Iron absorption
With respect to the mechanism of absorption, there are two kinds of dietary iron: heme iron and non-heme iron (20). In the human diet the primary sources of heme iron are the haemoglobin and myoglobin from consumption of meat, poultry, and fish whereas non-heme iron is obtained from cereals, pulses, legumes, fruits, and vegetables. The average absorption of heme iron from meat-containing meals is about 25 percent (21) The absorption of heme iron can vary from about 40 percent during iron deficiency to about 10 percent during iron repletion (22). Heme iron can be degraded and converted to non-heme iron if foods are cooked at a high temperature for too long. Calcium (see below) is the only dietary factor that negatively influences the absorption of heme iron and does so to the same extent that it influences non-heme iron (Table 41) (23).
Table 41
Factors influencing dietary iron absorption
HEME IRON ABSORPTION
Iron status of subject
Amount of dietary heme iron, especially as meat
Content of calcium in meal (e.g., milk, cheese)
Food preparation (time, temperature)
NON-HEME IRON ABSORPTION
Iron status of subjects
Amount of potentially available non-heme iron (adjustment for fortification iron and contamination iron)
* Balance between enhancing and inhibiting factors
Enhancing factors
Ascorbic acid (e.g., certain fruit juices, fruits, potatoes, and certain vegetables)
Meat, chicken, fish and other seafood
Fermented vegetables (e.g., sauerkraut), fermented soy sauces, etc.
Inhibiting factors
Phytates and other inositol phosphates (e.g., bran products, bread made from high-extraction flour, breakfast cereals, oats, rice [especially unpolished rice], pasta products, cocoa, nuts, soya beans, and peas)
Iron-binding phenolic compounds (e.g., tea, coffee, cocoa, certain spices, certain vegetables, and most red wines)
Calcium (e.g., milk, cheese) Soy proteins
Non-heme iron is the main form of dietary iron. The absorption of non-heme iron is influenced by individual iron status and by several factors in the diet. Dietary factors influencing iron absorption are outlined in Table 41. Iron compounds used for the fortification of foods will only be partially available for absorption. Once iron is dissolved, its absorption from fortificants and food contaminants is influenced by the same factors as the iron native to the food substance (24, 25). Iron originating from the soil (e.g., from various forms of clay) is sometimes present in considerable amounts on the surface of foods as a contaminant originating from dust on air-dried foods or from water used in irrigation. Even if the fraction of iron that is available is often small, contamination iron may still be nutritionally important because of the great amounts present (26, 27).
Reducing substances (i.e., substances that keep iron in the ferrous form) must be present for iron to be absorbed (28). The presence of meat, poultry, and fish in the diet enhance iron absorption. Other foods contain factors (ligands) that strongly bind ferrous ions, that subsequently inhibit absorption. Examples are phytates and certain iron-binding polyphenols.
Inhibition of iron absorption
Phytates are found in all kinds of grains, seeds, nuts, vegetables, roots (e.g., potatoes), and fruits. Chemically, phytates are inositol hexaphosphate salts and are a storage form of phosphates and minerals. Other phosphates have not been shown to inhibit non-heme iron absorption. In North American and European diets, about 90 percent of phytates originate from cereals. Phytates strongly inhibit iron absorption in a dose-dependent fashion and even small amounts of phytates have a marked effect (29, 30).
Bran has a high content of phytate and strongly inhibits iron absorption. Whole-wheat flour, therefore, has a much higher content of phytates than does white wheat flour (31). In bread some of the phytates in bran are degraded during the fermentation of the dough. Fermentation for a couple of days (sourdough fermentation) can therefore almost completely degrade the phytate and increase the bio-availability of iron in bread made from whole-wheat flour (32). Oats strongly inhibit iron absorption because of their high phytate content, that results from native phytase in oats being destroyed by the normal heat process used to avoid rancidity (33). Sufficient amounts of ascorbic acid can counteract this inhibition (34). By contrast, non-phytate-containing dietary fibre components have almost no influence on iron absorption.
