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	Highlights
	Introduction
	Causes
	Risk Factors
	Complications
	Symptoms
	Diagnosis
	Dietary Factors
	Treatment
	Resources
	References

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Anemia

Highlights

FDA Issues Labeling Changes for Drugs That Boost Red Blood Cells

In November 2007, the U.S. Food and Drug Administration (FDA) made several changes to the prescribing labels for erythropoiesis-stimulating drugs. These drugs -- epoietin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp) -- increase the production of red blood cells. They are used to treat anemia associated with chronic kidney failure, cancer chemotherapy, and antiretroviral HIV therapy.

The new labels have stronger warnings and updated dosing-related safety information. The FDA advises:

• For cancer, erythropoiesis-stimulating drugs are used only to treat anemia associated with chemotherapy. Dosing should increase hemoglobin levels to no more than 12 g/dL. These drugs can shorten survival time and increase tumor growth when hemoglobin levels are raised beyond this point. Treatment should stop as soon as chemotherapy is completed. Erythropoiesis-stimulating drugs are not safe or appropriate for all patients undergoing chemotherapy. Patients should discuss the risks and benefits with their oncologists.
• For chronic kidney failure, erythropoiesis-stimulating drugs should be used to maintain a hemoglobin level between 10 - 12 g/dL. Higher hemoglobin levels increase the risk for stroke, heart attack, heart failure, or death.
• Erythropoiesis-stimulating drugs are used to increase red blood cell numbers and reduce the need for blood transfusions. They do not help improve anemia symptoms, fatigue, or quality of life for patients with cancer or HIV.
• Patients who take these drugs should contact their doctors if they experience symptoms such as leg pain or swelling, increased shortness of breath, increased blood pressure, dizziness, or extreme fatigue.

Introduction

Anemia is an abnormal reduction in red blood cells.

This photmicrograph shows normal red blood cells (RBCs) as seen in the microscope after staining.

Anemia is a global problem, at its worst in developing countries. But it is by no means absent in industrialized nations. An estimated 3.4 million Americans suffer from anemia. Anemia is not a single disease but a condition, like fever, with many possible causes and many forms. Causes of anemia include nutritional deficiencies, inherited genetic defects, medication-related side effects, and chronic disease. It can also occur because of blood loss from injury or internal bleeding, the destruction of red blood cells, or insufficient red blood cell production. The condition may be temporary or long-term, and can manifest in mild or severe forms.

As it is impossible to discuss all types of anemia, this report focuses on three of the most common forms:

• Iron deficiency anemia
• Anemia of chronic disease (ACD)
• Megaloblastic anemia (caused by deficiencies in the B vitamins folate, vitamin B12, or both)

Some less common causes and types of anemia are included in a table in this report.

Blood

Blood has two major components:

• Plasma is a clear yellow liquid that contains proteins, nutrients, hormones, electrolytes, and other substances. It constitutes about 55% of blood.
• White and red blood cells and platelets make up the balance of blood. The white cells are the infection fighters for the body, and platelets are necessary for blood clotting. The important factors in anemia, however, are red blood cells.

Red blood cells (RBCs), also known as erythrocytes, carry oxygen throughout the body to nourish tissues and sustain life. Red blood cells are the most abundant cells in our bodies. Men have about 5.2 million red blood cells per cubic millimeter of blood, and women have about 4.7 million per cubic millimeter of blood.

Hemoglobin and Iron

Each red blood cell contains 200 - 300 hemoglobin molecules. Hemoglobin is a complex molecule, and it is the most important component of red blood cells. It is composed of protein (globulin) and a molecule (heme), which binds to iron.

In the lungs, the heme component binds to oxygen in exchange for carbon dioxide. The oxygenated red blood cells are then transported to the body's tissues, where the hemoglobin releases the oxygen in exchange for carbon dioxide, and the cycle repeats. The oxygen is used in the mitochondria, the power source within all cells.

Red blood cells typically circulate for about 120 days before they are broken down in the spleen. Most of the iron used in hemoglobin can be recycled from there and reused.

Structure and Shape of Red Blood Cells

Red blood cells -- the erythrocytes -- are extremely small and look something like tiny, flexible inner tubes. This unique shape offers many advantages:

• It provides a large surface area to absorb oxygen and carbon dioxide.
• Its flexibility allows it to squeeze through capillaries, the tiny blood vessels that join the arteries and veins.

Abnormally shaped or sized erythrocytes are typically destroyed and eliminated.

Blood Cell Production (Erythropoiesis)

The actual process of making red blood cells is called erythropoiesis. (In Greek, erythro means "red," and poiesis means "the making of things.") The process of manufacturing, recycling, and regulating the number of red blood cells is complex and involves many parts of the body:

• The body carefully regulates its production of red blood cells so that enough are manufactured to carry oxygen but not so many that the blood becomes thick or sticky (viscous).
• Most of the work of erythropoiesis occurs in the bone marrow. In children younger than 5 years old, the marrow in all the bones of the body is enlisted for producing red blood cells. As a person ages, red blood cells are eventually produced only in the marrow of the spine, ribs, and pelvis.
• If the body needs more oxygen (at high altitudes, for instance), the kidney triggers the release of the hormone erythropoietin (EPO), a hormone that acts in the bone marrow to increase the production of red blood cells.
• The lifespan of a red blood cell is 90 - 120 days. The liver and the spleen remove old red blood cells are removed from the blood by the liver and spleen.
• When old red blood cells are broken down for removal, iron is returned to the bone marrow to make new cells.

Click the icon to see an image of the formed elements of blood.

Click the icon to see an image of hemoglobin.

Causes

Iron Deficiency Anemia

Iron deficiency anemia occurs when the body lacks mineral iron to produce the hemoglobin it needs to make red blood cells. In general, there are three stages leading from iron deficiency to anemia:

• First, there is an insufficient supply of iron, which causes iron stores in the bone marrow to be depleted. This stage generally has no symptoms.
• Second, iron deficiencies develop and begin to affect hemoglobin production. (Tests will show low hemoglobin and hematocrit levels.)
• Hemoglobin production declines to the point where anemia develops.

Most of the iron used in the body can be recycled from blood and reused. Nevertheless, iron deficiency can occur from a number of conditions.

Inadequate Iron Intake. A healthy diet easily provides enough iron. In general, most people need just 1 mg, and menstruating women need 2 mg of extra iron each day. This means that lack of iron in the diet is not a common cause of iron deficiency anemia, except in infants. In fact, most American adults may be consuming too much iron in their diet. Most of the iron in red blood cells is recycled and reused. Iron-poor diets are a cause of anemia only in people with existing risks for iron deficiency. Children who have not yet eaten iron-fortified formulas or iron-enriched cereal may also become anemic.

Blood Loss. Iron deficiencies most commonly occur from internal blood loss due to other conditions that range in severity. These conditions include:

• Peptic ulcers, which may be caused by H. pylori infections, or aspirin and drugs or nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen. About 70% of long-term users of these medications have some sign of gastrointestinal bleeding, although it is rarely significant enough to cause anemia.
• Duodenal ulcers
• Hemorrhoids
• Colon polyps
• Colon, stomach, and esophageal cancer
• Very heavy periods (menorrhagia) are the most common causes of anemia in premenopausal women.
• Bleeding from esophageal varices, often present in alcoholics

Impaired Absorption of Iron. Impaired absorption of iron is caused by:

• Certain intestinal diseases (inflammatory bowel disease, celiac disease)
• Surgical procedures, particularly those involving removal of parts of the stomach and small intestine, can impair the ability of the stomach or intestine to absorb iron. (Such conditions also often impair folic acid absorption as well.)
• Pica, the craving for non-food substances such as ice, starch, or clay, is a possible cause of iron deficiency. To complicate matters, pica (particularly ice cravings) may also be a symptom, rather than a cause, of anemia.
• Certain intestinal infections, such as hookworm and other parasites.

