Compendium of the most significant studies with reference to properties, intake, effects.

Girelli, D., Marchi, G., & Camaschella, C. (2018). Anemia in the elderly. HemaSphere, 2(3).

Abstract. Anemia affects a substantial fraction of the elderly population, representing a public health problem that is predicted to further increase in coming years because of the demographic drive. Being typically mild, it is falsely perceived as a minor problem, particularly in the elderly with multimorbidity, so that it often remains unrecognized and untreated. Indeed, mounting evidence indicates that anemia in the elderly (AE) is independently associated with disability and other major negative outcomes, including mortality. AE is generally multifactorial, but initial studies suggested that etiology remains unexplained in near one-third of cases. This proportion is consistently declining due to recent advances highlighting the role of several conditions including clonal hematopoiesis, “inflammaging,” correctable androgen deficiency in men, and under-recognized iron deficiency. Starting from a real-world case vignette illustrating a paradigmatic example of anemia in an elderly patient with multimorbidity, we review the main clinical and pathophysiological aspect of AE, giving some practical insights into how to manage similar cases.

Cullis JO, Fitzsimons EJ, Griffiths WJ, Tsochatzis E, Thomas DW; British Society for Haematology. Investigation and management of a raised serum ferritin. Br J Haematol. 2018 May;181(3):331-340. doi: 10.1111/bjh.15166.

Abstract. Serum ferritin level is one of the most commonly requested investigations in both primary and secondary care. Whilst low serum ferritin levels invariably indicate reduced iron stores, raised serum ferritin levels can be due to multiple different aetiologies, including iron overload, inflammation, liver or renal disease, malignancy, and the recently described metabolic syndrome. A key test in the further investigation of an unexpected raised serum ferritin is the serum transferrin saturation. This guideline reviews the investigation and management of a raised serum ferritin level. The investigation and management of genetic haemochromatosis is not dealt with however and is the subject of a separate guideline.

Hurrell R, Ranum P, de Pee S, Biebinger R, Hulthen L, Johnson Q, Lynch S. Revised recommendations for iron fortification of wheat flour and an evaluation of the expected impact of current national wheat flour fortification programs. Food Nutr Bull. 2010 Mar;31(1 Suppl):S7-21. doi: 10.1177/15648265100311S102. 

Abstract. Background: Iron fortification of wheat flour is widely used as a strategy to combat iron deficiency. Objective: To review recent efficacy studies and update the guidelines for the iron fortification of wheat flour. Methods: Efficacy studies with a variety of iron-fortified foods were reviewed to determine the minimum daily amounts of additional iron that have been shown to meaningfully improve iron status in children, adolescents, and women of reproductive age. Recommendations were computed by determining the fortification levels needed to provide these additional quantities of iron each day in three different wheat flour consumption patterns. Current wheat flour iron fortification programs in 78 countries were evaluated. Results: When average daily consumption of low-extraction (< or = 0.8% ash) wheat flour is 150 to 300 g, it is recommended to add 20 ppm iron as NaFeEDTA, or 30 ppm as dried ferrous sulfate or ferrous fumarate. If sensory changes or cost limits the use of these compounds, electrolytic iron at 60 ppm is the second choice. Corresponding fortification levels were calculated for wheat flour intakes of < 150 g/day and > 300 g/day. Electrolytic iron is not recommended for flour intakes of < 150 g/day. Encapsulated ferrous sulfate or fumarate can be added at the same concentrations as the non-encapsulated compounds. For high-extraction wheat flour (> 0.8% ash), NaFeEDTA is the only iron compound recommended. Only nine national programs (Argentina, Chile, Egypt, Iran, Jordan, Lebanon, Syria, Turkmenistan, and Uruguay) were judged likely to have a significant positive impact on iron status if coverage is optimized. Most countries use non-recommended, low-bioavailability, atomized, reduced or hydrogen-reduced iron powders. Conclusion: Most current iron fortification programs are likely to be ineffective. Legislation needs updating in many countries so that flour is fortified with adequate levels of the recommended iron compounds.

Wang X, Dong H, Zeng Q, Xia Q, Zhang L, Zhou Z. Reduced Iron-Containing Clay Minerals as Antibacterial Agents. Environ Sci Technol. 2017 Jul 5;51(13):7639-7647. doi: 10.1021/acs.est.7b00726. 

Abstract. Previous work documented the general antibacterial mechanism of iron containing clays that involved hydroxyl radical (•OH) production from soluble Fe2+, and attack of cell membrane and intracellular proteins. Here we explore the role of clay structural Fe(II) in •OH production at near neutral pH and identify a lipid involved in the antibacterial process. Structural Fe(III) in nontronite NAu-2 was reduced (rNAu-2) and E. coli, a model bacterium, was exposed to rNAu-2 in oxic suspension. The antibacterial activity of rNAu-2 was dependent on pH and Fe(II) concentration, where E. coli were completely killed at pH 6, but survived at pH 7 and 8. In the presence of a •OH scavenger or in anaerobic atmosphere, E. coli survived better, suggesting that cell death may be caused by •OH generated from oxidation of structural Fe(II) in rNAu-2. In-situ imaging revealed damage of a membrane lipid, cardiolipin, in the polar region of E. coli cells, where reactive oxygen species and redox-active labile Fe were enriched. Our results advance the previous antibacterial model by demonstrating that the structural Fe(II) is the primary source of •OH, which damages cardiolipin, triggers the influx of soluble Fe2+ into the cell, and ultimately leads to cell death.

