Iron deficiency anemia arises when the balance of iron intake, iron stores, and the body's loss of iron are insufficient to fully support production of erythrocytes. Iron deficiency anemia rarely causes death, but the impact on human health is significant. In the developed world, this disease is easily identified and treated, but frequently overlooked by physicians. In contrast, it is a health problem that affects major portions of the population in underdeveloped countries.
Overall, the prevention and successful treatment for iron deficiency anemia remain woefully insufficient worldwide, especially among underprivileged women and children. Here, clinical and laboratory features of the disease are discussed, and then focus is placed on relevant economic, environmental, infectious, and genetic factors that converge among global populations.
Nutritional anemias: iron, vitamins A and B12, folate, and riboflavin
Nutritional anemias result when concentrations of hematopoietic nutrients—those involved in RBC production or maintenance—are insufficient to meet those demands.13 Causes of nutrient deficiency include inadequate dietary intake, increased nutrient losses (e.g., blood loss from parasites, hemorrhage associated with childbirth, or heavy menstrual losses), impaired absorption (e.g., lack of intrinsic factor to aid vitamin B12 absorption, high intake of phytate, or
Helicobacter pylori infection that impair iron absorption), or altered nutrient metabolism (e.g., VA or riboflavin deficiency affecting mobilization of iron stores). While nutrient supplementation is a common preventive and treatment strategy for nutritional anemias—for example, iron supplementation for the prevention of IDA—the bioavailability and thus absorption from different nutrient supplement preparations can vary, potentially limiting their impact.53ID is considered the most common nutritional deficiency leading to anemia, though other nutritional deficiencies can also cause anemia, including deficiencies of vitamins A, B12, B6, C, D, and E, folate, riboflavin, copper, and zinc.54 Several of these nutrients—vitamins A, B6, and B12, folic acid, and riboflavin—are needed for the normal production of RBCs; other nutrients, such as vitamins C and E, may protect RBCs through their antioxidant function. Trace elements, such as copper and zinc, are found in the structures of enzymes that act on iron metabolism (e.g., copper and ceruloplasmin).56 Copper may also contribute to anemia development through reductions in erythropoietin (EPO) and antioxidant enzymes that require copper,
thus increasing oxidative stress and reducing RBC life span;57 the mechanisms through which zinc deficiency is associated with anemia are not as well characterized.57 The extent to which each of these deficiencies contributes to the global anemia burden is still a subject of investigation. While some of these nutrient deficiencies are rare and may contribute little to the burden of anemia globally, deficiencies in multiple micronutrients likely have a synergistic effect on anemia development.
ID develops when dietary iron intake cannot meet iron needs over a period of time, especially during periods of life when iron requirements are particularly high (e.g., during periods of rapid growth and development, such as infancy and pregnancy) or when iron losses exceed iron intake. ID typically evolves in three stages: storage iron depletion, iron-deficient erythropoiesis, and IDA (defined as concomitant ID plus anemia).
The WHO recommends assessing iron status using serum ferritin or soluble transferrin receptor (sTfR).60,61 Serum ferritin, a measure of body storage iron and a sensitive measure of ID, is elevated by the acute phase response; sTfR levels when high indicate tissue ID, but sTfR may also be affected by inflammation and other causes of erythropoiesis.60,61 Because of the effect of inflammation on many biomarkers of iron status, acute phase proteins (e.g., C-reactive protein (CRP) and alpha-1-acid glycoprotein (AGP)) should be assessed when possible.
A fuller review of iron status indicators, outside the scope of the paper here, is available elsewhere.61Estimates from the late 1990s placed the number of individuals affected by ID at 2 billion, and ID has long been assumed to contribute to approximately 50% of anemia cases globally. A recent systematic analysis of global anemia data that calculated cause-specific attribution for 17 conditions related to anemia ranked ID as the most common cause in almost all global regions examined.2 The WHO used the change in Hb concentration from iron supplementation studies to estimate the “proportion of all anemia amenable to iron” as 50% of anemia among nonpregnant and pregnant women, and 42% of anemia in children.