Almost all plants contain phenolic compounds as part of their defence system against insects, animals, and humans. Only some of the phenolic compounds (mainly those containing galloyl groups) seem to be responsible for the inhibition of iron absorption (35). Tea, coffee, and cocoa are common plant products that contain iron-binding polyphenols (36-39). Many vegetables, especially green leafy vegetables (e.g., spinach), and herbs and spices (e.g., oregano) contain appreciable amounts of galloyl groups, that strongly inhibit iron absorption. Consumption of betel leaves, common in areas of Asia, also has a marked negative effect on iron absorption.
Calcium, consumed as a salt or in dairy products interferes significantly with the absorption of both heme and non-heme iron (40-42). Because calcium and iron are both essential nutrients, calcium cannot be considered to be an inhibitor in the same way as phytates or phenolic compounds. The practical solution for this competition is to increase iron intake, increase its bio-availability, or avoid the intake of foods rich in calcium and foods rich in iron at the same meal (43).
The mechanism of action for absorption inhibition is unknown, but the balance of evidence strongly suggest that the inhibition is located within the mucosal cell itself at the common final transfer step for heme and non-heme iron. Recent analyses of the dose-effect relationship show that no inhibition is seen from the first 40 mg of calcium in a meal. A sigmoid relationship is then seen, reaching a 60 percent maximal inhibition of iron absorption by 300-600 mg calcium. The form of this curve suggests a one-site competitive binding of iron and calcium (Figure 24). This relationship explains some of the seemingly conflicting results obtained in studies on the interaction between calcium and iron (44).
For unknown reasons, the addition of soy protein to a meal reduces the fraction of iron absorbed (45-48). This inhibition is not solely explained by the high phytate content of soy protein. However, because of the high iron content of soy proteins, the net effect on iron absorption of an addition of soy products to a meal is usually positive. In infant foods containing soy proteins, the inhibiting effect can be overcome by the addition of sufficient amounts of ascorbic acid. Some fermented soy sauces, however, have been found to enhance iron absorption (49, 50).
Figure 24. Effect of different amounts of calcium on iron absorption
Enhancement of iron absorption
Ascorbic acid is the most potent enhancer of non-heme iron absorption (34, 51-53). Synthetic vitamin C increases the absorption of iron to the same extent as the native ascorbic acid in fruits, vegetables, and juices. The effect of ascorbic acid on iron absorption is so marked and essential that this effect could be considered as one of vitamin C’s physiologic roles (54). Each meal should preferably contain at least 25 mg of ascorbic acid and possibly more if the meal contains many inhibitors of iron absorption. Therefore, a requirement of ascorbic acid for iron absorption should be taken into account when establishing the requirements for vitamin C, that are set only to prevent vitamin C deficiency (especially scurvy).
Meat, fish, and seafood all promote the absorption of non-heme iron (55-58). The mechanism for this effect has not been determined. It should be pointed out that meat also enhances the absorption of heme iron to about the same extent (21). Meat promotes iron nutrition in two ways: it stimulates the absorption of both heme and non-heme iron and it provides the well-absorbed heme iron. Epidemiologically, the intake of meat has been found to be associated with a lower prevalence of iron deficiency.
Organic acids, such as citric acid, have in some studies been found to enhance the absorption of non-heme iron (29). This effect is not observed as consistently as is the effect of ascorbic acid (47, 52). Sauerkraut (59) and other fermented vegetables and even some fermented soy sauces (49, 50) enhance iron absorption. The nature of this enhancement has not yet been determined.
Iron absorption from meals
The pool concept (see above) in iron absorption implies that there are two main pools in the gastrointestinal lumen - one pool of heme iron and another pool of non-heme iron - and that iron absorption takes place independently from these two pools (24). The pool concept also implies that the absorption of iron from the non-heme iron pool results from all ligands present in the mixture of foods included in a meal. The absorption of non-heme iron from a certain meal not only depends on its iron content but also, and to a marked degree, on the composition of the meal (i.e., the balance among all factors enhancing and inhibiting the absorption of iron). The bio-availability can vary more than 10-fold among meals with a similar content of iron, energy, protein, fat, etc. (20). Just the addition of certain spices (e.g., oregano) or a cup of tea may reduce the bio-availability by one-half or more. However, the addition of certain vegetables or fruits containing ascorbic acid may double or even triple iron absorption, depending on the other properties of the meal and the amounts of ascorbic acid present.
