Introduction

Iron has an essential physiologic role, as it is involved in oxygen transportation and energy formation. The body cannot synthesize iron and must acquire it. Food is the only natural source of iron, and the mineral is ingestable in supplement form. Although the human body can recycle and reutilize this mineral, it loses some iron daily; these lost pools need replacement. Recycling the iron from senescent erythrocytes meets most of the body's iron needs by macrophages; only 5 to 10% of iron requirements come from food.[1]

The average iron content in a 70 kg male is about 3 grams. Of this amount, 65% is incorporated into the hemoglobin molecule in red blood cells, which serves a vital role in carrying oxygen from the lungs to tissue cells. Iron is also involved in energy production through its role in the electron transport chain (ETC). Several heme-containing molecules also called cytochromes, are directly involved in electron transport for ATP production by reducing iron in the heme from its ferric form (Fe3+) to its ferrous form (Fe2+) and vice versa. Additionally, by these same ionic properties of electron transfer, iron plays a crucial role as a cofactor for enzymes involved in oxidation-reduction reactions, such as those involved in synthesizing amino acids, neurotransmitters, collagen, and hormones. Considering these vital functions for iron, it becomes clear why maintaining physiologic stores and replenishing the daily losses in the iron cycle, mostly via dietary intake, is crucial for life and health.

Function

Before reviewing dietary iron and factors affecting its intake and bioavailability, it is important to understand how the body handles and regulates iron physiologically. Special proteins such as ferritin and transferrin help in the process of iron absorption, distribution, and storage.[2] Transferrin binds with iron in plasma to transport it to where it is necessary for tissues, and by this transferrin binding, iron does not exist in its free form, where it could damage cell proteins and membranes by free radical formation. Ferritin is the storage form of extra iron and is usually present in the liver and reticular-endothelial system. Iron elimination from the body is limited and commonly occurs by shedding intestinal endothelial cells into the feces.[3] The body achieves iron balance mostly through the regulation of iron absorption, and this is where iron differs from other body minerals due to the absence of any physiological process of excretion.[4][5] The peptide hepcidin is a primary regulator of iron homeostasis in the liver, and it has been implicated in anemia of chronic diseases.[6] The types of dietary iron play some role in influencing iron absorption.

Issues of Concern

Dietary iron requirements are estimated using multifactorial modeling. Factors that affect iron needs include the basal physiologic iron loss, periodic loss of iron in females with menstruation, fetal requirements in pregnancy, elevated requirements during growth stages of life, iron storage, etc.[7] A normal individual loses about 1 mg of iron in feces daily.[8] This loss increases in menstruating women by an additional 0.5 mg/day or approximately 14 mg of iron loss in 28 days. So women of childbearing age require higher iron intake than men. The bioavailability of iron differs in various food sources depending on the types of dietary iron and the presence or absence of iron absorption enhancers or inhibitors.

Types of Dietary Iron

Dietary iron has two primary forms: heme and nonheme.

All plant-derived and animal-derived foods contain nonheme iron, while heme iron is found only in the foods derived from animals, mainly meat, fish, poultry, and eggs. Heme iron has a higher bioavailability and is absorbed easier without the need for absorption-enhancing cofactors. Nonheme iron, which is the most important dietary source in vegetarians, shows lower bioavailability; its absorption depends on the balance between dietary enhancers and inhibitors and body iron stores.

About 25% of dietary heme iron gets absorbed, while 17% of dietary nonheme iron gets absorbed. Based on the studies, iron bioavailability is estimated to be 14 to 18% for mixed diet consumers and 5 to 12% for vegetarian diet consumers.[9] Therefore, less than one-fifth of the amount of dietary iron gets absorbed by the body. In western populations, heme iron contributes 10 to 15% of total dietary iron intake. Due to its higher bioavailability, it represents up to 40% of the total absorbed iron.[10]

Factors influencing Dietary Iron Intake

Dietary factors: 

Many different dietary components either enhance or inhibit dietary iron absorption when they are simultaneously present in the diet.

Enhancers:

• MFP Factor: It is a peptide present in meat, fish, and poultry. It enhances the absorption of nonheme iron present in the same meal. Studies consistently showed an enhanced effect on vegetarian iron absorption by animal proteins.[11] One study demonstrated that the addition of chicken, beef, or fish in a meal increased nonheme iron absorption by 2 to 3 fold with no influence of the same quantity of protein added as egg albumin.[12] The detailed underlying mechanism is still not known. However, evidence suggests that cysteine-containing peptides present in the meat act by inhibiting luminal inhibitors and eventually form luminal carriers for iron transportation.[13]
• Ascorbic Acid (Vit C): Studies have convincingly shown the dose-dependent enhancing effect of natively present or added vitamin C on iron absorption. This effect is mainly due to its iron-chelating and reducing abilities, converting ferric iron to ferrous iron, which has higher solubility.[14][15] Vitamin C also has been shown to have an inhibitory effect on iron absorption inhibitors such as phytate, polyphenols, and calcium.