Click the icon to see an image of inflammatory bowel disease.

Genetic Causes. Some people are born with iron deficiency. Certain cases may be due to a mutation of the Nramp2 gene, which regulates a protein responsible for delivering iron to the cells.

Anemia of Chronic Disease (ACD)

Anemia of chronic disease (ACD), also called anemia of chronic inflammation (ACI), is a common condition associated with a wide variety of persistent inflammatory diseases. It can be very severe and require transfusions.

The Inflammatory Process and ACD. ACD is not completely understood. In ACD, iron is not efficiently recycled from blood cells, and red blood cell survival is reduced. In addition, there is impaired response to erythropoietin, the hormone that acts in the bone marrow to increase the production of red blood cells. (Abnormal function and low levels of erythropoietin, in fact, may be the most important factor in ACD, with iron insufficiencies being a consequence.)

The process leading to ACD may occur in the following way:

• The immune system activates white blood cells and releases various compounds during times of infection that are intended to fight invaders and heal wounds. Such an event causes an inflammatory state in the areas of the attack.
• White blood cells called macrophages release small but powerful proteins known as cytokines, which are critical in the development of ACD. Cytokines are indispensable for healing. However, cytokines are overproduced often in chronic and inflammatory diseases, causing serious tissue injury and, in some cases, even organ damage. In the case of ACD, they prevent production of erythropoietin, the hormone that acts in the bone marrow to increase the production of red blood cells. Specific cytokines implicated in anemia are interleukin 1 (IL-1), tumor necrosis factor (TNF), and interferons.
• As part of this process, mechanisms prevent the release of recycled iron needed in the bone marrow for the manufacturing of red blood cells. Iron absorption in the intestines is also blocked. Theoretically, this is a protective measure, since iron may help infectious organisms proliferate. In such cases, iron stores are high, but the usable iron in circulation is low.
• Researchers have identified a peptide called hepcidin, which prevents iron absorption in the intestine and blocks the release of iron by immune factors for red blood cell production. Some experts believe high levels of the peptide may play a central role in preventing the release of iron during infection and inflammatory states, and is critical in ACD.

Diseases Associated with ACD and Inflammation. The chronic diseases that are associated with this process include:

• Certain cancers. Examples include lymphomas and Hodgkin's disease.
• Autoimmune diseases. Examples include rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, and polymyalgia rheumatica.
• Long-term infections. Examples include chronic or recurrent urinary tract infections and osteomyelitis.
• Hepatitis C. The liver cirrhosis associated with hepatitis C can reduce the production of red blood cells. Gastrointestinal bleeding may also contribute to blood loss.
• Heart failure. Experts estimate that 25 - 60% of patients with heart failure also have anemia. However, it is unclear whether anemia actually causes or worsens heart failure. Recent research suggests it may actually be a sign (marker) of heart failure. Iron deficiency in heart failure can be due to a number of factors. It may be caused by a lack of nutrients in a persons diet or by the bodys inability to absorb nutrients from food. Heart failure can also cause a back up of fluid (edema). This edema produces a higher volume of blood plasma (the liquid part of blood), which can dilute red blood cells and cause anemia.
• Chronic kidney disease. The hormone erythropoietin (EPO) is produced in the kidneys and stimulates the bone marrow production of red blood cells. Diseased kidneys do not release sufficient amounts of EPO; anemia can result and is universal in end-stage renal disease. Chronic kidney disease is a common complication of diabetes.
• HIV/AIDS. The inflammatory process associated with AIDS can adversely affect EPO levels and red blood cell production.
• Anemia in critically ill patients. Evidence suggests similarities between ACD and severe anemia in patients who are in intensive care. Some experts believe that the cause of anemia in such critically ill patients may also be due to inflammatory responses that promote impaired responsiveness to erythropoietin.

Not all chronic diseases involve the inflammatory process and anemia. For example, high blood pressure is a chronic disease, but it does not affect red blood cells.

Treatment-Related Anemia. Anemia can also result from the therapies used to treat conditions. For example, anemia is a common side effect of cancer treatments. Chemotherapy and radiation can impair the bone marrow's production of red blood cells and contribute to the extreme fatigue that many patients experience during cancer therapy. Patients with hepatitis C frequently receive combination therapy of ribavirin and interferon; ribavirin can induce anemia. Hepatitis C also affects many patients with HIV or AIDS. In addition to ribavirin, patients with HIV or AIDS can develop anemia as a result of highly active anti-retroviral therapy (HAART) and, in particular, from the drug AZT.

Other medications that increase the risk for anemia are certain antibiotics, some antiseizure medications (phenytoin), immunosuppressive drugs (methotrexate, azathioprine), antiarrhythmic drugs (procainamide, quinidine), and anti-clotting drugs (aspirin, warfarin, heparin).

Megaloblastic Anemia

Megaloblastic anemia is the end-product of deficiencies in the B vitamins folate or vitamin B12 (also called cobalamin), or both. Such deficiencies produce abnormally large red blood cells (megaloblastic ) that have a shortened lifespan. Neurologic problems are also associated with these deficiencies. Several conditions can cause these deficiencies.

Click the icon to see an image of red blood cells seen in megaloblastic anemia.

Causes of Vitamin B12 Deficiency. Conditions that cause vitamin B12 deficiencies include:

• Vitamin B12 deficiency from diet is very rare, since the liver stores over a 3-year supply. It usually does not occur even in alcoholism, vegetarianism, or in malnourished people with kidney failure or cancer. Since animal products are the chief source, however, true vegan vegetarians may need a supplement, fortified food, or appropriate food selection known to contain adequate amounts of this vitamin
• Pernicious anemia. Pernicious anemia is an autoimmune disease in which antibodies are tricked into attacking stomach cells. This results in impaired production of intrinsic factor (IF), a compound that is critical for absorption of vitamin B12. Pernicious anemia is diagnosed in about 1% of people over age 60, with women having a higher risk than men.
• Complications of gastrointestinal surgery. Surgeries such as stomach bypass or stapling, which remove part or all of the stomach, pose a 15 - 30% chance of causing vitamin B12 deficiencies.
• Overgrowth of intestinal bacteria
• Tropical sprue (an acquired malabsorption disease occurring in tropical climates)

Click the icon to see an image of the benefits of vitamin B12.

Causes of Folate Deficiency. The body stores only about 100 times its daily requirements for folate and can exhaust this supply within about 3 months if the diet is deficient in folate.

• Poor diet coupled with alcoholism is the most common cause of folate deficiency. Alcohol abuse not only contributes to malnutrition but also causes chemical changes that can result in lower folate levels.
• Any condition that disturbs the small intestine and impairs its absorption ability can cause a deficiency. Such disorders include inflammatory bowel disease or celiac sprue (a sensitivity reaction to gluten)

Click the icon to see an image of foods that contain gluten.

