Which of the following should the nurse include as a food that enhances iron absorption when consumed with nonheme iron?

Iron

Dietary iron consisted of heme and nonheme irons. Heme iron is rich in meat and fish while nonheme iron is rich in plant foods and eggs. According to a metaanalysis (Hunnicutt et al., 2014), dietary total iron intake was inversely associated with risk of incident CHD; the pooled RR (95%CI) of CHD for the highest versus lowest quintiles of dietary total iron intake was 0.85 (0.73–0.999) (Hunnicutt et al., 2014), while dietary heme iron intake was positively associated with risk of incident CHD; the pooled RR (95%CI) of CHD for the highest versus lowest quintiles of dietary heme iron intake was 1.57 (1.28–1.94) (Hunnicutt et al., 2014). Heme iron, nonheme iron, and total iron intakes were not associated with fatality from CHD (Hunnicutt et al., 2014). A prospective study of British showed that dietary heme iron and nonheme iron intakes were not associated with mortality from CVD (Bates et al., 2011). For stroke, a prospective study of Swedish men showed that dietary nonheme iron intake was not associated with the incidence of total, ischemic, and hemorrhagic strokes, while dietary heme iron intake was positively associated with the incidence of total and ischemic strokes (Kaluza et al., 2013).

6.7.1 The Iron-Overload Hypothesis

Dietary iron availability is a strong contributor to iron homeostasis: the estimated iron content of a typical mixed diet (6 mg/1000 kcal) dictates that young women of child-bearing age (RDA=18 mg/day) will have difficulty obtaining sufficient iron from food, while postmenopausal women and men (RDA=8 mg/day) can easily consume iron in excess of their needs (Micronutrients, 2001). Regulation of iron homeostasis is discussed elsewhere (refer to Essentials II: Heavy Metals, Retinoids and Precursors: Iron). An imbalance of homeostatic mechanisms that control the risk from unbound iron can result in systemic and parenchymal siderosis and contribute to organ damage such as β-cell dysfunction, fibrosis in liver diseases, and atherosclerotic plaque growth and instability as reviewed by Fernández-Real and Manco (2014).

Dietary iron availability can be reduced by limiting consumption of heme in red meat, avoiding iron in fortified foods or as dietary iron supplements and reducing intake of other readily absorbable iron sources. It should be noted that soybeans and other legumes contain iron as ferritin, a large, stable, phytate-resistant nanocage that surrounds hundreds of iron and oxygen atoms. Iron absorbed as ferritin is taken up by receptor-mediated endocytosis and absorption is much more efficient than iron presented as single inorganic iron atoms (Theil, 2011). It is not yet certain whether consumption of legume ferritin contributes to elevated iron status in men and postmenopausal women.

2.4.1 Ferrireductases for Iron Absorption

Dietary iron is found in two forms, either as heme iron, found in meat and meat products, or non heme iron, present in vegetables, fruits and beans. Non-heme iron predominates in most diets, comprising 90–95% of total daily iron intake. The absorption of dietary iron occurs at the apical membrane of duodenal enterocytes. The primary form of nonheme iron in food is Fe3+, which is insoluble and must be reduced to Fe2+ form before transporting across enterocytes (Fig. 2). The responsible enzyme is thought to be cytochrome b-like ferrireductase (Dcytb) (McKie et al., 2001). However, Gunshin, Starr, et al., (2005) demonstrated that the absence of Dcytb did not impair body iron stores when mice were fed normal chow diet, indicating that there was no major effect on intestinal absorption. They concluded that Dcytb is dispensable for intestinal iron absorption in mice. However, mice are capable of synthesizing ascorbic acid and may have less need for a duodenal surface ferric reductase (Sharp & Srai, 2007). In addition, direct iron absorption was not measured in the knockout study. The role of Dcytb in intestinal iron absorption remains unclear. The recently identified Steap2 protein might be another candidate for the ferrireductase role in the small intestine (Ohgami, Campagna, McDonald, & Fleming, 2006). Other dietary components, such as ascorbic acid, histidine and cysteine, are also able to reduce Fe3+ to Fe2+ (Glahn & Van Campen, 1997; Han, Failla, Hill, Morris, & Smith, 1995; Swain, Tabatabai, & Reddy, 2002).

