The World Health Organization estimates that 2 billion people – about 30% of the global population – are anemic as a consequence of iron deficiency, making iron-deficiency anemia one of the most prevalent nutritional conditions worldwide (WHO 2012a). The incidence of anemia increases with advancing age, with 6–11% of people >65 years and over 20% of people over 85 diagnosed with the condition in the United States and England (Guralnik 2004; Patel 2008; Mindell 2012). It occurs more frequently in African Americans (CDC 2001; Zakai 2009) and women due to menstrual blood loss (Mayo Clinic 2011a). Accordingly, in the United States, black women have the highest and white men the lowest incidence of anemia (Zakai 2005).
Treating this nutritional condition is of the utmost importance in stroke patients because anemic stroke patients exhibit up to a 3-fold higher mortality within 1 year of a stroke than non-anemic patients (AHA 2012). Moreover, anemia is present in up to 90% of chronic kidney disease patients (Barros 2011), and it significantly increases the mortality risk in this population (KDOQI 2007).
Causes & Risk Factors
There are a variety of specific pathologies that lead to anemia, and many different risk factors. The mechanisms by which these pathologies occur include decreased red blood cell production, excessive blood loss, and increased red blood cell destruction (Mayo Clinic 2011a).
Iron deficiency anemia. In the United States, about 17% of anemia cases among the elderly are attributable to iron-deficiency (Guralnik 2004; Patel 2008). Iron is the key oxygen-binding element in hemoglobin, a red blood cell component that allows for oxygen transport and dispersion throughout the body. Also, low iron levels are associated with impaired red blood cell production (Aspuru 2011; MedlinePlus 2011a). Moreover, occult bleeding from the gastrointestinal tract an important cause of iron-deficiency anemia in men and postmenopausal women, and gastrointestinal bleeding is found in about half of all patients with iron deficiency anemia (Zhu 2010).
The 2 forms of iron encountered in the diet are heme and non-heme. Heme iron is derived from animal products that contain hemoglobin, such as red meat, fish, and poultry; non-heme iron is derived from plants, which do not contain hemoglobin (ODS 2012). Iron in red meat, which is predominantly found in its native heme form in the hemoglobin molecule, is absorbed more efficiently than non-heme iron (Ekman 1993); although the exact reason for this is unclear (Aspuru 2011; Gaitan 2012).
Vegetarian diets are associated with anemia. One reason is because non-heme iron from vegetarian sources, such as legumes and leafy greens, has poor bioavailability (Aspuru 2011). For example, in a controlled feeding study in healthy young men, 37% of heme iron was bioavailable compared to only 5% of non-heme iron (Bjorn-Rasmussen 1974). These results were confirmed in a study of obese patients wherein the absorption of heme and non-heme iron was 23.9% and 11.1%, respectively (Ruz 2012). Also, healthy young women showed roughly 35% greater absorption of iron administered as heme iron compared to ferrous sulfate (Young 2010).
Vitamin B12 and folate deficiency anemia. Deficiency of vitamin B12 and folate, both of which are involved in the production and/or function of red blood cells, can lead to anemia.
Folate deficiency. The body’s folate stores, which amount to about 20 mg, must be continuously replenished, or symptoms of folate deficiency appear in as little as 4 months (Gentili 2012). In the United States, folate deficiency has become less common due to mandatory folic acid enrichment of some foods (Dietrich 2005); although certain factors, such as high alcohol consumption, increase risk (Koike 2012). One study of patients >65 years showed that 53% were anemic, and 21% of the anemia cases were attributable to folate deficiency (Petrosyan 2012). Folate-deficiency anemia is also prevalent among patients suffering from inflammatory bowel disease like Crohn’s disease, likely due to impaired folate absorption (Mullin 2012).