• Parasitic diseases such as giardiasis
• Short bowel syndrome
• Deficiencies can also arise due to high demand for folic acid caused by conditions such as cancer, pregnancy, severe psoriasis, severe hyperthyroidism, and hemolytic anemia.
• Some drugs, including phenytoin, methotrexate, trimethoprim, and triamterene, may also hinder folate absorption.

Click the icon to see an image of red blood cells found in sickle cell anemia.

Risk Factors

Although nutritional iron-deficiency anemia has declined in industrialized nations, it affects an estimated 2 billion people worldwide. Even in the U.S., iron deficiency is the most prevalent nutritional deficiency. It is highly associated with poverty. People in lower socioeconomic groups have double the risk of those who are middle or upper class.

Among Americans with iron deficiency anemia, young children have the highest risk followed by premenopausal women. Adolescent and adult men and postmenopausal women have the lowest risk. Men, in fact, are at risk for iron overload, probably because of their higher meat intake.

Infants and Children

General Risk Factors for Anemia in Infants and Children. Up to 20% of American children and 80% of children in developing countries become anemic at some point during their childhood and adolescence. Iron deficiency is the most common cause in children, but other forms of anemia, including hereditary blood disorders, can also cause anemia in this population. Hispanic American children have double the rates of iron deficiency as African-American and Caucasian children.

Iron deficiency affects about 9% of children younger than 2 years. About 3% of children in this age group are anemic as a result. Children in lower-income homes are at higher risk than those in higher income homes. In a study of low-income children, ages 6 months to 5 years, the prevalence of anemia was over 10%, and was nearly 18% in children younger than 2 years. However, children in any income group can develop iron deficiency.

Young children 9 - 18 months have the highest risk for iron deficiency anemia in the U.S. Such children also are at great risk for problems in mental development from anemia. Infant boys may have 10 times more risk than baby girls. In general, full-term, breast-fed infants have enough iron stores for their first 6 months of life. After that, they must rely on other sources for iron.

Iron-deficiency anemia in infants and small children can be due to one or more of the following factors:

• Stopping breast-feeding too early or using formula that isn't iron-fortified.
• Bottle-feeding too long. Studies indicate that the longer children are bottle-fed, the greater the risk for iron-deficiency and anemia. Toddlers 12 months and older should not drink more than 2 cups of milk a day. Cows milk is good for children, but it does not contain enough iron. Too much milk can decrease childrens appetite and prevent them from eating the iron-rich food they need. When babies who are bottle-fed are 7 - 9 months old, they should be weaned from bottles and given sippy cups. By the age of 12 months, all children should be using a cup instead of a bottle.
• Toddlers preferences for iron-poor food. Parents should make sure that their children eat iron-rich foods, such as beans, meat, fortified cereals, eggs, and green leafy vegetables

Better social services and more accurate ways of diagnosing and monitoring anemia are needed in these high-risk groups. There is still considerable debate on how to define iron deficiency and anemia in infants. New research suggests that a reticulocyte hemoglobin content (CHr) test may be better than a standard hemoglobin test for detecting iron deficiency in babies. Reticulocytes are immature red blood cells. The CHr test measures the amount of hemoglobin in these cells.

Premenopausal Women

Up to 10% or more of adolescent and adult women under 49 years are iron deficient. Hispanic American and African-American women have double the prevalence for anemia compared to Caucasian women. The risk for anemia in adolescent girls is about 3%. Anemia is generally mild in young women, however, and is more likely to occur with one or more of the following conditions:

• Heavy menstruation for longer than 5 days
• Abnormal uterine bleeding, such as from fibroids
• Pregnancy. About 20% of women in industrialized countries have iron deficiency during pregnancy. Multiple pregnancies and births significantly increase the risk.

Older Adults

Although studies have reported various estimates on the prevalence of anemia in older adults, one survey suggested that anemia affects about 10% of adults aged 65 years and older, and more than 20% aged 85 years and older. The causes of anemia in older adults were equally distributed among nutritional deficiencies, chronic inflammatory disease, chronic renal disease, and unexplained anemia. Most cases were mild.

Alcoholism

People with alcoholism are at risk for anemia both from internal bleeding as well as folate- and vitamin B deficiency-related anemias.

People with Iron-Poor Diets

Although most Americans probably consume too much iron in their diets, some people may be at risk for diet-related iron deficiencies, including:

• People whose diets are high in processed foods and lack any meat.
• Strict vegetarians. Vegetarians who avoid all animal products may have a slightly higher risk for deficiencies in iron and some B vitamins. Although dried beans and green vegetables often contain iron, it is less easily absorbed from plants than from meat. Fortunately, most commercial cereals are fortified with vitamin B12 and folic acid (the synthetic form of folate).

Chronic or Critical Illnesses

Anyone with a chronic disease that causes inflammation or bleeding is at risk for anemia. Critical illness in the intensive care unit is also highly associated with anemia.

Excessive Exercise

Working out regularly may cause some iron loss, which is comparable to that from menstruation and rarely worrisome. Dietary choices may account for most cases of sports anemia. Intense, sustained exercise, such as that performed by marathon runners, may cause a condition called sports anemia, which may be due to slight gastrointestinal bleeding, damaged red blood cells, low iron intake, or poor intestinal absorption of iron.

Pregnancy

Iron deficiency occurs in 20% of pregnant women in developed countries. Even worse, 50% or more of women in nonindustrialized nations become iron deficient, and 30 - 50% are deficient in folic acid. Severe anemia is associated with a higher mortality rate among pregnant women. Mild-to-moderate anemia, however, does not pose any elevated risk.

Pregnancy increases the risk for anemia in different ways:

• It increases the body's demand for folic acid and, therefore, poses a risk for deficiencies and an increased risk for megaloblastic anemia. Low levels of folate during pregnancy increase the risk of neural tube defects in newborns.
• It increases the body's demand for iron, thus posing a risk for iron deficiency anemia. Pregnant or nursing women need 30 mg of iron per day. Maternal iron deficiency anemia is associated with increased weight or size of the placenta, a condition that may later pose a risk for high blood pressure in the offspring. Pregnant women with low hemoglobin levels (the iron-bearing component in the blood) have an elevated risk for pre-term or low birth weight infants.
• Pregnancy is also associated with fluid retention, which in turn may produce high volumes of plasma (the fluid component of blood). This can dilute red blood cells, which may lead to anemia.
• After delivery, heavy bleeding, which occurs in 5 - 10% of women who have given birth, can cause symptoms of anemia.

Diagnosing of Iron Deficiency During Pregnancy. A diagnosis of iron deficiency is problematic in pregnant women. The standard test is a measurement of ferritin levels, which are low in most people with iron deficiency. Pregnant women, however, may have high ferritin blood levels into their third trimester but still be iron deficient. A newer test that measures a factor called serum transferrin receptor may prove to be a useful way of diagnosing iron deficiency in women. Researchers are also investigating Doppler ultrasonography as an imaging technique for detecting anemia in the fetus. Traditionally, fetal anemia is diagnosed through amniocentesis. Doppler ultrasonography is a non-invasive method that does not risk causing a miscarriage or a worsening of fetal anemia.

Preventing Anemia in Pregnant Women.