Recent analyses from the BRINDA project indicated that along with age and malaria, ID was one of the factors most consistently associated with anemia, though the proportion of anemic children and women with ID varied by infectious disease burden.46,49 Another study that assessed the role of ID in anemia burden among PSC and nonpregnant WRA, across a range of countries with varying rankings on the Human Development Index, showed that between approximately a quarter to a third of anemia among PSC and WRA was associated with ID. In countries where the prevalence of anemia was greater than 40% and in countries where inflammation levels were high, ID played a much smaller role.
Thus, while ID remains a primary cause in many settings, the proportion of anemic individuals with ID varies by contextual factors, and poor iron nutrition cannot be assumed to be the primary cause in all cases. Yet, iron interventions (e.g., supplementation, fortification, and dietary interventions) are central to most anemia control programs, and WHO currently has 17 guidelines on iron supplementation. Given the complex etiology of anemia, the extent to which ID accounts for the anemia burden continues to be investigated.
Vitamin A deficiency
VAD is prevalent in many LMICs, particularly among PSC, pregnant women, and WRA. In 2005, the WHO estimated that 190 million PSC and 9.1 million pregnant women from regions at risk of VAD were VA deficient (based on serum retinol concentrations), which represents a third of PSC and 15% of pregnant women from these countries.
VAD and anemia have been observed to occur in the same populations for decades, and significant correlations between VA status biomarkers and Hb have been described in multiple countries and populations including preschool and school-age children, adolescents, and adults.
VA supplementation has been shown to increase Hb concentrations, hematocrit, and some iron status indices, even when administered in the absence of iron supplements. VAD is thought to cause anemia through multiple mechanisms, including the role of retinoids in erythropoiesis, VA’s importance for immune function, as well as VA’s well-established role in iron metabolism.
Other conditions associated with anemia: undernutrition and overweight/obesity
Stunting, wasting, and being underweight have been associated with anemia in some studies, but not all. In analyses from the BRINDA project, stunting, underweight, and wasting were associated with anemia in PSC in more than half of the surveys (9/15, 10/15, and 5/15, respectively) for which these variables were available.49 These manifestations of poor nutritional status are associated with anemia due to similar factors (though not constituting a causal relationship), including poor maternal nutrition, inadequate home and community environments, inadequate complementary feeding practices leading to poor micronutrient and animal-source food intake, contaminated water, and poor sanitation, suboptimal breastfeeding practices, and clinical and subclinical infections.
While more related to ID than anemia per se, overweight and obese individuals have an increased risk for ID, as data from multiple countries show. The primary link between these conditions is thought to be through hepcidin, a peptide hormone produced predominantly by the liver and responsible for iron homeostasis, which is elevated in the presence of inflammation. The chronic subclinical inflammation present in overweight and obese individuals increases hepcidin levels, resulting in reduced iron absorption. However, Hb concentrations tend to be within the normal range.
MAJOR CAUSES OF IRON DEFICIENCY ANEMIA
Each milliliter of packed RBCs (∼2.5 mL of whole blood) contains ∼1.0 mg of iron. Each day, 1.0 mg of iron is absorbed from the diet and 20 mg of iron from senescent erythrocytes are available to support erythropoiesis. Once iron stores are depleted, dietary and recycled erythrocyte iron are not usually sufficient to compensate for acute blood loss.
In all cases of iron deficiency anemia, blood loss should be considered. Hemorrhage itself is by far the most common mechanism for acute iron loss and anemia. Hemorrhage decreases the host’s red cell mass, decreases the supply of iron for erythropoiesis, and increases the iron demand for erythropoiesis. Chronic blood loss from menstruation or hookworm infection (see below) has the greatest impact worldwide. Less than 2 mL of blood is lost daily in the stool of healthy adults (Ahlquist et al. 1985). Detection of occult blood losses of up to 60 mL/d may be difficult without specialized stool tests
The Maternal–Fetal Bridge of Iron Deficiency
Requirements for iron are greatest around the time of birth. Iron demand is high in menstruating as well as pregnant females. During pregnancy, it is estimated that ∼1200 mg of iron are required from conception through delivery.
Iron intake and stores in the mother must satisfy fetal development, and blood loss at delivery. Additionally, the maternal erythrocyte mass should increase from 350 to 450 mL. By comparison, pregnant women without iron supplements only increase their red cell mass by 180–250 mL
Maternal iron deficiency anemia during pregnancy and the perinatal period have devastating effects on both the mother and child. In addition to the direct effects of anemia, reduced fetal brain maturation, pediatric cognitive defects, and maternal depression are associated with iron deficiency anemia.