- Vitamin B12 deficiency. Vitamin B12 deficiency anemia is rare in people who consume meats and plant-based foods. One study showed that vegetarians have significantly lower plasma B12 levels compared with non-vegetarians (Gammon 2012). Despite the fact that B12 can be stored in the liver for years (NIH 2011), vegetarianism, alcohol consumption, and gastrointestinal disorders such as Crohn’s disease may reduce B12 status and, in the long run, result in clinical B12 deficiency (Langan 2011).
Vitamin B12 is necessary for two biological reactions. The first is the conversion of folate to its active form, tetrahydrofolate; thus, B12 deficiency causes a functional folate deficiency known as the “folate trap” (Bender 2003). The second is the conversion of methylmalonyl-CoA into succinyl-CoA, which is an important step in the extraction of chemical energy from foods (Hvas 2006). Blood levels of methylmalonate accumulate in B12 deficiency and can be used to differentiate it from folate deficiency (Miller 2009).
Anemia of chronic disease. Anemia of chronic disease (ACD) is an adaptive response that develops in conjunction with inflammation and mimics iron deficiency, although there is no shortage of iron per se; the iron is instead sequestered by mononuclear phagocytes, which are cells of the immune system responsible for engulfing pathogens and cellular debris (Weiss 2009; Zarychanski 2008). Anemia of chronic disease is associated with chronic, inflammatory diseases, such as cancer, autoimmune diseases, chronic microbial infections (Kumar 2009a), and chronic kidney disease (Sun 2012; Zarychanski 2008; Weiss 2009).
Anemia due to blood loss. Blood loss, a more direct cause of anemia, is frequently observed during surgery, due to lesions in the gastrointestinal tract, and as a consequence of excessive bleeding during menstruation in women (MSMR 2012). Anemia is more common in people with celiac disease due to gastrointestinal bleeding (Ludvigsson 2009). Blood loss due to colorectal cancer is also an important cause of iron deficiency anemia, and patients who present to a physician with anemia for which other causes have been ruled out should be screened for cancer, especially of the ascending colon (Raje 2007; Moldovanu 2012). In one study, anemia was present in over 65% of patients who underwent surgery for ascending colon cancer (Moldovanu 2012).
Aplastic Anemia. Aplastic anemia is a rare condition in which the production of all blood cells is reduced (Mayo Clinic 2011b). It is a bone marrow disorder that is thought to occur when the immune system mistakenly attacks healthy bone marrow cells (MedlinePlus 2012b). Although an exact cause is not defined, autoimmunity and genetics may play a role. The condition has been associated with toxin exposure, chemotherapy, hepatitis, and rheumatoid arthritis (Kumar 2009b; NHLBI 2011).
Sickle cell anemia and thalassemia. Sickle cell anemia results in malformation and malfunction of red blood cells. It is caused by a genetic mutation in the hemoglobin gene, which leads to misshapen red blood cells that are unstable and less able to transport oxygen to tissues. This condition results in anemia because the life span of the affected red blood cells is reduced by about 90%. Thalassemia causes formation of abnormal hemoglobin, which leads to excessive red blood cell destruction (Mayo Clinic 2011d,e). Oxidative stress is an important pathophysiologic aspect of sickle cell anemia that both contributes to symptoms and arises as a consequence of pathologies such as vaso-occlusive crises. Reactive oxygen species can be markers of disease severity, and may serve as targets for antioxidant therapies (Nur 2011). Therefore, interventions with antioxidants, such as N-acetyl cysteine, represents a therapeutic option in individuals with sickle cell anemia (Chirico 2012; Nur 2012).
Sickle cell anemia and thalassemia are genetic conditions; thus, the major risk factor is family history. Sickle cell is more common in people from Africa, India, Saudi Arabia, and South America (Mayo Clinic 2011e), whereas thalassemia is concentrated in people of Italian, Greek, Middle Eastern, Asian, and African ancestry (Mayo Clinic 2011g). Both sickle cell anemia and thalassemia are more prevalent in tropical regions because the genetic mutation underlying these conditions confers partial resistance to malaria (Penman 2012).