• Iron Supplements. For the past 40 years, iron supplements have been recommended for all pregnant women. This practice has been challenged recently, however. There is no clear-cut evidence that the mild iron deficiency most pregnant women experience is harmful. In addition, iron supplements cause gastrointestinal side effects and may not be completely harmless. Some experts suggest iron supplements for all pregnant women whose hemoglobin levels are less than 11 g/dl, and pregnant women whose serum ferritin levels are low, beginning in their 20th - 24th weeks of pregnancy.
• Vitamin Supplements. Women who are trying to conceive, who are pregnant, and who are breast-feeding should take 400 mcg of folic acid a day. They should be sure this is folic acid and not folate. Folate is the natural form of folic acid, but 400 mcg supplements of folate are half as potent as the same dose of folic acid. Pregnant and nursing women who are vegetarians should be sure to have supplements of folic acid and other B vitamins as well, since many of these nutrients are found primarily in animal products. Vitamin B12 deficiencies during pregnancy can also produce anemia in both mother and child.
• Diets Rich in Vitamin C. Eating foods rich in vitamin C can help absorb iron.

Treating Anemia During Pregnancy. Pregnant women who become anemic and need treatment may be given oral iron supplements, or blood transfusions in severe cases. Intravenous or intramuscular administration of iron helps improve blood levels better than oral iron supplements, but may cause more serious side effects.

Complications

Most cases of anemia are mild, including those that occur as a result of chronic disease. Nevertheless, even mild anemia can reduce oxygen transport in the blood, causing fatigue and a diminished physical capacity. Moderate-to-severe iron-deficiency anemia is known to reduce endurance. Some studies indicate that even iron deficiency without anemia can produce a subtle but still lower capacity for exercise.

Because a reduction in red blood cells decreases the ability to absorb oxygen from the lungs, serious problems can occur in prolonged and severe anemia that is not treated. Anemia can lead to secondary organ dysfunction or damage, including heart arrhythmia and heart failure.

Certain inherited forms of anemia, including thalassemia major, pernicious anemia, and sickle-cell anemia, can be life threatening. Thalassemia major and sickle-cell anemia affect children and are particularly devastating.

Effects of Anemia in Pregnant Women

Pregnant women with significant anemia may have an increased risk for poor pregnancy outcomes, particularly if they are anemic in the first trimester.

Complications from Anemia in Children and Adolescents

In children, severe anemia can impair growth and motor and mental development. Children may exhibit a shortened attention span and decreased alertness. Children with severe iron-deficiency anemia may also have an increased risk for stroke.

Effects of Anemia in the Elderly

Anemia is common in older people and can have significantly more severe complications than anemia in younger adults. Some studies have reported higher mortality rates in anemic individuals 85 and older compared to their non-anemic peers. (The rates were higher in anemic men than in women.) The following are examples of its effects from different studies:

• Anemia may have adverse effects on the heart and increase the severity of cardiac conditions, including reducing survival rates from heart failure and heart attacks.
• Elderly people with lower levels of hemoglobin are at an increased risk of death.
• Anemia may be associated with an increased incidence of falls.
• Even mild anemia may possibly lead to cognitive impairment. A 2006 study of elderly women found that mild anemia worsened problem-solving abilities and other cognitive functions. Anemia may worsen an already existing dementia.

Effects of Vitamin B12 Deficiencies and Pernicious Anemia

In addition to anemia, vitamin B12 deficiency can cause neurologic damage, which can be irreversible if it continues for long periods without treatment.

Anemia in Patients with Cancer

Anemia is particularly serious in cancer patients. In people with many common cancers, the presence of anemia is associated with a shorter survival time.

Anemia in Patients with Kidney Disease

Anemia is associated with higher mortality rates and possibly heart disease in patients with kidney disease.

Anemia in Patients with Heart Failure

The combination of anemia and heart failure can increase the risk of hospitalization or death by 30 - 60%. Patients with heart failure whose hemoglobin levels decline do worse than patients with stable levels.

Effects of Excess Iron

Blood transfusions. Patients with certain types of anemia require frequent blood transfusions. These transfusions can cause iron overload. Patients are treated with iron chelation therapy, which uses a drug that binds to iron. Excess iron is then eliminated by the kidneys. The standard drug for iron chelation therapy, deferoxamine (Desferal), is injected intravenously through an infusion pump. The treatment can be difficult for many patients. In 2005, the FDA approved a new drug, deferasirox (Exjade), to treat iron overload due to blood transfusions. Patients dilute the pills in liquid once a day and drink the mixture.

Symptoms

Symptoms of anemia vary depending on the severity of the condition. Anemia may occur without symptoms and be detected only during a medical examination that includes a blood test. When they occur, symptoms may include:

• Weakness and fatigue are the most common symptoms of even mild anemia. Even iron deficiency without anemia can reduce working capacity in some people.
• Shortness of breath on exertion
• Rapid heartbeat
• Lightheadedness or dizziness
• Headache
• Ringing in the ears (tinnitus)
• Irritability and other mood disturbances
• Pale skin (however, healthy-looking skin color does not rule out anemia if a patient has risk factors and other symptoms of anemia)
• Mental confusion
• Loss of sexual drive

Unusual Symptoms

Pica. One odd symptom, in some cases a cause of iron deficiency, is pica. This is the habit of eating unusual substances, such as ice (called pagophagia), clay, cardboard, foods that crunch, or raw starch. For example, in one study, half of people whose pica took the form of pagophagia (eating at least one tray of ice every day for 2 months) or eating foods that crunch (such as raw potatoes, carrots, or celery) were iron deficient. The pica often stops, particularly in children, when iron supplements are given. Pica is difficult to detect because patients are often ashamed to admit to such cravings.

Frequent Breath Holding. Studies have also indicated that children who hold their breath frequently when angry or upset, even to the point of fainting, may be iron-deficient. In one study, taking iron supplements reduced this phenomenon in 88% of treated children.

Symptoms of Megaloblastic Anemia and its Causes

Symptoms of Megaloblastic Anemia. The symptoms of megaloblastic anemia from vitamin B12 or folic acid deficiencies include not only standard anemic symptoms but also:

• Inflammation of the mouth (stomatitis)
• Inflammation of the tongue (glossitis), which involves shrinkage at the surface and edges of the tongue

Over time, psychiatric and neurologic problems develop. Vitamin B12 deficiencies cause neurologic symptoms (numbness and tingling, depression, memory loss, and irritability), and folate deficiency may result in depression and dementia (in severe cases).

Symptoms of Pernicious Anemia. Early neurologic symptoms of pernicious anemia are due to B12 deficiency. They include numbness and tingling, depression, memory loss, and irritability. Advanced nerve damage can cause loss of balance and staggering, confusion, dementia, spasticity, loss of bladder control, and erectile dysfunction. Folic acid deficiency does not cause neurologic damage, although people with this deficiency can be irritable, forgetful, and experience personality changes. Of concern for patients with pernicious anemia and B12 deficiency anemia is that folic acid supplements can mask the presence of this disease in its early stages but not cure it. The only cure is vitamin B12 supplementation.

Diagnosis

The first step in any diagnosis is a physical examination to determine if the patient has symptoms of anemia and any complications. Because anemia may be the first symptom of a serious illness, determining its cause is very important. This may be difficult, particularly in the elderly, malnourished, or people with chronic diseases, whose anemia may be caused by one or more factors. A detailed medical, personal, and dietary history should report:

• Any family or personal history of anemia
• A history of gallbladder disease, jaundice, or enlarged spleen
• Heavy menstrual bleeding in women
• Any occurrence of blood in the stool or other signs of internal bleeding. (Even if the patient has not observed any bleeding, nonvisible blood may be present, so a rectal exam and stool test are essential.)
• Any dietary history, particularly in people who are elderly, poor, or both

The doctor should examine the patient carefully, especially checking for swollen lymph nodes, an enlarged spleen, and pale skin and nail color.