General aspects

Dietary iron is found mainly as iron salts, partly as haem from the myoglobin and Hb in meat. Dietary iron exists as haem iron only in animal tissues; in plant foods it is present as non-haem iron, which is less easily absorbed. In a mixed omnivorous diet, around 25% of dietary iron is non-haem iron. The amount of iron absorbed from various foods ranges from around 1–10% from plant foods to 10–20% from animal foods. Fibre, phytates, oxalates and phosphates present in plant foods, and tannin in tea, can inhibit iron absorption. Foods rich in vitamin C, including citrus fruits, green peppers and fresh leafy green vegetables, promote absorption of non-haem iron. Citric acid, sugars, amino acids and alcohol, as well as meat, poultry, fish and orange juice, also promote intestinal absorption of iron. Good sources of iron for vegetarians include wholegrain cereals and flours, leafy green vegetables, pulses such as lentils and kidney beans, and some dried fruits. Gastric acid is needed for the adequate conversion of iron salts from ferric to ferrous forms for their absorption from the proximal small intestine. Iron is stored in the bone marrow as haemosiderin. The remainder is stored in the liver and spleen, and a small amount is present as myoglobin, which acts as an oxygen store in muscle tissue. Iron is required for synthesis of haem, respiratory cytochromes and myeloperoxidase. It also plays a vital role in many metabolic reactions (Fig. 8.26).

The most common causes of anaemia in developed countries are iron deficiency as a result of nutritional deficiencies or chronic blood loss, while in developing countries, malaria and chronic blood loss (Fig. 8.27) are the most frequent.

Excessive chronic menstrual or gastrointestinal blood loss is the main cause – women of childbearing age and older are mainly affected. About 5% of American women may have mild iron-deficiency anaemia and up to 25% may have low iron levels without anaemia. Neonates maintained on a milk diet may become iron-deficient. Very many older children are mildly iron-deficient because of the high demands for growth, especially during adolescence. By contrast, iron deficiency in an adult male almost invariably indicates blood loss, usually from the gastrointestinal or genitourinary tract. The same holds true for postmenopausal women.

Iron metabolism

(Fig. 57.4)

Dietary iron (Fe3 +) is first reduced to Fe2 + by duodenal cytochrome B (DcytB), a ferrireductase present on the apical membranes of enterocytes. Fe2 + then enters the enterocytes by divalent metal transporter-1 (DMT1) expressed on the apical membrane. Once inside, Fe2 + can be stored as ferritin or can leave the enterocyte through ferroportin (Fpn, Ireg1, MTP1), expressed on the basolateral membrane. Prior to the transport of iron outside the cell, intracellular iron must be converted to Fe3 + via either hephaestin or ceruloplasmin, both of which have ferroxidase activity (Mills et al., 2010).

Intracellular iron is regulated by the IRE (iron regulatory element)–IRP (iron regulatory proteins) system. So, in case of elevation of intracellular iron, and particularly of the LIP (labile iron pool), the synthesis of ferritin is increased (allowing the storage of the overload iron) and the expression of the receptor for transferrin (RTf1) reduced (limiting the entrance of iron to the cell). Hepcidin produced by hepatocytes is an important regulator of cellular iron export by controlling the amount of ferroportin that is the primary determinant of gastrointestinal absorption and iron release from reticuloendothelial stores. Ceruloplasmin is a major copper-containing protein in the serum (Lutsenko et al., 2007). This α-2-glycoprotein is synthesized in the hepatic microsomes, as apoceruloplasmin. Loaded with six copper atoms per molecule, it is excreted into the circulation as holoceruloplasmin. Its essential function is a ferroxidase activity which is necessary to release iron from storage.