Hemolytic anemia. Hemolytic anemia is a type of anemia caused by excessive red blood cell destruction (Jilani 2011). This can be due to intrinsic factors within the red blood cells such as oxidative stress (Jilani 2011), or extrinsic factors such as an enlarged, overactive spleen (MedlinePlus 2011b). Oxidative stress is a central feature of diseases characterized by hemoglobin or red blood cell abnormalities, and it can damage red blood cells. Red blood cell defects can lead to increased production of free radicals, which damage cellular membranes and disrupt their function, promoting increased destruction and impaired production of red blood cells (Fibach 2008). Several inherited or acquired red blood cell and hemoglobin abnormalities can cause hemolytic anemia (Mayo Clinic 2013). One sign of this anemia subtype is the development of jaundice: red blood cell destruction releases hemoglobin, which is broken down into bilirubin, leading to yellowing of the skin and the whites of the eyes (NHLBI 2011).
Signs, Symptoms, and Diagnosis
In general, a complete blood count (CBC) is used for routine blood examination. Anemia can be ascertained through hemoglobin, hematocrit and/or red blood cell count (Elghetany 2011; WHO 2011a; A.D.A.M. 2012).
Iron deficiency anemia. Symptoms of iron deficiency anemia include fatigue, pale skin, weakness, shortness of breath, headache, dizziness or lightheadedness, cold hands and feet, irritability, tongue inflammation or soreness, brittle nails, fast heartbeat, and poor appetite (Mayo Clinic 2011c). Iron provides color and size to erythrocytes; thus, red blood cells in iron deficiency anemia appear hypochromic (“less color”) and microcytic (“small”) under microscopic examination (Urrechaga 2009). The results of a CBC blood test provide insights that can help identify iron-deficiency anemia: low mean corpuscular volume (MCV) corresponds with “microcytic” red blood cells, and low mean corpuscular hemoglobin (MCH) corresponds with “hypochromic” red blood cells (Laboratory Corporation of America 2013a).
Another indicator of iron deficiency anemia is serum ferritin level (Weiss 2005; WHO 2011b). Ferritin, an iron storage protein, is regulated directly in proportion to iron status. As iron stores in the body decline, ferritin serves as a sensitive marker of iron deficiency (Weiss 2005; Clark 2008).
Anemia of chronic disease (ACD). ACD is usually not a severe form of anemia; therefore, anemia symptoms are generally mild. Thus, the most prominent symptoms associated with ACD are those of the underlying chronic disease (Merck 2011). It is important to differentiate between ACD and iron deficiency anemia because the main treatment of iron deficiency anemia (supplemental iron) can be harmful in ACD patients, whose iron levels may already be increased. In both conditions, hemoglobin and transferrin saturation is low; in iron deficiency anemia this is because total body iron stores are low, and in ACD this is because iron has been sequestered out of the blood. Transferrin is an iron-binding protein found in the blood, and “transferrin saturation” represents the proportion of transferrin bound to iron. Serum ferritin levels can be used to differentiate the two diseases, since generally serum ferritin is reduced in iron deficiency anemia but not ACD (Weiss 2005).
Vitamin deficiency anemia. In addition to the symptoms of iron deficiency, vitamin-deficiency anemia is associated with weight loss, diarrhea, muscle weakness, and mental confusion or forgetfulness (Mayo Clinic 2011h).
Folate deficiency causes megaloblastic anemia, a type of anemia in which red blood cells are enlarged or “macrocytic” (increased MCV) upon microscopic examination (MedlinePlus 2011a). The red blood cells are enlarged because of abnormal DNA synthesis in red blood cell precursors, which results in abnormal erythrocyte development (Khanduri 2007). The normal range for red blood cell folate is 499 – 1504 ng/mL (Laboratory Corporation of America 2013b).