Iron absorption from the whole diet
There is limited information about the total amounts of iron absorbed from the diet because no simple method is available to measure iron absorption from the whole diet. It has been measured by chemical balance studies using long balance periods or by determining the haemoglobin regeneration rate in subjects with induced iron deficiency anaemia and a well-controlled diet over a long period of time.
A method was recently developed to measure iron absorption from the whole diet. In the first studies all non-heme iron in all meals over periods of 5-10 days was homogeneously labelled to the same specific activity with an extrinsic inorganic radioiron tracer (43, 60). Heme iron absorption was then estimated. In a further study, heme and non-heme iron were separately labelled with two radioiron tracers as biosynthetically labelled haemoglobin and as an inorganic iron salt (22). New information could be obtained, for example, about the average bio-availability of dietary iron in different types of diets, overall effects of certain factors (e.g., calcium) on iron nutrition, and regulation of iron absorption in relation to iron status. Iron absorption from the whole diet is the sum of the absorption of iron from the single meals included in the diet. It has been suggested that the iron absorption of single meals may exaggerate the absorption of iron from the diet (61, 62). Iron absorption from single meals can never represent iron absorption from the whole diet, but iron absorption from a single meal was the same when the meal was served in the morning after an overnight fast or at lunch or supper (63). The same observation was made in another study when a hamburger meal was served in the morning or 2-4 hours after a breakfast (42).
Because energy expenditure and energy intake set the limit for the amount of food eaten and for meal size, it is practical to relate the bio-availability of iron in different meals to energy content (bio-available nutrient density). The use of bio-available nutrient density is a feasible way to compare different meals, construct menus, and calculate recommended intakes (64).
Intake of energy and essential nutrients such as iron was probably considerably higher for early humans than it is today (65-67). The present low iron intake associated with a low-energy lifestyle implies that the interaction between different factors influencing iron absorption, will be more critical. For example, the interaction between calcium and iron absorption probably had no importance in the nutrition of early humans, who had a diet with ample amounts of both iron and calcium.
Iron balance and regulation of iron absorption
The body has three unique mechanisms for maintaining iron balance and preventing iron deficiency and iron overload. The first is the continuous re-utilisation of iron from catabolised erythrocytes in the body. When an erythrocyte dies after about 120 days, it is usually degraded by the macrophages of the reticular endothelium. The iron is released and delivered to transferrin in the plasma, which brings the iron back to red blood cell precursors in the bone marrow or to other cells in different tissues. Uptake and distribution of iron in the body is regulated by the synthesis of transferrin receptors on the cell surface. This system for internal iron transport not only controls the rate of flow of iron to different tissues according to their needs but also effectively prevents the appearance of free iron and the formation of free radicals in the circulation.
The second mechanism is the access of the specific storage protein, ferritin, which can store and release iron to meet excessive iron demands. This iron reservoir is especially important in the third trimester of pregnancy.
The third mechanism involves the regulation of absorption of iron from the intestines, with an increased iron absorption in the presence of decreasing body iron stores and a decreased iron absorption when iron stores increase. Iron absorption decreases until an equilibrium is established between absorption and requirements. For a given diet this regulation of iron absorption, however, can only balance losses up to a certain critical point beyond which iron deficiency will develop (68). About half of the basal iron losses are from blood, primarily in the gastrointestinal tract. Both these losses and the menstrual iron losses are influenced by the haemoglobin level; during the development of an iron deficiency, menstrual and basal iron losses will successively decrease when the haemoglobin level decreases. In a state of more severe iron deficiency, skin iron losses may also decrease. Iron balance (absorption equals losses) may be present not only in normal subjects but also during iron deficiency and iron overload.
The three main factors that affect iron balance are absorption (intake and bio-availability of iron), losses, and amount in stores. The interrelationship among these factors was recently been described in mathematical terms, making it possible to predict, for example, the amount of stored iron when iron losses and bio-availability of dietary iron are known (69). With increasing iron requirements or decreasing bio-availability, the regulatory capacity to prevent iron deficiency is limited (68). However, to prevent iron overload with increasing dietary iron intake or bio-availability, the regulatory capacity seems to be extremely good (69).
