Cook, 1990). The most important regulation of the iron balance in the body is Hepcidin. When iron deficiency is present, iron stores are depleted, and the hepatic BMP SMAD pathways that enhances hepcidin’s expression is shut down by a variety of mechanism ( Sangkhae and Nemeth 2017.). Therefore, the circulating levels of hepcidin drop, ferroportin and the divalent metal transporter (DMT)-1 are both expressed in full on enterocytes and intestinal iron absorption is increased ( Sangkhae and Nemeth 2017.). In women in their early years, serum hepcidin and absorption of an iron intake are in negative correlation ( Young et al. 2009.). In young males, plasma hepcidin is a predictor of 36percent of variance in iron absorption according to a multi-regression model ( Roe et al. 2009). In women in their early years plasma hepcidin was a less reliable indicator of the iron bioavailability in food which accounted for 28 percent of the variation of the absorption of iron ( Zimmermann et al. 2009.).
Together with hepcidin local regulation of enterocytes also is a major factor in the absorption of iron. Intestinal hypoxia-inducible factors (HIF)-2a can be sensitive to oxygen and iron levels and regulates the apical and Basolateral Iron transporters ( Schwartz et al. in the year 2019). In enterocytes, the increased HIF-2a’s stability and activity contributes to the adaptive rise in iron absorption that occurs during iron deficiency under supervision of hepcidin/ferroportin-axis ( Schwartz et al. 2019.).
Iron intakes from the mouth acutely raise the plasma the hepcidin
Plasma Hepcidin does not only react to changes in the body’s iron stores, but its synthesis is also stimulated by high doses orally administered iron ( Zimmermann et al. 2009; Nemeth et al. 2004). In hepatocytes from murine there was a rise in the mRNA of hepcidin in response to the holo-transferrin (TF) but not the apo-TF. TF was found to regulate hepcidin by the BMP2/6-dependent HJV process ( Lin et al. 2007,). This suggests that the sudden rise in iron bound to TF after an iron dosage taken orally enhances the expression of hepcidin through the BMP-SMAD pathways ( Sangkhae and Nemeth, 2017). In adults, urinary Hepcidin excretion increased in the 24 hours after a dose of iron and was inversely proportional to maximum the saturation in transferrin that reflects the absorption of iron ( Nemeth et al. 2004,; Lin et al., 2007). For iron-deficient men in the study, a 60 mg dose of iron increased circulating iron absorption after 2 hours and resulted in an increase of 30% in the mean plasma hepcidin level after 6 hours; a 3.8 milligram dose of iron did not cause an increase in the amount of hepcidin ( Zimmermann et al. Zimmermann et al.,). Plasma hepcidin has an acyclical rhythm that typically rises throughout the course of the day ( Kroot et al. in 2009; Schaap et al.. (2013)). The question of whether a morning dose of iron will enhance this circadian increase, and if this could impact the iron absorption in the afternoon or the morning dose is unknown. To address this issue, and to develop a schedule of supplementation that could maximize the amount of iron absorbed by fractions We conducted various studies on young women. The studies assessed the hepcidin levels after various doses of ferrous sulfurate, which were identified using stable ferrous isotopes. This allowed us to determine the effects variations in hepcidin concentrations to iron bioavailability, by testing the erythrocyte incorporation to the labels after 14 days of the dose, as explained in the following section.
By analyzing hepcidin profiles as well as iron stable isotopes, we can determine the ideal iron dosing regimens
In the first study we looked into the extent to which the acute increase in iron in hepcidin affects the absorption in the course of daily iron doses and twice daily iron intakes ( Moretti et al. 2015.). Three separate studies were conducted in order to measure the rise in hepcidin due to ferrous sulfate supplementation while assessing the iron absorption. We enlisted 54 healthy females in their teens (median (IQR) time study 27 (23-32) years study 2 23 (21-25) years Study 3 22 (21-25) years) with ferritin in plasma 20 mg/L or less. In all studies, the subjects were used as their own control. In these and the ones below the 8.00 a.m. tests were taken following having a fast for the night. We measured plasma hepcidin as well as iron status markers prior to administering and up to 48 hours after administration between 8.00 a.m., 12.00 p.m. in addition to 5.00 p.m. In the study 1 employing an inverse design we administered two iron challenges in either a one-time dose or in two doses over consecutive days. Subjects were randomly assigned begin the study with either of the treatment options. Iron was given on the same day at 8.00 a.m. with four different concentrations of iron (40 80, 160 and 240 mg as the elemental Fe). In the second study in which we administered two amounts of 60 mg elemental iron around 8:45 a.m. over two consecutive days. We also evaluated the hepcidin response up to 48 hours after administration. In the studies one and two, after 24 hours after administration of doses greater than 60 mg, hepcidin levels were increased (p less than 0.01) and the fractional iron absorption reduced by 35%-45 percent (p less than 0.01) (Fig. 1A and B). As the dose increased of iron, fractional absorption declined however absolute absorption increased 6 times the iron dosage (40-240 mg) was only a threefold increase in iron absorption (6.7-18.1 mg) (Fig. 1C). In the study 3 we examined the effects on the body of 60 mg Fe twice a day over 24 hours (three doses total) on iron and hepcidin absorption. The amount of iron absorption through three dosages (two in the mornings, between 10.00 a.m. as well as one afternoon at 5.00 p.m. afternoon time of 5.00 p.m.) did not appear to be significantly higher than the iron absorbed from two doses in the morning (Fig. 2). In conclusion the short-term results suggested that, in order to maximize the absorption of fractions: (A) oral iron in doses greater than 60 mg should be separated by 48 h (B) dosing should be spread over 48 h; and (B) daily dosing twice is not recommended.