Sickle cell anemia. Symptoms of sickle cell anemia include pain (especially in the back and hips), fatigue, reduced exercise tolerance, and jaundice (Mayo Clinic 2011d; Parsh 2012). Sickle cell can be confirmed using a lab test called hemoglobin electrophoresis, which allows for careful evaluation of the structure of hemoglobin in a blood sample (Lanzkron 2010).
Thalassemia. Thalassemia can be caused by a number of genetic mutations with varying degrees of severity; in general, however, symptoms of the minor forms of thalassemia resemble anemia, whereas the more severe variations may also present with jaundice, skin ulcers, and abdominal fullness or discomfort (Merck 2008b). This form of anemia resembles iron deficiency in that the red blood cells appear microcytic and hypochromic, although iron levels are elevated (MedlinePlus 2012c).
Iron deficiency anemia. Iron deficiency anemia is typically treated with oral supplemental iron (Aspuru 2011). Early studies indicate potential tolerability and efficacy advantages of a form of iron called iron protein succinylate over other forms of supplemental ironin the treatment of iron-deficiency anemia (Cremonesi 1993; Landucci 1987; Haliotis 1998; Kopcke 1995).
Vitamin C facilitates the absorption of iron by reducing dietary nonheme iron, which is found in its oxidized “ferric” (Fe3+) form, to the “ferrous” (Fe2+) form (Higdon 2006; Munoz 2011). Parenteral iron therapy is generally reserved for severe iron deficiency, although one study showed no difference in the efficacy of intravenous iron therapy compared to treatment with oral iron in the form of ferrous fumarate (Garrido-Martin 2012). Furthermore, erythropoietin (Aranesp®), a kidney-derived hormone that stimulates erythrocyte production, co-administered with intravenous iron sucrose showed no benefits over intravenous iron alone in the management of iron deficiency anemia (Terrovitis 2012). Collectively, these results suggest that oral iron therapy is adequate in managing common iron-deficiency anemia.
Erythropoietin and similar mimetic drugs are not without benefits, however, particularly in patients with kidney disease when synthesis and secretion of the hormone is impaired (Macdougall 2012). Peginesatide (Omontys®), one such drug, was approved by the Food and Drug Administration (FDA) in 2012 for the treatment of anemia in adults with chronic kidney disease (FDA 2012). In a review of phase II and III clinical trials of peginesatide, it was noted that doses as low as 0.1 mg/kg body weight administered once a month significantly increased hemoglobin levels compared to placebo and was well tolerated (Mikhail 2012).
Vitamin deficiency anemia. Megaloblastic anemia, which is characterized by an abundance of abnormally large and dysfunctional red blood cells, is most commonly caused by folate and/or B12 deficiency. Megaloblastic anemia due to B12 deficiency is either caused by inadequate intake, in which case oral supplementation is sufficient, or poor absorption potentially due to a reduction in “intrinsic factor.” Intrinsic factor, which is synthesized by cells in the stomach, is secreted into the gastrointestinal tract to bind dietary B12 and facilitate its absorption (Wickramasinghe 2006). In the case of impaired absorption, injections of 1000 mcg B12 are typically administered daily for one week, then weekly for one month, and monthly thereafter (Hvas 2006). However, when directly compared to a similar dosing regimen administered orally in a population of megaloblastic anemics, injectable B12 was not superior to oral dosing (Bolaman 2003). A comprehensive review of randomized controlled trials confirmed the adequacy of oral dosing in most cases of B12 deficiency (Vidal-Alaball 2005).