If left untreated during infancy, childhood, and adolescence, anemia and iron-associated cognitive defects may conceivably be passed between generations much like genetic traits. Unless the iron deficiency is treated at some stage of life, the cycle of iron deficiency from mother to child may remain unbroken for several generations.
Iron deficiency anemia and malaria coexist in most tropical regions of the world. Malaria contributes to iron deficiency anemia by causing intravascular hemolysis with subsequent loss of hemoglobin iron in the urine. This clinical feature was described in 1898 as blackwater fever.
Malaria also causes an immune response that suppresses erythropoietin (Burgmann et al. 1996) as well as direct effects on erythropoiesis (Skorokhod et al. 2010). The host may also increase hepcidin expression for protection from liver-stage malaria (Portugal et al. 2011). Of course, increased hepcidin restricts iron and might delay erythroid recovery.
It is essential to understand the complex interplay between iron, hepcidin, and malaria when considering efforts to eradicate iron deficiency in malaria-endemic regions. If iron redistribution by hepcidin is beneficial for malaria, restricted iron could benefit the infected host. This hypothesis may help explain the recent report of potential harm caused by iron supplementation among preschool children in malaria-endemic areas
However, a recent Cochrane paper recommended, “iron supplementation should not be withheld from children living in malaria-endemic countries” (Okebe et al. 2011). Treatment of iron deficiency anemia is less clear in areas where access to proper malarial prevention and treatment are suboptimal. Further studies and resolution of this critical, but complex issue are awaited.
Like iron deficiency anemia, hookworm infection affects several hundred million humans worldwide. Amazingly, a recent study reported that there is considerable overlap between malaria and hookworm in sub-Saharan Africa.
Worldwide, there are two hookworm species that infect humans. Both are found in tropical regions based on the requirement of moist soil for survival. The worm is introduced to the soil by fecal matter in regions where sanitation is not present. From the soil, the parasite accesses the duodenum of a new human host directly by mouth, or indirectly via the skin.
Once in the gut, the worm may be retained for several years as it releases eggs in the stool. A hookworm infection should be suspected in cases of travel or habitation in the tropics, iron deficiency anemia, and mild eosinophilia. Owing to their location in the small bowel, capsule endoscopy is helpful for diagnosis if eggs are not present in the stool.
Understanding Iron Biology
It is predicted that advances in global therapy for iron deficiency anemia will be greatly assisted by basic research efforts. Perhaps the most significant advance in this regard is the discovery and development of hepcidin biology over the last decade .
Hepcidin biology will undoubtedly evolve into applications for iron deficiency anemia among all world populations. For instance, the recognition that hepcidin expression is highly variable and influenced by a circadian rhythm should be advantageous in improving dosing regimens.
The kinetics of hepcidin expression in response to iron supplementation for iron deficiency remain largely unexplored as another research avenue aimed toward the optimization of therapy. Clinical comparisons of oral versus intravenous therapies will help determine if a rapid pulse of therapy can improve the chances of success for certain individuals or groups of patients.
Certain populations do not benefit from universal iron supplementation (Ghio 2011). With inherited hemochromatosis, the absorption of dietary iron increases. Some genetic variants are quite common, especially in northern Europeans.
As evidenced by the importance of iron for malarial pathogenesis, further research into the complex relationships between deprivation of iron for this pathogen and iron deficiency anemia are needed to determine the best course of therapy. Determination of hookworm effects on hepcidin expression should also be pursued. In populations afflicted with one or both of these parasites, efforts to supplement iron can be confounded by the host’s inflammatory response.
Relationships between hookworm and intestinal iron absorption should be studied further, understood, and incorporated into eradication efforts. Ideally, strategies will be tested that incorporate vaccination, sanitation, malarial treatment, deworming, and iron supplements into the same research plan. Although such strategies seem ambitious in a world of limited resources, it is crucial to remember that hundreds of millions stand to benefit worldwide.
