Dietary Heme Iron: A Review of Efficacy, Safety and Tolerability

Abstract

Iron is a fundamental micronutrient essential for oxygen transport, enzymatic activity, and metabolic homeostasis. Yet it remains the most deficient nutrient in the world, with more than 2 billion people estimated with iron deficiency anemia. In the diet, animal foods provide iron primarily as heme iron. Dietary heme iron is absorbed through the active transport pathways catalyzed by heme oxygenase in the intestinal enterocyte. This form of heme differs in its bioavailability, absorption mechanisms, and tolerability compared to non-heme forms of iron, including iron salts and chelates. Adding more heme iron to a diet, including through iron supplements, may help to reduce the prevalence of iron deficiency. Future research should focus on research of heme iron supplementation strategies to enhance absorption efficiency, gut microbiome health, and safety, ensuring optimal iron status across diverse populations.

1. Introduction

Iron is an essential nutrient and a critical component of hemoglobin, necessary for various metabolic processes including oxygen transport, immunity, cell function, and gene expression [1,2,3]. Dietary iron requirements increase in response to factors such as body weight, muscle mass, blood loss, hypoxia, pregnancy, and periods of rapid growth [4].

Iron exists in two primary forms in the diet: heme iron, derived from animal sources such as meat and fish, and non-heme iron, predominantly found in plant-based foods and widely used in iron supplements [3]. These two forms exhibit distinct absorption mechanisms, with heme iron being more bioavailable and less influenced by dietary inhibitors than non-heme iron [2,3].

Iron deficiency (ID) and iron deficiency anemia (IDA) are widespread global health concerns and common conditions in clinical practice. ID is one of the most prevalent nutritional deficiencies globally, affecting approximately 27% of the world’s population [1,3,5,6,7]. Iron deficiency is typically identified through low serum ferritin (<30 ng/mL in men, <15 ng/mL in women) and transferrin saturation (Tsat < 20%), reflecting depleted iron stores without necessarily lowering hemoglobin levels [1,2]. Iron deficiency is associated with symptoms such as fatigue and shortness of breath, and if left untreated, may increase the risk of morbidity and mortality.
In contrast, IDA develops when prolonged iron depletion results in hemoglobin levels dropping below the diagnostic threshold, leading to impaired oxygen transport and anemia-related symptoms [3]. The World Health Organization (WHO) defines IDA as a hemoglobin (Hb) level below 13 g/dL in men and 12 g/dL in women, marking the transition from iron depletion to anemia. The highest rates of IDA are in women and children, where it contributes to the risk of low birth weight, pre-term delivery, and cognitive impairment in infants and children [3,8].

In the United States, IDA is a recognized public health concern, as highlighted by NHANES data from 2003 to 2012, which identified vulnerable subgroups including African Americans, Latin Americans, individuals over the age of 60, breastfed infants, vegetarians, pregnant women, and women of reproductive age [8,9]. An increase in mortality has mirrored the rise in iron deficiency in the U.S. Of food items in the USDA database with revised concentrations from 1999 to 2015, 62% reported lower concentrations of iron. During this time, dietary iron intake decreased by 7% and 10% for males and females in the U.S., respectively. Likewise, iron status markers were shown to decrease during this time [10].

Furthermore, recent findings indicate that approximately 30% of American children aged 1–2 years are classified as iron deficient [11]. If left untreated, IDA can progress to microcytic anemia, leading to quality-of-life symptoms such as fatigue, weakness, difficulty concentrating, depression, decreased productivity, and restless leg syndrome, as well as adverse pregnancy outcomes like low birth weight or pre-term delivery.

Iron insufficiency, which often precedes clinical deficiency, affects nearly half of the general American population, disrupting metabolic processes, increasing chronic disease risk, and negatively impacting overall quality of life and physical and mental performance [3,8,9]. Given its critical role in human metabolism and the widespread prevalence of deficiency, understanding dietary sources and supplementation options for iron is vital to addressing this public health challenge.

This review examines the role of heme iron supplements, emphasizing their differentiation from non-heme iron and the potential to address iron deficiency and insufficiency with improved efficacy and tolerability.

6. Innovations Beyond Non-Heme Iron Salts and Chelates

Non-heme iron salts and chelates were introduced in the early 20th century as food and supplement ingredients to address nutritional shortages during the war era, providing a mass-producible form of iron to meet regulatory, supply, and economic requirements [30]. Examples include ferrous gluconate, citrate, fumarate, and sulfate, which are synthesized through the purification of mined Earth minerals and processed using industrial techniques. Over the years, studies have documented both the benefits and limitations of these industrially produced iron salts and chelates.

Common ferrous and ferric iron salts include ferrous gluconate, citrate, and sulfate, with ferrous iron exhibiting higher bioavailability than ferric iron [8]. Among iron supplements, ferrous sulfate is the most widely used, providing 20% elemental iron [30,45]. Ferrous fumarate contains 33% elemental iron, while ferrous gluconate contains 12% elemental iron [30]. Both fumarate and gluconate release iron more slowly than ferrous sulfate [33]. Slow-release tablets, designed to reduce gastrointestinal side effects, improve tolerance through controlled release mechanisms achieved by polymeric matrices or tablet coatings [46]. However, their efficacy depends on gastric emptying, as incomplete dissolution of the tablet in the stomach reduces iron absorption [46].