Anemia of Chronic Disease (ACD). The primary goal in treating ACD is to target the underlying disorder, although management of anemic symptoms is also necessary. Hepcidin, a primary regulator of iron absorption and storage, is increased by inflammation and thought to mediate much of ACD pathology (von Drygalski 2012). During inflammation, hepcidin levels rise and promote sequestration of serum iron into immune cells called macrophages. This gives rise to functional iron-deficiency anemia because iron sequestered in these immune cells is unavailable to perform functions vital to the production and maintenance of red blood cells. Hepcidin functions similarly in the intestine; it reduces systemic iron absorption by causing ingested iron to be retained in cells that line the gut (ie, enterocytes). Systemic inflammation is associated with increased levels of the cytokine Interleukin-6 (IL-6), which has been shown to enhance the synthesis and secretion of hepcidin (Hentze 2010). Tocilizumab (Actemra®) (a drug that blocks the IL-6 receptor), when administered at a dose of 8 mg/kg every other week, was shown decrease hepcidin and improve all iron-related blood parameters in a year-long study of patients with ACD (Song 2010). However, due to the drug’s immune suppressing effects, those taking Tocilizumab are at an increased risk for serious health conditions, including infections that may lead to hospitalization or death (MD Consult 2012).
Sickle cell anemia. The major treatment for blood abnormalities in sickle cell anemia is targeted at increasing the amounts of fetal hemoglobin, a molecule that functions similarly to hemoglobin but lacks the sickle cell mutation and is primarily found in the developing fetus. A study that administered 100 mg alpha-tocopherol per day for 6 weeks to children with sickle cell anemia reported a significant increase in the percent fetal hemoglobin and hemoglobin concentration, in addition to increasing the resistance of the red blood cells to lysis (Jaja 2005). Fetal hemoglobin can also be increased with hydroxycarbamide (Hydrea®), an anti-cancer drug (Wang 2011). In a double-blind, randomized, clinical trial, a group of sickle cell anemia patients receiving hydroxycarbamide experienced significantly less pain and required fewer blood transfusions than those receiving placebo (Charache 1995). This result has been confirmed in longer-term studies, in which total mortality was reduced in the group receiving hydroxycarbamide after 9 (Steinberg 2003) and 17.5 years of follow-up (Steinberg 2010). Several other treatment strategies are employed to manage conditions associated with sickle cell anemia, particularly drugs to manage pain during vaso-occlusive crisis or “flares”, such as opioids and non-steroidal anti-inflammatory drugs (NSAIDs). Derivatives of the anticoagulant heparin have also been investigated in the context of sickle cell pain crisis and have met with some success and may help prevent crises, though more studies are needed to confirm these findings (Qari 2007; Mousa 2010). Physicians should also aggressively diagnose and treat suspected infections with antibiotics (Ferri 2013a). Several tests can help guide treatment upon initial presentation of sickle-cell related pain, including a CBC, blood chemistry profile, folate and vitamin B12 status, thyroid function tests, urine analysis, and chest x-ray (Mousa 2010).
Thalassemia. Minor forms of thalassemia are generally asymptomatic and do not require therapeutic intervention (Merck 2008b). For more serious forms, however, patients often depend on lifelong blood transfusions. A vital factor in these patients is iron overload, although when present, it can be effectively managed by chelation therapy (Berdoukas 2012). For example, in one study, thalassemia patients undergoing regular blood transfusions and administration of the iron chelators deferasirox (Exjade®, 20–30 mg/kg daily by mouth) and deferoxamine (35–50 mg/kg intravenous or subcutaneous infusions every other day) had significantly reduced iron stores and ferritin levels over the course of 12 months (Lal 2012). The rationale for using multiple chelators is so the individual dose of each agent can be lower, which reduces the risk of adverse events without decreasing clinical efficacy (Grady 2012). In addition to blood transfusions and iron chelation, hormone replacement may be employed; hormonal disorders can occur in thalassemia, and strategies to support bone health should not be overlooked since osteoporosis is common in this population. Surgical removal of the spleen (ie, splenectomy) may be required in cases where the organ is over-functioning. The drug hydroxyurea (Hydrea®), which is often used to treat painful crises in sickle cell anemia, may be of benefit in some thalassemia patients (Rund 2005).
