Anemia is a condition in which too few red blood cells are in circulation. The most frequent cause is iron deficiency, in which inadequate iron levels in the body lead to decreased red blood cell production. Symptoms are nonspecific and include weakness, fatigue, irritability, mood swings, headache, exercise intolerance, decreased appetite (especially in children), pica, pallor (in dark-pigmented persons, pallor may be evident in sclera and palmar surfaces), shortness of breath, and restless legs syndrome. Iron deficiency in young children increases the risk of developmental delays and behavioral disturbances.[1]

The most common cause of iron deficiency is blood loss, usually through menorrhagia or gastrointestinal bleeding. The condition may also be caused by:

• Inadequate intake.
• Increased utilization often related to rapid growth such as during infancy, adolescence, and pregnancy.
• Malabsorption such as in cases of celiac disease or previous gastric surgery, including gastric bypass.
• Increased losses such as in cases of phlebotomy, hemolysis, and other rare instances such as intense athletic training.

Anemia develops after iron stores (found mainly in the liver, spleen, bone marrow, and the blood itself) are depleted. Symptoms of mild iron deficiency from depleted iron body stores may be present without resulting anemia.[2]

An estimated 2% of children, up to 5% of females of childbearing age, and 1 out of every 6 pregnant females have iron deficiency. Serum ferritin levels have been found to increase 2- or 3-fold in women after menopause.[3] While men are less likely to be iron deficient, all adults over age 65 have increased rates of iron deficiency, between 12-17%.[4][5][6]

Iron deficiency is common in low- and middle-income countries, with a prevalence of 30-70%.[7] In high-income countries, the prevalence of iron deficiency is much lower—roughly 20%—due partly to iron fortification of grain products.[8] However, only one-third to half of iron-deficient individuals actually have iron deficiency anemia.[9]

Risk Factors

Age. Children are at risk due to increased demands from tissue and muscle growth. Older adults are at increased risk due to renal disease and nutritional deficiencies.[6]

Gender. Women generally consume less iron than men do (because of lower energy requirements), but a female patient may have a greater need for iron, depending on her stage of life. On average, a menstruating woman loses approximately 1 mg of iron per cycle, though this number can be as high as 5 mg or more in cases of menorrhagia.[10] Iron requirements from the diet and bodily stores during pregnancy are elevated to meet needs including development of the fetus, placenta, and loss during childbirth.[11] Even though maternal requirements return to closer to baseline after birth, additional intake for replenishment may be necessary.[12]

Peptic ulcer disease and gastritis. These disorders lead to blood loss, which can deplete iron stores. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are often contributing factors. Helicobacter pylori infection may also present in a similar manner.

Gastrointestinal pathology. Iron is mainly absorbed in the duodenum so conditions that affect this segment can affect iron absorption. Such conditions include active celiac disease, Crohn’s disease, and small bowel surgery, including gastric bypass procedures.

Malignancy. Esophageal, gastric, colon, and other gastrointestinal cancers often cause occult bleeding.

Individuals infected with Helicobacter pylori. H. pylori competes with the host for iron and reduces the amount of vitamin C in gastric secretions.[13] Iron therapy becomes unnecessary after eradication of H. pylori and may be ineffective for treating iron deficiency anemia unless patients receive antimicrobial treatment.[14]

Excessive exercise. Blood losses may occur due to intense exercise—e.g., “foot strike” hemolysis in distance runners. Increased sweating also results in iron losses. Such losses may predispose adolescent female athletes, in particular, to frank anemia.[15]

Dietary and absorptive factors (see Nutritional Considerations below).

Diagnosis

Laboratory testing is necessary to diagnose iron deficiency anemia. A complete blood count reveals a low hematocrit and hemoglobin concentration, and usually a decreased mean corpuscular volume. The red blood cell distribution width is elevated. Iron deficiency can also cause thrombocytosis.