Blood Tests to Determine the Presence of Any Anemia

Specific blood tests are given to determine anemia from any cause.

Blood and Hemoglobin Counts. A complete blood count (CBC) test is performed to determine the presence of anemia. The red blood cells, or erythrocytes, and their iron-bearing component, hemoglobin, are measured.

For example, severe anemia in adults is defined by the World Health Organization as:

• Hemoglobin concentrations below 12 g/dL (7.5 mmol/L) in women. (Some evidence suggests that in older women anemia should be diagnosed at 13 g/dL and below.)
• Below 13 g/dL (8.1 mmol/L) in men.

A low red blood cell (RBC) count could indicate a number of problems, including bleeding or a failure by bone marrow to manufacture red blood cells.

Hematocrit. Calculating the percentage of red blood cells in blood plasma (a measurement called the hematocrit) is also important. Plasma is the liquid portion of blood. People with a high volume of plasma may be anemic even if their blood count is normal because the blood cells have become diluted.

Normal percentages are highest in the very youngest individuals and decline as people age. They also vary by gender. The following are some examples of normal range:

• Newborns: 42 - 60%
• Children: 35 - 45%
• Adult males: 41 - 53%
• Adult women: 36 - 46%

Normal value ranges may vary slightly among different laboratories.

Smokers, people at high altitudes, and those who are dehydrated tend to have higher than normal hematocrit levels. Those at greater risk for low hematocrit levels include pregnant women and patients with cirrhosis, heart failure, and splenomegaly.

Reticulocyte Count. Reticulocytes are immature red blood cells, and their count reflects the rate of red blood cell production. The upper normal limit is about 100,000/mL. A low count, when bleeding isn't the cause, suggests problems in production in the bone marrow. An abnormally high count indicates that the red blood cells are being destroyed in high numbers and indicates hemolytic anemia. New research suggests that the reticulocyte hemoglobin content (CHr) test may be more accurate than a standard hemoglobin test for detecting iron deficiency in infants. This test may help identify babies who are at risk for becoming anemic and help them get treated earlier.

Blood Morphology. A blood smear viewed under a microscope allows an expert to classify the blood by its color, size, and shape ( morphology ). Generally red blood cells are categorized as:

• Pale-colored (hypochromic) and abnormally small (microcytic)
• Normal colored and normal sized (normochromic, normocytic)
• Abnormally large (macrocytic)

The shape of the red blood cells, which can be distorted in many blood disorders, is also important in determining a diagnosis.

Diagnosing Iron Deficiency Anemia and its Causes

There are two steps in making a diagnosis in patients with symptoms of iron deficiency anemia:

• The first step is to determine if a person is actually deficient in iron.
• If iron stores are low, the second step is to diagnose the cause of the iron deficiencies, which will help determine treatment.

Determining if Iron Stores are Low. The following findings are important in determining that a person is iron deficient:

• Blood cells viewed under the microscope are pale (hypochromic) and abnormally small (microcytic). They are also mostly uneven in shape. (These findings suggest iron deficiency, but they can also appear in cases of anemia due to chronic disease and thalassemia.)
• Hemoglobin and iron levels are low. (These findings further suggest iron deficiency, but they can also occur in cases of anemia due to chronic disease.)
• Ferritin levels are low. Ferritin is a protein that binds to iron. Low levels typically mean reduced iron stores. High ferritin levels in the blood do not always mean sufficient iron stores. For example, pregnant women may have high ferritin levels into their third trimester but still be iron deficient. Ferritin levels may also be normal or even elevated in patients with inflammation from anemia due to chronic disease, even if they also have low iron stores.
• In children with iron deficiencies, reticulocytehemoglobin levels are low. Reticulocytes are immature red blood cells, and this test may be the most effective approach for diagnosing iron deficiency in children.
• A test that measures a factor called serum transferrin receptor (TfR) is proving to be very sensitive in identifying iron deficiency in problematic patients, including the elderly with chronic diseases and possibly pregnant women. (It is often very difficult to identify iron deficiencies in patients who also have anemia due to chronic diseases because their ferritin levels are often normal or even high.) For example, levels of TfR are high in patients with ACD and iron deficiency anemia, but they are normal or only slightly raised in ACD alone. The test is expensive, however, and some experts recommend it should be used only when there is a high suspicion of iron deficiency in the elderly.
• Measuring erythrocyte zinc protoporphyrin (ZPP), a product of abnormal heme synthesis, is under investigation and may prove to be a simple and precise measure of iron deficiencies, particularly in children.

If internal bleeding is suspected as the cause, the gastrointestinal tract is usually the first suspect as the source. A diagnosis in these cases can often be made if the patient has noticed blood in the stools, which can be black and tarry or red-streaked. Often, however, bleeding may be present but not visible. If so, stool tests for this hidden (occult ) blood are required. Additional tests may then be needed to diagnose the precipitating condition. Endoscopy, in which a fiber optic tube is used to view into the gastrointestinal tract, is helpful in many patients, particularly when the source of bleeding is unclear. A colonoscopy may also be recommended to rule out colorectal cancer.

If the patient's diet suggests low iron intake and other causes cannot be established using inexpensive or noninvasive techniques, then the patient may simply be given a monthly trial of iron supplements. If the patient fails to respond, further evaluation is needed.

Diagnosing Anemia of Chronic Disease (ACD)

Usually anemia of chronic disease is recognized during the management of the primary disease and, if the anemia is mild, additional diagnostic tests are rarely needed. The following are typical findings in ACD:

• The blood cells are normal looking.
• Blood tests may typically show low levels of iron in the blood, but ferritin levels are normal or even high. (Low levels of ferritin, a protein that binds to iron, indicate iron deficiency.)

Diagnosing Vitamin B-Related Anemias

Doctors need a multi-step diagnostic procedure for determining vitamin B deficiencies and the anemias that cause or are caused by them. Doctors may arrive at a diagnosis of vitamin B12 or folic acid deficiencies from different routes:

• They may diagnose deficiencies after detecting megaloblastic anemia from abnormal blood tests.
• They may suspect vitamin deficiencies first from symptoms and history and then look for anemia.

Diagnosing Megaloblastic Anemia. Very large oval red blood cells indicate megaloblastic anemia. Abnormally shaped neutrophils (certain white blood cells) may also be present. Bone marrow aspiration may need to be performed if the disease is strongly suspected but the diagnosis is not clear.

Determining Vitamin Deficiency. Once megaloblastic anemia has been diagnosed, the doctor will need to determine which vitamin deficiency is causing it. This is extremely important, because if a vitamin B12-deficient patient receives folate replacement only, then irreversible nerve injuries may develop. Even if blood tests for megaloblastic anemia are normal, patients with neurologic and psychiatric abnormalities that have no detectable cause should still be tested for vitamin B12 deficiency.

Often, vitamin B deficiencies cannot be determined by a history or symptoms alone. Blood tests are the primary indicators of both vitamin B12 and folic acid deficiencies, but even blood tests for these vitamins are not always straightforward:

• Folic acid and vitamin B12 levels must always be measured at the same time because each vitamin may affect the other.
• Folate levels may be temporarily low in some people who are not truly deficient.
• Folate levels may temporarily rise in deficient people if they have just eaten foods containing the vitamin.
• Antibiotics can interfere with B12 levels.