Inhibitors:

• Phytates: They are known inhibitors of nonheme iron absorption.[10] Food sources high in phytates include soybean, black beans, lentils, mung beans, and split beans. Unrefined rice and grains also contain phytate.
• Polyphenols: They inhibit nonheme iron by binding with it in the intestine. They are commonly found in tea as tannic acid and also in red wine and oregano.
• Ca in milk: Calcium has been found to have an inhibitory effect on both heme and nonheme iron absorption. Its exact mechanism is unclear.

Person-related Factors

• Vegetarians: Since heme iron is more bioavailable than non-heme iron, the estimated bioavailability of iron from a vegetarian diet is 10% instead of 18% from meat containing a mixed diet. Thus, vegetarians need 1.8 times higher dietary intake of iron than meat-consuming individuals.
• Menstruating females: Extra iron loss occurs through menstrual blood loss, placing higher body demands for dietary iron. In South Asian populations where the diet is predominately plant-based, adolescent girls and premenopausal women are advised to supplement iron.
• Infants and children: Cow’s milk does not contain iron; it is also not recommended for infants below 1 year of age because of the risk of enteropathy. Even during the preadolescent growth spurt period, both boys and girls are advised to take extra dietary iron to meet the demand for iron by the newly developing tissue and the expanding blood volume.
• Blood Donors: 500 ml of blood donated just once a year translates to an additional iron loss of approximately 0.6 mg/day.
• Ethnicity: - based on variation in the USA.[16]
• People from developing countries: Poor socioeconomic status and access to food variety make people prone to dietary iron deficiency along with other malnutrition problems. People living in rural settings in developing parts of the world, in particular, are more prone to iron deficiency anemia. In these environments, there is also a higher prevalence of parasitic intestinal infections, which lead to GI blood loss and malabsorption. As such, local health care agencies and providers pay attention to the iron needs of these populations.[17][18]
• Drugs: The use of oral contraceptives decreases blood loss in adolescents and women during their childbearing age, possibly contributing to lower oral iron requirements.
• HRT (Hormone replacement therapy) sometimes causes uterine bleeding. In such a situation, postmenopausal women who are taking HRT will need higher iron requirements than postmenopausal women who are not taking HRT.

GI Disorders

Any of the following medical problems could interfere with iron absorption and lead to a higher demand for iron through either dietary means or medical supplementation.

• Malabsorptive disorder
• History of gastric bypass surgery
• Celiac disease
• Crohn’s disease

Recommended Dietary Allowance of Iron: Illustrated in Table 1.

Sources of Iron

1. Food: Table 2 illustrates the daily value (DV) of iron intake in certain foods based on the FDA-developed DVs to help compare the iron content in different foods. The U.S. Department of Agriculture (USDA) lists the nutrient content of many foods and provides a comprehensive list of foods containing iron arranged by nutrient content and food name.
2. Iron Supplements: Iron is available in many dietary supplements. Best supplements are those that contain easily absorbable iron that also causes minimal side effects. It is advisable to take iron under medical supervision. Multivitamin/multimineral supplements with iron, especially those designed for women, typically provide 18 mg of iron (100% of the DV for women in their reproductive years). Multivitamin/multimineral supplements for men or seniors frequently contain less or no iron. Iron-only supplements usually deliver more than the DV, with many providing 65 mg iron (360% of the DV). An iron-containing multivitamin is not sufficient to treat iron deficiency conditions, and medical supervision of iron replacement is recommended. Iron-containing supplements often include iron in either of its two forms: Ferrous or ferric salts. Examples include ferrous sulfate or gluconate and ferric citrate or sulfate.[19] The gluconate form is more tolerated than the sulfate form. Also, ferrous ionic forms of iron have higher solubility and bioavailability than the more charged ferric ionic forms in salts. Iron supplementation in doses greater than 45 mg/day may cause enough gastrointestinal side effects such as constipation, nausea, and diarrhea, to make them intolerable to patients. Other more tolerable forms of iron include those heme-based iron polypeptides, carbonyl iron, iron amino-acid chelates, and polysaccharide-iron complexes.[19] The amount of elemental iron in supplements varies. Ferrous fumarate, for example, contains 33% elemental iron, whereas the ferrous sulfate form has 20%, and the ferrous gluconate form has 12%. The elemental iron content is listed on the supplements facts panel to guide users on safe use without having to calculate elemental iron content. Approximately 14% to 18% of Americans take a supplement containing iron.[20]
3. Iron contamination: For cooking, sometimes an iron skillet is a utensil used for cooking vegetables and other food to increase iron content in that food. Such a source of contaminated iron is sometimes practiced in some regions of the world.