The cellular and intercellular iron transport mechanisms in the CNS are still poorly understood. Blood–brain barrier limits iron entry to the brain from the blood, so disturbances of systemic iron homeostasis exhibit minimal effects on CNS iron content or metabolism (Moos and Morgan, 2004). Molecular mechanisms of iron transport seem similar to those described in the peripheral tissues; ferritine, DMT 1, ferroportine, hephaestine, and ceruloplasmin are all expressed in the CNS. Brain endothelial cells express the transferrin receptor 1 in their luminal membrane; this receptor binds iron-loaded transferrin and internalizes this complex in endosomes. Then ceruloplasmin, which acts as a ferroxidase, oxidizes ferrous iron to ferric iron, which binds to the transferrin in brain interstitial fluid (Benarroch, 2009).

Endometrial Cancer

Heme iron intake has been shown to be positively associated with the risk of diabetes and obesity, both of which are suspected or established risk factors for endometrial cancer (EC).19 However, epidemiological studies have shown mixed results (Table 13.3). A recent population-based case-control study in Shanghai, China showed that the animal-derived iron intake was positively associated with EC risk (p for trend < 0.01; OR = 1.86 in the Q4 vs. Q1, 95% CI 1.22–2.85), predominantly after menopause (p for trend < 0.01; OR = 2.02 in the Q4 vs. Q1, 95% CI 1.15–3.55) and in postmenopausal women with BMI ≥ 25 kg/m2 (p for trend = 0.002; OR = 3.25 in the Q4 vs. Q1, 95% CI 1.41–7.50).20 However, the Canadian National Breast Screening Study, a prospective cohort study, reported no association of meat intake or any of the dietary iron-related variables with the risk of EC.21 In contrast, a prospective cohort study with 720 EC cases ascertained in the Swedish Mammography Cohort of 21 years of follow-up, heme iron intake (p for trend = 0.02; RR = 1.24 in the Q4 vs. Q1, 95% CI 1.01–1.53), total iron intake (p for trend = 0.009; RR = 1.31 in the Q4 vs. Q1, 95% CI 1.07–1.61) and liver consumption (p for trend = 0.01; RR = 1.29 in ≥ 100 g/wk vs. < 100g/wk, 95% CI 1.06–1.56) were associated with increased risk of EC.22 Also, a meta-analysis observed random-effects dose-response summary estimates of 1.26 (95% CI 1.03–1.54) per 100 g of total meat/d, 1.51 (95% CI 1.19–1.93) per 100 g of red meat/d, 1.03 (95% CI 0.32–3.28) per 100 g of poultry/d.23 The authors suggested that meat consumption, particularly red meat, increases EC risk.

TABLE 13.3. Epidemiological Evidences on the Association of Iron and Meat Intake with Endometrial Cancer (EC) Risk

5.1 Iron

Iron intakes can be higher in vegetarians and vegans than in nonvegetarians, but iron stores (ferritin levels) are consistently lower in vegetarians (Hunt, 2003), as nonheme iron is less absorbable, and its absorption is almost inversely proportional to ferritin levels: as iron stores approach depletion, the absorption of heme and nonheme iron becomes similar (Hallberg et al., 1997; Hallberg and Hulthén, 2000). The lower stores in vegetarians do not seem to translate to increased iron deficiency (Hunt, 2003). The reader may refer to Chapter 39 for a general review.

Guralnik et al. (2004) report that in the general population in the United States, prevalence of anemia increases substantially with age within the elderly population, and only about a third of anemia in people over 65 is explained by nutritional deficiencies. Nieman et al. (1989) found no evidence of differences in iron status between vegetarian and nonvegetarian women. Average hemoglobin levels were above 14 g/dL in both groups, and no participants had hemoglobin levels below 12.