Measuring methylmalonic acid and homocysteine, substances in the blood that increase when levels of one or both vitamins are low, improves accuracy.

Tests for Pernicious Anemia. Once a vitamin B12 deficiency has been established and the doctor has not found any intestinal abnormalities or other factors to account for the deficiency, the doctor presumes a diagnosis of pernicious anemia. Pernicious anemia may also be diagnosed through various blood (such as complete blood count) or urine tests.

Pernicious anemia is treated with vitamin replacement, but the condition is easily missed, particularly in patients whose diets are rich in folic acid. Folic acid can mask the early symptoms of pernicious anemia but not cure it. Consequently the disease may persist until serious neurologic symptoms occur. With folic acid now a required additive in many commercial foods, some experts are concerned about an increased incidence in pernicious anemia.

Dietary Factors

Iron found in foods is either in the form of heme or non-heme iron:

• Heme Iron. Foods containing heme iron are the best sources for increasing or maintaining healthy iron levels. Such foods include (in decreasing order of iron-richness) clams, oysters, organ meats, beef, pork, poultry, and fish.
• Non-Heme Iron. Non-heme iron is less well-absorbed. About 60% of the iron in meat is non-heme (although meat itself helps absorb non-heme iron). Eggs, dairy products, and iron-containing vegetables have only the non-heme form. Such vegetable products include dried beans and peas, iron-fortified cereals, bread, and pasta products, dark green leafy vegetables (chard, spinach, mustard greens, kale), dried fruits, nuts, and seeds.

The absorption of non-heme iron often depends on the food balances in meals. The following foods and cooking methods can enhance absorption of iron:

• Meat and fish not only contain heme iron -- the best form for maintaining stores -- but they also help absorb non-heme iron.
• Increasing intake of vitamin-C rich foods, such as orange juice, may enhance absorption of non-heme iron, although it is not clear if it improves iron stores in iron-deficient people. In any case, vitamin-C rich foods are healthy and include broccoli, cabbage, citrus fruits, melon, tomatoes, and strawberries.
• Riboflavin (vitamin B2) may help enhance the response of hemoglobin to iron. Food sources include dairy products, liver, and dried fortified cereals.
• Cooking methods can enhance iron stores. Cooking in cast iron pans and skillets is well-known to increase the iron content of food. According to one study, boiling, steaming, or stir-frying in utensils composed of any material significantly increased the release of non-heme iron stored in vegetables.
• Vitamins B12 and folate are important for prevention of megaloblastic anemia and for good health in general. The only natural dietary sources of B12 are animal products, such as meats, dairy products, eggs, and fish (clams and oily fish are very high in B12). As is the case with other B vitamins, however, B12 is added to commercial dried cereals. The recommended daily allowance (RDA) is 2.4 mcg a day. Deficiencies are rare in young people, although the elderly may have trouble absorbing natural vitamin B12 and require synthetic forms from supplements and fortified foods.

Click the icon to see an image of sources of vitamin B12.

• Folate is best found in avocado, bananas, orange juice, cold cereal, asparagus, fruits, green, leafy vegetables, dried beans and peas, and yeast. The synthetic form, folic acid, is now added to commercial grain products. Vitamins are usually made from folic acid, which is about twice as potent as folate. Many experts now recommend that adults have 400 mcg of folic acid daily -- considerably higher than standard recommendations of 400 mcg of folate. Women who are trying to conceive, who are pregnant, and who are breast-feeding should take 400 mcg of folic acid.

Click the icon to see an image of sources of folate.

Recommended Daily Allowance for Iron

The Recommended Daily Allowance (RDA) of iron for people who are not iron deficient varies by age group and other risk factors. (Iron supplements are rarely recommended in people without evidence of iron deficiency or anemia.) The RDA recommends these daily amounts of iron:

• Children 1 - 3 years old: 10 mg
• Teenage boys: 12 mg
• Teenage girls and premenopausal women: 15 mg
• Pregnant or nursing women: 30 mg
• Adult men (up to age 50): 10 mg
• Older men and women (over age 50): 10 mg

Preventing Anemia in Infants and Small Children

The main source of iron for an infant from birth to 1 year of age is in milk, from breast milk, iron-fortified infant formula, or cereal. The best methods for preventing iron deficiency during infancy are:

Breast-feeding and Iron-Supplemented Formulas. Mothers should be encouraged to breast-feed their babies for their first year. Up to half of the iron in breast milk is absorbed by the baby and is sufficient to prevent anemia for the first 4 - 6 months, assuming that the mother had adequate iron stores during pregnancy. Breast milk itself is low in iron, but if the mother's diet is healthy, vitamin C and lactose in the breast milk may enhance iron absorption. Breast-fed babies should have iron supplements after 4 - 6 weeks, even if they are still nursing.

Infants who are not breast-fed should start with iron-fortified formulas (7-12 mg/L). Most experts strongly discourage the use of low-iron formulas (less than 4.0 mg/L). Parents should discuss the best formula with their doctor. Children given iron supplements may have a slightly higher risk for diarrhea. Experts advise against cow's milk for the first year of life. When cereals are begun, they should be iron fortified.

Recommendations for Toddlers. Toddlers who did not have iron supplements during infancy should be checked for iron deficiency. After the first year, children should be given a varied diet that is rich in sources of iron, B vitamins, and vitamin C. Milk does not contain enough iron and can decrease children's appetite for iron-rich foods. Toddlers older than 1 year should not drink more than 2 cups of milk a day. A preference for apple juice over vitamin-C rich orange juice does not reduce iron absorption in children with any otherwise healthy diet.

Treatment

Oral iron supplements are the best way to restore iron levels for people who are iron deficient, but they should be used only when dietary measures have failed. However, iron supplements cannot correct anemias that are not due to iron deficiency.

One study reported that doctors prescribed iron pills for 64% of patients with anemia, without performing tests to confirm whether iron deficiency was actually the cause. The study suggested that iron replacement was appropriate in less than half of these patients. Iron replacement therapy can cause gastrointestinal problems, sometimes severe ones. Excess iron may also contribute to heart disease, diabetes, and certain cancers. Experts generally advise against iron supplements in anyone with a healthy diet and no indications of iron deficiency anemia. However, one study suggested that supplements help reduce fatigue in women with low iron stores but no signs of anemia.

Treatment of Anemia of Chronic Disease. In general, the best treatment for anemia of chronic diseases is treating the disease itself. In some cases, iron deficiency accompanies the condition and requires iron replacement. Erythropoietin, most often administered with intravenous iron, is used for some patients.

Treatment of Megaloblastic Anemia. The standard treatments for megaloblastic anemia are vitamin B12 injections and folic acid replacement.

Iron Supplements

Supplement Forms. To replace iron, the preferred forms of iron tablets are ferrous salts, usually ferrous sulfate (Feosol, Fer-In-Sol, Mol-Iron). Other forms include ferrous fumarate (Femiron, FerroSequels, Feostat, Fumerin, Hemocyte, Ircon), ferrous gluconate (Fergon, Ferralet, Simron), polysaccharide-iron complex (Niferex, Nu-Iron), and carbonyl iron (Elemental Iron, Feosol Caplet, Ferra-Cap). Specific brands and forms may have certain advantages. The following are some examples:

• Prolonged-release ferrous sulfate (Slow Fe) may enhance iron absorption with fewer side effects than standard ferrous sulfate pills.
• FerroSequels contains a stool softener, which helps prevent constipation.
• Polysaccharide-iron complex has fewer side effects and equal absorption rates compared to ferrous salts. It is very expensive, however.
• Carbonyl iron is composed of very fine tiny uniform spheres of iron powder and may prove to be less toxic than ferrous iron.
• Coated or combination pills do not appear to offer any additional advantages and may hinder absorption of the iron.