Clinical Significance

Iron Deficiency: Dietary iron deficiency affects more than 1.6 billion people globally. It is more prevalent in developing parts of the world, but it still affects 10 percent of toddlers, young girls, and women of childbearing age in the US and Canada. Iron deficiency develops in stages.

1. Early depletion of iron stores: at this early stage, body iron stores start to shrink without functionally affecting the body in areas that require iron. Although diagnostic indicators like serum ferritin level drop, iron transport molecules, such as transferrin, increase and the total iron-binding capacity (TIBC) goes up.
2. Early functional iron deficiency: at this stage, iron availability has decreased sufficiently to affect body compartments where iron is necessary for proper function, e.g., erythropoiesis. Though clinical anemia may not have yet developed, iron significantly decreases, and this is detectable by measuring transferrin levels and its saturation. There is more transferrin and less iron in the blood and a lower percentage of transferrin saturation with a deficiency. Besides, there are high levels of free erythrocyte protoporphyrins in circulation.[21]
3. Iron Deficiency Anemia: It is the most common nutritional deficiency worldwide. Clinically it causes symptoms such as weakness, lethargy. Hemoglobin levels decline, and red blood cells develop a smaller shape and form, becoming microcytic and hypochromic. Because iron is critical for multiple cell functions, iron deficiency can result in deficits affecting various systems and causing functional problems, including impaired hematopoiesis, gastrointestinal disturbances, impaired cognition, diminished immune function, altered exercise endurance or work performance, and impaired body temperature regulation. In infants and children, learning difficulties and neurocognitive and psychomotor problems can result from iron deficiency when necessary for growth and development, and the deficiency goes untreated.[22]

Iron Toxicity: Iron toxicity is less likely to occur with dietary sources of iron intake due to the body's ability to control iron absorption. However, iron toxicity could be an issue when a person consumes excessive iron supplements. Adverse effects may include the following:

1. Acute toxicity cause GI symptoms like vomiting and diarrhea. Further, it could produce cardiovascular, CNS, kidney, or liver toxicity specifically owing to the cellular damage by free iron radicals.
2. High dose supplement usually causes GI side effects such as constipation, nausea or vomiting.
3. Certain hematological disorders or repeated blood transfusions can cause secondary iron overload.

Enhancing Healthcare Team Outcomes

Iron is a crucial mineral for the body. It is naturally present in a variety of food substances in addition to being available as a dietary supplement that can be taken alone or can be added to fortify other foods. Iron is an integral component of the hemoglobin and myoglobin molecules and, therefore, plays a vital role in oxygen transport. Iron also plays a role in the structure of enzymes and the proper function of cells and is needed for growth and development. Most of the 4 grams of iron in the adult human body are in hemoglobin.[23]

Iron deficiency is often associated with poor diet and malnutrition, malabsorptive disorders, or conditions leading to loss of iron in hemoglobin through blood loss. There are populations and groups at risk of iron deficiency and resultant anemia. Iron deficiency anemia can affect infants, children, teenagers, menstruating women, and those who are pregnant. Additionally, frequent blood donors, people with cancer, heart failure, or those with gastrointestinal disorders affecting iron absorption or contributing to iron loss through gastrointestinal bleeding can all develop iron deficiency anemia. Caregivers need to be cognizant of these groups to recognize the need for early diagnosis and treatment and, thereby, benefit from coordinating care with appropriate specialists.

Primary care providers can solicit symptoms and look for signs to suggest the presence of anemia and use simple laboratory tests to confirm the diagnosis. Women of childbearing age and those who are pregnant would benefit from coordinating their care with their gynecologist or obstetrician, where appropriate and timely dietary iron supplementation can be provided to meet the maternal physiologic demands of pregnancy and those of fetal development. Pediatricians often recommend iron-fortified formula or foods rich in bioavailable iron to young children to minimize the risk of deficiency developing at 6 to 9 months of age.[24]

Adults, especially males, with anemia should undergo evaluation for gastrointestinal conditions such as celiac disease, inflammatory disease, or colon cancer that are common causes of iron deficiency. Referral to a gastroenterologist can help the primary care provider in the evaluation and workup, as specialized endoscopic testing and tissue biopsy can be performed via foregut endoscopy or colonoscopy. Given that iron has such an important role in health, nutritionists and educators are often the first line individuals to suspect a deficiency in young children or adults and request evaluations from appropriate specialists, whether that be in outpatient settings like schools and clinics or when patients present to hospital for care for other ailments. Hospitals need to be aware that iron can interact with multiple medications routinely used today, especially in our aging population. Examples of such medication include levothyroxine, levodopa, and proton pump inhibitors.[25][26][27] In these situations, attention is necessary to make appropriate dose adjustments or separate medication dosing to minimize interactions and influence on drug absorption.