One of the characteristic features in thalassemia is that red blood cells get destroyed at a faster rate. A promising therapeutic strategy is supplementation with vitamin E, based on a study showing that after supplementation with 350 mg vitamin E daily for 1 month, beta-thalassemia/hemoglobin patients with splenectomy (removal of the spleen) experienced a significant increase in their red blood cell membrane fluidity, suggesting that this approach could prevent red blood cell damage in this patient group (Sutipornpalangkul 2012).
Curing thalassemia depends on finding an exact donor match for the transplantation of bone marrow (Mehta 2012; Ferri 2013b). This procedure consists of eradicating the hematopoietic system with busulfan (Myleran®) and suppressing the immune system with cyclophosphamide (Endoxan®). Then, bone marrow obtained from the donor’s hipbone is infused intravenously over the course of 4–6 hours. Red blood cells and platelets are then transfused and a variety of antimicrobial agents are administered until the recipient’s bone marrow recovers (Lucarelli 2002). If an exact donor match cannot be found, an alternative to this procedure is the use of blood from the umbilical cord of an unrelated donor. One study showed the success rate of such a regimen is ≥80%, which is comparable to the success rate of donor-matched bone marrow transplantation (Jaing 2012).
Novel and Emerging Therapies
Anti-hepcidin therapy. Directly targeting hepcidin with specific anti-hepcidin antibodies has shown promise in animal models of ACD (Sasu 2010). For example, a dorsomorphin derivative (dorsomorphin is a small molecule inhibitor of inflammation-induced hepcidin) has been shown to be an effective treatment in a rat model of ACD (Theurl 2011). These novel therapeutics have the advantage over other agents of being highly specific and thus less likely to have ancillary side effects (Sun 2012).
The mainstay therapy for aplastic anemia includes immunosuppressants such as cyclosporine. Although able to reduce the immune system’s ability to attack and destroy bone marrow, this treatment is accompanied by potentially severe adverse drug reactions, and not all patients respond. Rituximab (Rituxan®), a highly specific antibody used to treat lymphomas and autoimmune diseases may benefit certain patients with refractory aplastic anemia (Gomez-Almaguer 2012). Eltrombopag (Promacta®), a platelet-enhancing drug indicated for the treatment of thrombocytopenia, has been shown to increase erythrocyte production in patients with aplastic anemia who were non-responders to immunosuppressants. In one study, 150 mg of eltrombopag significantly increased red blood cells and reduced the need for blood transfusions in patients with refractory aplastic anemia (Olnes 2012).
Peginesatide. Peginesatide (Omontys®), a long-acting erythropoietin mimetic drug, has been shown to be effective in anemic patients with chronic kidney disease. It also has the added benefit of a once-monthly dosing, as opposed to the much more frequent dosing required for the mainstay epoetin alfa treatment (Besarab 2012).
Sodium dimethylbutyrate. Sodium dimethylbutyrate, an experimental therapeutic, has also been tested for its ability to stimulate fetal hemoglobin in sickle cell anemics. In one short-term pilot study, sodium dimethylbutyrate increased fetal hemoglobin levels in a dose-dependent manner (Kutlar 2012). Thus, sodium dimethylbutyrate may be a promising alternative for those who cannot tolerate the side effects of hydroxycarbamide, which may include nausea, vomiting, diarrhea, constipation, and dizziness (Liebelt 2007).
Gene therapy. While thalassemia can be managed by lifelong blood transfusions and iron chelation therapy, or potentially cured by bone marrow transplantation or cord blood transfusions, none of these interventions are without side effects including neurotoxicity, cancer, and even death (Noe 2010; Montebugnoli 2011; Fossati 2010). Gene therapy, a therapeutic avenue that targets the underlying disorder (ie, the genetic mutation), consists of harvesting the patient’s own bone marrow, genetically transferring a proper copy of the defective hemoglobin gene, and infusing it back into the patient (Nienhuis 2012). Gene therapy has shown promise in animal models of thalassemia, and clinical trials are underway (Payen 2012; Raja 2012).