Schümann K, Elsenhans B, Mäurer A. Iron supplementation. J Trace Elem Med Biol. 1998 Nov;12(3):129-40. doi: 10.1016/S0946-672X(98)80001-1. 

Abstract. Iron deficiency affects approx. 20% of the world population. Due to predominantly vegetarian diets that reduce the bioavailability of food iron drastically, deficiency states are most widely distributed in developing countries. In addition, iron demand is increased by blood losses and by fast growth which increases the risk of iron deficiency in infants, young adolescents, and in menstruating and pregnant women. The symptoms of iron deficiency include impaired physical and intellectual performance. Iron supplementation may help to break the vicious cycle between inadequate nutrition and poverty. Fortification programs have to consider social and health aspects, including provision against iron overload. Excess iron stores may promote cancer and increase the cardiovascular risk, though the latter is a subject of current debate. The best approach to control such risks is individual iron supplementation geared to the demand by adequate laboratory controls. However, this approach is too costly for general application in developing countries. Food-iron fortification has successfully reduced iron deficiency in many trials and, in comparison, is much cheaper. As iron deficiency is widely distributed in most developing countries, the risk of inducing iron overload in the general population is low. Genetically determined diseases that may lead to siderosis, such as hereditary haemochromatosis or thalassaemia major, show a limited geographic and ethnic distribution. Such subgroups can be largely avoided by targeting food-iron fortification to infants, young adolescents, or pregnant women. Food vehicle and iron compound have to be matched in order to optimise iron bioavailability and to avoid rancidity in food, spoiling its taste and odour. The fortification of salt, sugar and spice mixtures or of bakery products with a short shelf-life are valid approaches to this end. Alternatively, haem iron can be used to fortify cereal-based food staples in developing countries such as tortillas or chappaties. Thus, a variety of options is available to solve the technical problems of food iron fortification. However, optimal solutions have to be tailored to the individual situation in each country.

He WL, Feng Y, Li XL, Yang XE. Comparison of iron uptake from reduced iron powder and FeSO4 using the Caco-2 cell model: effects of ascorbic acid, phytic acid, and pH. J Agric Food Chem. 2008 Apr 23;56(8):2637-42. doi: 10.1021/jf0730946. 

Abstract. The reduced iron powder has considerable potential for use as an iron fortificant because it does not change organoleptically during storage or food preparation for cereal flour, and its bioavailability is scarcely influenced by iron absorption inhibitors in foods. The objective of this article is to study the effects of ascorbic acid, phytic acid, and pH on iron uptake from reduced iron powder (43 microm) and FeSO 4, and to compare iron bioavailability of reduced iron powders among four selected granularity levels. The cell ferritin formation is used as a marker of iron uptake. Obviously, iron uptake of reduced iron powder is increased with decreasing of powder granularity and is much lower than FeSO 4 when the size is above 43 microm, but significantly higher at 40-60 nm. In the presence of ascorbic acid or phytic acid, Caco-2 cell iron absorption from reduced iron powder (43 microm) is significantly higher than that from FeSO 4. And iron uptake of Caco-2 cells is decreased with increasing of pH from 5.5 to 7.5. Moreover, the decrease trend is more obvious for reduced iron powder than for FeSO 4. Our results indicated that iron bioavailability of reduced iron powder by intestinal enterocytes is similar to that of iron salts, and reduced iron powder is more excellent than FeSO 4 as food fortificant, especially at ultramicroscopic granularity.

Walter, T., Pizarro, F., Boy, E., & Abrams, S. A. (2004). The poor bioavailability of elemental iron in corn masa flour is not affected by disodium EDTA. The Journal of nutrition, 134(2), 380-383.

Abstract. The most sustainable way to eradicate iron deficiency is through food fortification. Elemental iron powders are commonly utilized as fortificants due to their low cost and few sensory problems. However, their bioavailability is unknown. Our goals were to measure the bioavailability of elemental iron in Mexican style corn masa flour tortillas and to evaluate the effects of Na2EDTA. We used a stable isotope of H2-reduced iron powder, with and without Na2EDTA in tortillas prepared with corn masa flour. Two groups of 5- to 7-y-old children (n = 12/group) were fed tortillas to which was added 3 mg/100 g of H2-reduced 58Fe with a mean particle size of 15 μm. In one group, Na2EDTA was incorporated at a ratio of 1:2 mol/mol. The next day, 57Fe ascorbate was given as a reference dose. After 14 d, blood samples were analyzed for isotopic enrichment. When normalized to 40% absorption of the reference dose, the geometric mean (±range 1 SD) bioavailability of reduced iron in tortilla was 3.8% (2.7–5.3). The addition of Na2EDTA, tended to increase it (P = 0.18) to 5.1% (2.8–9.2). This observed low absorption was compounded by the use of iron isotopes with smaller particle size (mean diameter 15 μm) than typical of commercial elemental iron powder (<45 μm). We conclude that H2-reduced iron powder is an ineffective fortificant in corn tortillas.