The current preferred means of diagnosis is a serum ferritin test, which reflects total body iron stores. Note, however, that ferritin is an acute-phase reactant that may be elevated in cases of inflammation, infection, malignancy, and liver disease, producing a false-negative result.

A blood smear may reveal hypochromic, microcytic red blood cells; however, such cells are also found in the context of other disorders, such as anemia of chronic disease and thalassemia. Many people with iron deficiency in Western countries exhibit normal red blood cell morphology.

Additional useful tests include transferrin (often measured indirectly as the total iron-binding capacity, which is elevated in iron deficiency) and serum iron, which is usually decreased. These tests are less reliable during acute illnesses or in patients with severe chronic diseases. Transferrin is also elevated in women who are pregnant or using oral contraception.

Treatment

Treatment involves resolving the patient’s iron deficiency, as well as addressing the underlying etiology (e.g., ulcer, malignancy, menorrhagia, dietary deficiency, iron malabsorption). A careful dietary and menstrual history, hemoccult evaluation, endoscopy, or appropriate imaging may reveal the cause. Caution is essential, however, as some patients may have more than one cause of iron deficiency, such as malabsorption and occult malignancy.

Nonenteric-coated oral iron supplements are the first line of therapy. Ferrous sulfate is most commonly used and has the greatest bioavailability, but it may also lead to more stomach upset than the gluconate or fumarate forms. Enteric-coated tablets are often poorly absorbed, as they can pass intact through the duodenum (the site of highest iron absorption). Current evidence suggests that lower doses are more effective and better tolerated than the traditionally recommended 100 to 200 mg of elementary iron per day, and once daily or even alternate day schedules may be optimal.[16] A typical starting schedule would be 200 mg of ferrous sulfate (containing 65 mg ferrous iron) once a day.

Dairy products should be avoided because they interfere with the absorption of oral iron (see Nutritional Considerations below). Medications that alter gastric pH can also decrease iron absorption. These include antacids, proton pump inhibitors, and H2 blockers. Supplements should be taken on an empty stomach, if tolerated, and at least 2 hours before or 4 hours after these classes of medications.

Simultaneous intake of ascorbic acid increases absorption of iron. For example, a glass of orange juice or lime juice contains sufficient vitamin C to significantly increase iron absorption from foods.[17] If the patient does not tolerate oral supplements or in cases of poor absorption, intramuscular and intravenous iron treatments are available.

After 2 weeks of maximal ferrous sulfate treatment, laboratory values generally show improvement, with values typically normalizing after 2 months. Supplementation continued for 6 additional months should replenish iron stores. However, if anemia is due to internal bleeding, stopping iron supplementation when values normalize will allow an assessment as to whether blood loss persists.

Nutritional Considerations

Dietary iron is available in 2 forms: heme iron, found in animal muscle and blood, and nonheme iron, found in both animal products and plant foods. High heme iron intake may contribute to iron overload and increased risk of colorectal cancer, cardiovascular disease, and Alzheimer’s disease.[8][18][19]

Heme iron in the diet is absorbed at a rate of 15-35%, independent of other dietary factors.[20] Nonheme iron absorption varies, depending on iron status and other dietary factors, as described below.[21] As body stores of iron decrease, the percentage of nonheme iron absorbed increases significantly by hepcidin suppression.[22]

Healthful sources of iron include greens and legumes. Although the myth persists that meat is a preferred iron source, a balanced vegetarian diet that includes legumes, fortified or whole grains, dried fruit, nuts, seeds, and green vegetables easily provides adequate iron.[23] Studies have shown that the incidence of iron deficiency anemia is no greater among individuals in Western nations consuming a healthy vegetarian diet than among omnivores.[13]