Anemia signs and symptoms vary depending on the cause and severity of anemia. Depending on the causes of your anemia, you might have no symptoms.Signs and symptoms, if they do occur, might include:
- Pale or yellowish skin
- Irregular heartbeats
- Shortness of breath
- Dizziness or lightheadedness
- Chest pain
- Cold hands and feet
What red blood cells do
Your body makes three types of blood cells — white blood cells to fight infection, platelets to help your blood clot, and red blood cells to carry oxygen from your lungs to the rest of your body and carbon dioxide from the body back to the lungs.Red blood cells contain hemoglobin — an iron-rich protein that gives blood its red color.
Hemoglobin enables red blood cells to carry oxygen from your lungs to all parts of your body and to carry carbon dioxide from other parts of the body to your lungs to be exhaled.
Most blood cells, including red blood cells, are produced regularly in your bone marrow — a spongy material found within the cavities of many of your large bones. To produce hemoglobin and red blood cells, your body needs iron, vitamin B-12, folate and other nutrients from the foods you eat.
Causes of Anemia
Different types of anemia have different causes. They include:
- Iron deficiency anemia. This most common type of anemia is caused by a shortage of iron in your body. Your bone marrow needs iron to make hemoglobin. Without adequate iron, your body can't produce enough hemoglobin for red blood cells.Without iron supplementation, this type of anemia occurs in many pregnant women. It's also caused by blood loss, such as from heavy menstrual bleeding; an ulcer in the stomach or small bowel; cancer of the large bowel; and regular use of some pain relievers that are available without a prescription, especially aspirin, which can cause inflammation of the stomach lining resulting in blood loss. It's important to determine the source of iron deficiency to prevent the recurrence of the anemia.
- Vitamin deficiency anemia. Besides iron, your body needs folate and vitamin B-12 to produce enough healthy red blood cells. A diet lacking in these and other key nutrients can cause decreased red blood cell production. Some people who consume enough B-12 aren't able to absorb the vitamin. This can lead to vitamin deficiency anemia, also known as pernicious anemia.
- Anemia of inflammation. Certain diseases — such as cancer, HIV/AIDS, rheumatoid arthritis, kidney disease, Crohn's disease and other acute or chronic inflammatory diseases — can interfere with the production of red blood cells.
- Aplastic anemia. This rare, life-threatening anemia occurs when your body doesn't produce enough red blood cells. Causes of aplastic anemia include infections, certain medicines, autoimmune diseases, and exposure to toxic chemicals.
- Anemias associated with bone marrow disease. A variety of diseases, such as leukemia and myelofibrosis, can cause anemia by affecting blood production in your bone marrow. The effects of these types of cancer and cancer-like disorders vary from mild to life-threatening.
- Hemolytic anemias. This group of anemias develops when red blood cells are destroyed faster than bone marrow can replace them. Certain blood diseases increase red blood cell destruction. You can inherit a hemolytic anemia, or you can develop it later in life.
- Sickle cell anemia. This inherited and the sometimes serious condition is hemolytic anemia. It's caused by a defective form of hemoglobin that forces red blood cells to assume an abnormal crescent (sickle) shape. These irregular blood cells die prematurely, resulting in a chronic shortage of red blood cells.
These factors place you at increased risk of anemia:
- A diet lacking in certain vitamins and minerals. A diet consistently low in iron, vitamin B-12, folate and copper increases your risk of anemia.
- Intestinal disorders. Having an intestinal disorder that affects the absorption of nutrients in your small intestine — such as Crohn's disease and celiac disease — puts you at risk of anemia.
- Menstruation. In general, women who haven't had menopause have a greater risk of iron deficiency anemia than do men and postmenopausal women. Menstruation causes the loss of red blood cells.
- Pregnancy. Being pregnant and not taking a multivitamin with folic acid and iron, increases your risk of anemia.
- Chronic conditions. If you have cancer, kidney failure or another chronic condition, you could be at risk of anemia of chronic disease. These conditions can lead to a shortage of red blood cells.Slow, chronic blood loss from an ulcer or other source within your body can deplete your body's store of iron, leading to iron deficiency anemia.
- Family history. If your family has a history of an inherited anemia, such as sickle cell anemia, you also might be at increased risk of the condition.
- Other factors. A history of certain infections, blood diseases and autoimmune disorders increases your risk of anemia. Alcoholism, exposure to toxic chemicals and the use of some medications can affect red blood cell production and lead to anemia.
- Age. People over age 65 are at increased risk of anemia.