Regimen. The general guidelines for iron replacement are as follows:

• For adults, doctors usually advise one ferrous sulfate tablet (300 mg) three times a day.
• Iron replacement doses for children with deficiencies are significantly lower. In general, they are given as drops or syrup administered three times a day. A single-dose daily regimen is showing promise. IMPORTANT: As few as three adult iron tablets can poison children, even fatally. This includes any form of iron pill.
• No one, even adults, should take a double dose of iron if one is missed.

Other tips for taking iron are as follows:

• For best absorption, iron should be taken between meals. (Iron may cause stomach and intestinal disturbances, however, and some experts believe that low doses of ferrous sulfate can be taken with food and are still absorbed but with fewer side effects.)
• Always drink a full 8 ounces of fluid with an iron pill. Taking orange juice with an iron pill may help increase iron absorption. (Some doctors also recommend taking a vitamin C supplement with the iron pill.)
• Tablets should be kept in a cool place. (Bathroom medicine cabinets may be too warm and humid, which may cause the pills to disintegrate.)

Full recovery takes 6 - 8 weeks. Recovery will take longer in people with internal bleeding that is not under control. Iron replacement therapy must continue for about 6 months, even if anemia has been reversed. Treatment must be continued indefinitely for people with chronic bleeding; in such cases, iron levels should be closely monitored.

Side Effects. Common side effects of iron supplements include the following:

• Constipation and diarrhea are very common. They are rarely severe, although iron tablets can aggravate existing gastrointestinal problems such as ulcers and ulcerative colitis.
• Nausea and vomiting may occur with high doses, but can be controlled by taking smaller amounts. Switching to ferrous gluconate may help some people with severe gastrointestinal problems.
• Black stools are normal when taking iron tablets. In fact, if they do not turn black, the tablets may not be working effectively. This tends to be a more common problem with coated or long-acting iron tablets.
• If the stools are tarry looking as well as black, if they have red streaks, or if cramps, sharp pains, or soreness in the stomach occur, gastrointestinal bleeding may be causing the iron deficiency and the patient should call the doctor promptly.
• Acute iron poisoning is rare in adults but can be fatal in children who take adult-strength tablets.

Interactions with Other Drugs. Certain medications, including antacids, can reduce iron absorption. Iron tablets may also reduce the effectiveness of other drugs, including the antibiotics tetracycline, penicillamine, and ciprofloxacin and the Parkinson's disease drugs methyldopa, levodopa, and carbidopa. At least 2 hours should elapse between doses of these drugs and iron supplements.

Supplements. The following vitamin and mineral supplements may improve iron absorption:

• Adding either ascorbic acid (vitamin C) or succinic acid to ferrous sulfate therapy will improve absorption of iron stores.
• Some studies have found that the addition of zinc to iron supplements increases hemoglobin levels more than iron alone. Some evidence for this suggests that zinc affects a hormone called insulin-like growth factor-I (IGF-I), which plays a role in the regulation of red blood cell production.

Intravenous or Injected Iron

In some cases, iron is administered through muscular injections or intravenously. Intravenous iron has the advantage of causing less gastrointestinal discomfort and inconvenience. It may be in the form of iron dextran (Dexferrum, InFed), sodium ferric gluconate complex in sucrose (Ferrlecit), or iron sucrose (Venofer). Ferrlecit or Venofer are proving to be at least equally effective and safer than iron dextran.

Candidates. The injected or intravenous forms should be limited to the following patients with iron deficiency:

• People with iron deficiency anemia in whom oral therapy has clearly failed.
• Patients with bleeding disorders in which blood loss continues to exceed the rate at which oral iron is absorbed.
• In emergencies, when people need red blood cells but transfusion is not appropriate or available.
• In people with serious gastrointestinal disorders, such as inflammatory bowel disease, who cannot take iron therapy by mouth.
• People undergoing hemodialysis who receive supplemental erythropoietin therapy. Sodium ferric gluconate complex in sucrose (Ferrlecit) or iron sucrose (Venofer) is specifically approved as first-line therapy for these patients.

Certain patients, even if they meet these qualifications, may not be appropriate candidates or should be monitored closely for complications. They include:

• Patients with any underlying autoimmune disease.
• Malnourished patients who also have an underlying infection.
• Patients who are at risk for iron overload.

Side Effects. Some side effects differ depending on how the iron is administered and include the following:

• Muscular injections include pain at the site.
• Intravenous administration can cause pain in the vein, flushing, and metallic taste, all of which are brief.

For both methods, side effects and serious complications can include:

• Blood clots
• Fever
• Joint aches
• Headache
• Rashes
• A delayed reaction of joint and muscle aches, headache, and malaise occurs 1 - 2 days after the infusion (most commonly with iron dextran) in about 10% of patients. These symptoms respond quickly to NSAIDs, such as ibuprofen or naproxen, in most people.
• Iron toxicity. Symptoms include nausea, dizziness, and a sudden drop in blood pressure. Sodium ferric gluconate in sucrose (Ferrlecit) or iron sucrose (Venofer) may pose a lower risk for toxicity than iron dextran.
• Allergic reactions. Allergic reactions that occur with intravenous iron can be very serious and, in rare cases, even fatal. Iron dextran appears to pose a much higher risk than sodium ferric gluconate complex in sucrose or iron sucrose, although allergic reactions can also occur with the latter forms.

Oral and injected iron should never be given at the same time. Intravenous iron therapy may be appropriate for some pregnant women who meet these requirements, depending on the pregnancy term and other factors.

Transfusions and Bloodless Medicine

Transfusions are used to replace blood loss due to injuries and during certain surgeries. They are also commonly used to treat severely anemic patients who have thalassemia, sickle cell disease, myelodysplastic syndromes, or other types of anemia. Some patients require frequent blood transfusions. Iron overload can be a side effect of these frequent blood transfusions. If left untreated, iron overload can lead to liver and heart damage.

Iron chelation therapy is used to remove the excess iron caused by blood transfusions. Patients take a drug that binds to the iron in the blood. The excess iron is then removed from the body by the kidneys. For many years, deferoxamine (Desferal) was the only drug used in chelation therapy. This drug is usually injected intravenously, using an infusion pump. The infusion can last 8 - 12 hours and may be needed 5 - 7 days a week until iron levels are normal. A new drug, deferasirox (Exjade), was approved in 2005 for children and adults as a once-daily treatment for iron overload due to blood transfusions. It does not require injections. Patients mix the deferasirox tablets in liquid and drink the medicine. Doctors hope that this new drug may make it easier for patients to tolerate chelation therapy. Studies have shown that deferasirox works as well as deferoxamine in ridding the body of excess iron.

Bloodless Medicine. Bloodless medicine and surgery is a new field designed to reduce or minimize blood loss and transfusions. It also attempts to address the problems in treating certain religious groups, such as Jehovah's Witnesses, who refuse transfusions. Some techniques involved in this field include new surgical procedures or drugs that minimize blood loss, the use of erythropoietin, volume expanders (administration of fluids to dilute blood), using tiny blood samples for testing, and methods (Cell Saver) for recovering and recycling blood during surgery.