Dairy products and eggs are very poor sources of iron and decrease iron absorption. Caseins from milk and certain forms of calcium inhibit iron absorption. In addition, infants who are allergic to cow’s milk may be particularly susceptible to intestinal blood losses due to the irritating effect of dairy products.[20] Iron status measured as serum ferritin is inversely associated with greater consumption of dairy products in infants and toddlers, particularly when they displace foods that contain iron or that facilitate iron absorption.[24] Eggs (especially yolks) also appear to inhibit iron absorption.[25]

Fruits and vegetables aid the absorption of nonheme iron. Fruits and vegetables contain vitamin C and organic acids (e.g., citric acid) that keep iron in a reduced form, increasing absorption of nonheme iron when consumed in the same meal.[26] Vitamin A and carotenoids also appear to enhance iron absorption by overcoming the inhibiting effect of polyphenols and phytates (found in whole grains and legumes) on iron absorption. Adding vitamin A to an iron supplement regimen has also been shown to result in greater anemia reduction than iron alone.[27]

Tea, coffee, and cocoa should not be consumed with meals if poor iron status is suspected. Polyphenols and tannins in these beverages inhibit the absorption of nonheme iron. Black tea appears to be the most potent in this regard.[28]

Adequate iron intake before pregnancy can help prevent anemia in both mothers and infants. Iron deficiency is more common in women of childbearing age, especially during pregnancy.[29] The physiologic need for iron increases almost 10-fold during pregnancy and to some extent during lactation (possibly driven mostly by the need to replenish stores lost during pregnancy), and iron deficiency in the first trimester results in significantly poorer indicators of fetal growth, neural development, and behavior in offspring, compared with what happens when mothers have adequate iron status.[30] In mothers with iron deficiency, exclusive breastfeeding often results in iron deficiency in infants. Without adequate iron stores prior to conception, iron supplementation may be necessary during pregnancy (see below).

Breast milk contains significant iron. Breastfeeding is preferable for many reasons (see Life Cycle chapter), and cow’s milk consumption by infants and toddlers is associated with iron deficiency.[31][32] There is very little iron in breast milk (0.4 mg/L) but it seems to be highly absorbable.[33] Soy- and dairy-based formulas are typically fortified with as much as 8-14 mg/L, though studies have not found that lower levels (2 mg/L) affect iron status in infants.[34]

Iron supplementation should be individualized. The Centers for Disease Control and Prevention recommends that iron supplementation be individualized based on hemoglobin screening of at-risk individuals.[35] Iron supplementation should be avoided in cases lacking documented need because excess iron stores are associated with greater risks for colon cancer, coronary heart disease, insulin resistance, and possibly breast cancer.[36][37][38][39][40]

Alcohol intake enhances iron absorption but should not be used as a means of regulating iron status. Consumption of any amount of alcohol is associated with a 40% reduction in the risk of iron deficiency anemia. However, the prevalence of markers of iron overload, which may be more harmful than mild reductions in iron status, was found to be significantly elevated among individuals who consumed > 2 alcoholic drinks per day.[41] Increasing alcohol consumption is obviously not a recommended treatment for improving a person’s iron status.

Beeturia. A curious finding is beeturia, the production of red-tinged urine after eating beets. It occurs in a small number of healthy individuals but is seen in about 66-80% of those who are iron deficient.[42] It results from the lack of ferric ions that normally decolorize the red beet pigment through redox reactions.[43] While beeturia is benign, it can be indicative of pernicious anemia or a malabsorptive disorder.[44]

Orders

See Basic Diet Orders chapter.

To improve absorption, avoid having iron-rich foods or iron supplements at the same time as coffee, tea, cocoa, and foods or supplements high in calcium. Consuming ascorbic acid increases iron absorption and may be recommended when taking iron supplements.

What to Tell the Family

Iron deficiency anemia is usually preventable and highly treatable. A diet of fortified or whole grains, legumes, nuts and seeds, and fruits and vegetables can provide for healthy iron balance. During times of increased iron requirements or when an iron deficiency has been diagnosed, iron supplementation may be needed. Simple blood tests can accurately assess a person’s iron status.

References