Iron bisglycinate chelate provides improved bioavailability compared to ferrous salts by avoiding insoluble compound formation with dietary inhibitors like oxalates, phytates, and tannins [45]. This is due to its unique composition, wherein the ferrous cation is coupled with two glycine molecules [45]. Equal doses of iron bisglycinate are expected to yield more significant improvements in iron status compared to ferrous sulfate [45].
Non-heme iron absorption is influenced by numerous factors that impact real-life benefits. Some of these factors include the form of iron, the timing of administration, whether taken with food or an empty stomach, the composition and amount of food, whether taken with Vitamin C, etc. [1]. Additional individual variables—such as age, gender, menstrual cycle timing, health conditions, other nutrient deficiencies, nutrient interactions, and medications—further impact absorption [1]. These factors greatly complicate the accurate measurement of iron status, which remains the primary diagnostic tool for identifying iron deficiency or insufficiency [1].

The complex system of non-heme iron metabolism has been reviewed by others [43]. For non-heme iron, duodenal enterocytes absorb inorganic dietary iron via divalent metal transporter 1 (SLC11A2 or DMT1) after reduction by membrane-bound ferrireductases (DCYTB), the enzymes that reduce ferric iron to ferrous iron, often as a by-product of other pathways (Figure 1) [43]. The transport through DMT-1 is competitive with calcium, magnesium and other minerals in food. At maximum, daily absorbed iron, in the range of 1–3 mg, represents only a fraction of the total body iron. In all instances, iron must be replenished for all people daily, due to the recycling of heme from erythrocytes by reticuloendothelial macrophages, which provides the main fraction of circulating iron. Thus, while iron status is an important part of the iron nutrient picture, stored iron in the form of ferritin and hemoglobin provides a fuller picture compared to serum iron.

Iron salts and chelates pose significant limitations in addressing nutritional challenges due to their tendency to expose high concentrations of free iron in the gastrointestinal tract, which often remains unabsorbed. This results in ongoing concerns about the absorption, efficacy, and safety of these iron forms [45]. For instance, ferrous sulfate, one of the most commonly used iron supplements, provides 20% elemental iron but dissociates rapidly into free, unbound iron in the gut, which can exacerbate toxicity [30,45]. The absorption, distribution, metabolism, and excretion (ADME) characteristics of iron salts and chelates vary considerably. Some ferrous salts and chelates claim to offer a slower release compared to ferrous sulfate or ferric salts, theoretically reducing side effects associated with rapid dissociation. However, data on these claims remain mixed. “Slow-release” or gentler iron forms still demonstrate similar absorption rates, leading to adverse event rates between 20 and 30% [33]. Iron amino acid chelates, which hydrolyze faster and more extensively in the small intestine, present a greater magnitude of dissociation compared to heme iron [8].

Excess oral iron can lead to triggered hepcidin response, inflammation, and production of reactive oxygen species (ROS) in intestinal epithelial cells (Figure 4). These can trigger ferroptosis, apoptosis, and necrosis [6]. As the primary barrier to high iron concentrations, epithelial cells suffer damage when exposed to excess free iron, resulting in inflammation and oxidative stress [28]. Mitochondrial damage and endoplasmic reticulum dysfunction are also hallmarks of excess cellular iron [44]. Simultaneously, free iron can trigger the growth of intestinal pathogens, resulting in gastrointestinal symptoms and increased levels of intestinal inflammation. The easier dissociation of iron in the gut, especially under conditions of high concentration, significantly increases the likelihood of severe intestinal inflammation [28].

 

Iron amino acid chelates are believed to interact less with dietary inhibitors like oxalates, phytates, and tannins, though direct comparative evidence is limited [45]. Studies indicate that iron chelated to purified amino acids such as glycine may enhance absorption slightly compared to conventional iron salts. However, comparative analyses consistently show that equivalent doses of iron bisglycinate and ferrous sulfate produce comparable improvements in iron status [45].

9. Conclusions

Iron deficiency anemia (IDA) remains a pervasive global health challenge, affecting millions of individuals worldwide. Addressing this issue requires effective and sustainable solutions that balance efficacy, safety, and long-term feasibility. This review has highlighted the critical distinctions between heme and non-heme iron, emphasizing the superior bioavailability, tolerability, and sustainability of heme iron compared to its non-heme counterparts.

Heme iron’s efficient absorption mechanism, minimal interference from dietary inhibitors, and reduced gastrointestinal side effects make it an ideal candidate for addressing the limitations of traditional non-heme iron supplements. Incorporating heme iron into dietary strategies not only enhances overall iron uptake but also offers a safer alternative for populations vulnerable to the adverse effects of non-heme iron. Products like SalmoFer®, which utilize byproducts of the fish industry, underscore the potential of combining nutritional efficacy with environmental sustainability [11,19].

Despite these advantages, the broader dietary context in which heme iron is consumed, particularly through red and processed meats, presents challenges that require careful navigation. Red meat remains a potent source of bioavailable iron, yet its association with colorectal cancer and other chronic diseases necessitates the exploration of safer alternatives, from fish or poultry. Renewable produced alternatives provide an opportunity to mitigate health risks while meeting global iron demands [38,39].

Investigating the potential synergies between heme and non-heme iron in supplementation strategies could offer a balanced approach to improving iron bioavailability while reducing side effects. Additionally, exploring the impact of heme iron on gut microbiota, inflammation, and long-term health outcomes will strengthen its role in iron deficiency interventions [43]. Future research should prioritize refining heme iron supplements to enhance production consistency, optimize clinical efficacy, and expand accessibility to underserved populations.

In conclusion, balancing heme with non-heme iron in the diet is a science-based way to address iron insufficiency and deficiency in humans using diet and supplementation. Both heme and non-heme iron can play a pivotal role in addressing iron malnutrition globally.

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Kalman, D.; Hewlings, S.; Madelyn-Adjei, A.; Ebersole, B. Dietary Heme Iron: A Review of Efficacy, Safety and Tolerability. Nutrients 2025, 17, 2132. https://doi.org/10.3390/nu17132132