Erythropoiesis-Stimulating Drugs

Erythropoietin is the hormone that acts in the bone marrow to increase the production of red blood cells. It has been genetically engineered as recombinant human erythropoietin (rHuEPO) and is available as epoetin alfa (Epogen, Procrit, and Eprex). Novel erythropoiesis stimulating protein (NESP), also called darbepoetin alfa (Aranesp), lasts longer in the blood than epoetin alfa and requires fewer injections. These medications are also called erythropoiesis-stimulating drugs.

Levels of erythropoietin are reduced in anemia of chronic disease. Injections of synthetic erythropoietin can help increase the number of red blood cells in order to avoid receiving blood transfusions. Erythropoietin is used to treat anemia. It does not help improve anemia symptoms, fatigue, or quality of life for patients with cancer or HIV. This drug can cause serious side effects, including blood clots, and is approved only for treating patients with anemia related to the following conditions:

• Cancer. For select patients, erythropoietin is used to treat the anemia associated with chemotherapy.
• Chronic kidney failure. Erythropoietin is an important anemia treatment for patients with chronic kidney failure, including those on dialysis.
• HIV/AIDS. Erythropoietin helps treat the anemia caused by zidovudine (AZT) therapy.

In November 2007, the Food and Drug Administration (FDA) made major changes to the prescribing information for erythropoiesis-stimulating drugs. The new labels describe in detail the risks that Aranesp, Epogen, and Procrit can pose to patients with cancer and chronic kidney disease. The FDA has also established separate dosing recommendations for each of these conditions.

Erythropoiesis-Stimulating Drugs and Cancer. Erythropoietin should be used only to treat anemia caused by chemotherapy -- not anemia due to other causes in patients with cancer. Erythropoietin treatment does not help prolong survival. In fact, these drugs can shorten survival time and cause tumors to grow faster. Discuss with your doctor whether an erythropoiesis-stimulating drug is appropriate for you.

Survival and tumor growth risks are especially pronounced for patients with advanced breast, head and neck, lymphoid, or non-small cell lung cancer when dosing attempts to achieve a hemoglobin level of 12 g/dL or greater. However, there may be similar risks for patients dosed to less than 12 g/dL. (The American Society of Clinical Oncology and the American Society of Hematology recommend starting erythropoietin when a patients hemoglobin level falls to less than 10 g/dL.) The doctor should use the lowest effective dose and erythropoietin treatment should be stopped as soon as the chemotherapy course is completed.

Erythropoiesis-Stimulating Drugs and Chronic Kidney Failure. For patients with chronic kidney failure, the FDA recommends that erythropoiesis-stimulating drugs be used to maintain hemoglobin levels between 10 - 12 g/dL. (The exact level within this range varies by individual.) There is a greater risk of death and serious cardiovascular events, such as heart attack, stroke, and heart failure when these drugs are used to achieve higher hemoglobin levels (13.5 - 14g/dL) compared to lower hemoglobin levels (10- 11.3 g/dL).

Warning Symptoms. Contact your doctor if you experience any of the following symptoms while being treated with an erythropoiesis-stimulating drug:

• Pain or swelling in the legs
• Worsening in shortness of breath
• Increases in blood pressure (be sure to regularly monitor your blood pressure)
• Dizziness or loss of consciousness
• Extreme fatigue
• Blood clots in hemodialysis vascular access ports

Antibiotics for H. Pylori

H. pylori, the bacteria that cause peptic ulcers, is associated with anemias from vitamin B12 deficiency and iron deficiency. People whose anemia is associated with H. pylori infection, however, do not respond to iron therapy. Studies indicate that the eradication of H. pylori infection with antibiotics can reverse anemia in such patients and may lead to long-lasting recovery.

Vitamin Replacement for Megaloblastic Anemia

Vitamin B12 Therapy. Injections of vitamin B12 (usually formulations called cyanocobalamin or hydroxocobalamin), oral folic acid therapy, or both, rapidly reverse the production of abnormally large red blood cells. (Treatments still may not reverse neurologic symptoms if they are extensive or have continued for too long.)

A typical regimen for vitamin B12 replacement is as follows:

• If diagnostic tests indicate pernicious anemia and neurologic symptoms are present, vitamin B12 therapy should begin immediately. (Usually vitamin therapy is not an emergency, however.)
• Cyanocobalamin or hydroxocobalamin injections are given every day for up to 2 weeks. Only small doses are needed.
• This is followed by injections twice a week for another month. (Hemoglobin levels rise in the first week of therapy and reach normal levels in 8 weeks.)
• After that, injections are usually given monthly.
• During recovery, there is a risk of potassium deficiency as the new red cells take up the existing supply, so potassium supplements may be needed.

Other forms of vitamin B12 are also available and can be used to treat B12 deficiency. Vitamin B12 nasal spray offers the same advantage of avoiding the need for absorbing the vitamin in the GI tract without the inconvenience of the injections. Some experts feel that even oral B12 in high doses (2,000 mcg/day) can maintain B12 levels once the deficiency is treated.

The injections are safe and have no adverse side effects, but they may mask an underlying medical or psychological condition.

Some doctors give vitamin B12 injections for fatigue and other vague symptoms of general mild discomfort. In one study, 10% of patients in a rural clinic were given regular B12 shots, with 6% of patients having no medical need for them.

Folic Acid Treatment. Folate deficiency is easily remedied in 4 - 5 weeks with daily oral doses of 1 - 2 milligrams of folic acid. Many doctors give vitamin B12 along with folic acid unless B12 deficiency is definitely ruled out.

Resources

• www.anemia.org -- National Anemia Action Council
• www.nhlbi.nih.gov -- National Heart, Lung and Blood Institute
• www.irondisorders.org -- Iron Disorders Institute
• www.thalassemia.org -- Cooley's Anemia Foundation
• www.aamds.org -- Aplastic Anemia & MDS International Foundation
• http://kidney.niddk.nih.gov/kudiseases/pubs/anemia -- National Kidney and Urologic Diseases Clearinghouse (Anemia in kidney disease and dialysis)

References

Brotanek JM, Gosz J, Weitzman M, Flores G. Iron deficiency in early childhood in the United States: risk factors and racial/ethnic disparities. Pediatrics. 2007 Sep;120(3):568-75.

Killip S, Bennett JM, Chambers MD. Iron deficiency anemia. Am Fam Physician. 2007 Mar 1;75(5):671-8.

Komajda M, Anker SD, Charlesworth A, et al. The impact of new onset anaemia on morbidity and mortality in chronic heart failure: results from COMET. Eur Heart J. 2006 Jun;27(12):1440-6. Epub 2006 May 22.

KDOQI. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis. 2007 Sep;50(3):471-530.

Maguire JL, deVeber G, Parkin PC. Association between iron-deficiency anemia and stroke in young children. Pediatrics. 2007 Nov;120(5):1053-7.

Mart-Carvajal AJ, Sol I. Treatment for anemia in people with AIDS. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD004776.

Notebaert E, Chauny JM, Albert M. Short-term benefits and risks of intravenous iron: a systematic review and meta-analysis. Transfusion. 2007 Oct;47(10):1905-18.

Reveiz L, Gyte GM, Cuervo LG. Treatments for iron-deficiency anaemia in pregnancy. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD003094.

Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology Clinical Practice Guideline Update. J Clin Oncol. 2007 Dec 21 [Epub ahead of print]

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