Löwik et al. (1990) found lower hemoglobin levels in vegetarians, but based on a regression model included in this paper, this was accounted for by the vegetarians being about 10 years older. As expected, ferritin levels were much lower in the vegetarians (42 vs. 85 μg/L). Based on the same study, Brants et al. (1990) reported that the percentage of women with ferritin levels below 12 μg/L was similar in vegetarians and nonvegetarians (about 10%), but three out of 17 vegetarian men showed low ferritin compared to one out of 54 nonvegetarian men. The difference for men was statistically significant (P = .04), but the difference for men and women combined was not (P = .3).

Woo et al. (1998) found lower hemoglobin in vegetarian women compared with nonvegetarian women (12.3 vs. 13.4 g/dL), and 30% of vegetarians had levels below 12 compared with 10% of nonvegetarians. However, the prevalence of iron deficiency appeared similar among vegetarians and nonvegetarians, and only 15% of the anemic vegetarians showed confirmed iron deficiency. The vegetarians were about 10 years older than the nonvegetarians, which may partly explain their higher levels of anemia.

Deriemaeker et al. (2011) found very similar hemoglobin levels in vegetarians and nonvegetarians. Average ferritin levels were much lower in vegetarians compared with nonvegetarians (66 vs. 159 μg/L), but incidence of abnormally low ferritin values was similar.

Taken as a whole, the comparisons between elderly vegetarians and nonvegetarians suggest no clear difference in the prevalence of iron deficiency despite a clear difference in ferritin levels. In looking at anemia in the elderly, it is particularly important that comparisons are made between age-matched subjects.

Iron

The iron intakes of vegetarians are usually similar to those of omnivores. However, iron bioavailability may be decreased because nonheme iron absorption from plant foods is influenced by the presence of inhibitors, such as polyphenols, phytates, fiber, and tannins. Unleavened and unrefined cereals often contain many inhibitors. However, enhancers of nonheme iron absorption such as citric, ascorbic, and other organic acids that are often high in vegetarian diets may increase absorption. Also small amounts of animal foods, especially flesh foods, enhance absorption. Nevertheless, in infancy, pregnancy, the adolescent growth spurt and during other times of high iron requirements, without supplementation iron needs may not be met. Cereals highly fortified with iron or iron supplements may be acceptable iron sources to supplement other iron-rich foods.

The Role of Ascorbate in Iron Absorption

Inorganic dietary iron is absorbed as Fe2+, and not as Fe3+; ascorbic acid in the intestinal lumen not only maintains iron in the reduced state but also chelates it, increasing absorption considerably. A dose of 25 mg of vitamin C taken together with a meal increases the absorption of iron approximately 65%, whereas a 1-g dose gives a ninefold increase. This is an effect of ascorbic acid present together with the test meal; neither intravenous administration of vitamin C nor supplements several hours before the test meal affects iron absorption, although the ascorbate secreted in gastric juice should be effective. This is not a specific effect of ascorbate; a variety of other reducing agents including alcohol and fructose also enhance the absorption of inorganic iron. In addition, ascorbate is the electron donor for the intracellular ferric reductase in intestinal mucosal cells.

Iron Absorption

1.

Dietary iron is absorbed primarily in the crypt enterocytes of the duodenum. Only approximately 10% of dietary iron is absorbed in physiologically normal persons, with absorption regulated in accordance with body iron stores.

In normal persons, iron absorption is downregulated when serum transferrin saturation is high and following high dietary iron intake.

In persons with HH, iron absorption is increased and is not downregulated as in normal persons, thereby resulting in a positive iron balance.

Small bowel mucosal ferritin and ferritin mRNA levels are inappropriately decreased in HH; this pattern is typically associated with iron deficiency and is corrected by iron repletion.

Iron absorption involves the uptake of iron from the intestinal lumen into the enterocytes with subsequent transfer from enterocytes to plasma. Both processes are increased in HH. In vivo kinetic studies indicate that increased transport of iron from the serosal side of the intestine into plasma drives the increased iron absorption.

The effect of the HFE mutation is thought to be mediated by lack of sufficient expression of hepcidin in the liver in response to iron stores at the level of the hepatocyte; this leads in turn to a failure to inhibit iron absorption in the duodenum, thereby resulting in iron overload.