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Anemia

Highlights

Overview

Anemia is the name applied to many different conditions that are all characterized by an abnormally low number of healthy red blood cells. There are many different causes and types of anemia.

Iron-deficiency anemia, the most common type, is usually treated with dietary changes and iron supplement pills. Other types of anemia, such as those associated with chronic diseases or cancer, may need more aggressive treatment.

Preventing Iron Deficiency in Infants and Toddlers

The American Academy of Pediatrics' guidelines for preventing iron deficiency and iron deficiency anemia in infants and young children include:

Guidelines for Treating Anemia in People with Heart Problems

The American College of Physicians (ACP) has clinical practice guidelines for treating anemia in people with heart failure, coronary artery disease, or heart attack. According to the ACP, current evidence suggests as best practice for people with heart conditions:

Introduction

Anemia is a condition in which the body does not have enough healthy red blood cells. Red blood cells provide oxygen to body tissues.

Red blood cells, normal

Image of normal red blood cells (RBCs) as seen in the microscope after staining.

Anemia is not a single disease but a condition, like fever, with many possible causes and many forms.

Causes of anemia include nutritional deficiencies, medication-related side effects, or chronic diseases that cause bleeding or interfere with the production of red blood cells. The condition may be temporary or long term, and can manifest in mild or severe forms.

Anemia can also be caused by genetic (inherited) blood disorders such as sickle cell disease that damage the shape of the red blood cell.

This report focuses on the most common forms of anemia:

Blood

Blood is composed of about 55% plasma and 45% blood cells. It has 4 components:

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. On average, 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 280 million hemoglobin molecules. Hemoglobin 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.

Red 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:

Formed elements of blood

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

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.

Iron deficiency anemia results when the body's iron stores run low. This can happen because:

A number of medical conditions can cause iron deficiency anemia.

Blood Loss: Iron deficiencies most commonly occur from internal blood loss due to other medical conditions. These conditions include:

Impaired Absorption of Iron: Impaired absorption of iron can be caused by:

Inflammatory bowel disease

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

Inadequate Iron Intake: A healthy diet easily provides enough iron. In general, most people need just 1 mg of extra iron each day. (Menstruating women need 2 mg each day.) However, certain people are at risk of lack of iron in their diets. They include vegetarians and others who do not consume enough iron-rich foods, young children and pregnant women who have higher iron needs, and anyone who has a medical condition that places the at risk for iron deficiency.

Anemia of Chronic Disease

Anemia of chronic disease is associated with a wide variety of inflammatory conditions that reduce the production and survival of red blood cells. These diseases include:

Treatment-Related Anemia

Treatment-related anemia results 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 people experience during cancer therapy.

Megaloblastic Anemia and Pernicious Anemia

Megaloblastic anemia is caused by deficiencies in the B vitamins folate or vitamin B12 (also called cobalamin). Such deficiencies produce abnormally large (megaloblastic) red blood cells that have a shortened lifespan. Neurologic problems can result from vitamin B12 deficiency.

Pernicious anemia is a type of vitamin B12 anemia. It is considered an autoimmune disease. The body's immune system attacks the production of a special protein, called intrinsic factor (IF), which helps the intestines absorb vitamin B12. This protein is released by cells in the stomach. When the stomach does not make enough intrinsic factor, the intestine cannot properly absorb vitamin B12, and anemia occurs.

Vitamin B12 deficiency can also be caused by a weakened stomach lining (atrophic gastritis), which can be a complication of gastrointestinal surgery. In some cases, vitamin B12 deficiency can be caused by poor nutrition. The main dietary sources for vitamin B12 are meat, poultry, shellfish, eggs, and dairy products. Some cereals and soy-based foods are fortified with B12.

Megaloblastic anemia - view of red blood cells

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Vitamin B12 benefits

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

Folate deficiency can also be caused by poor diet. Alcoholism can compound the effects of malnutrition.

Medical conditions that impair the small intestine's absorption ability can cause folate deficiency. These disorders include celiac disease (a sensitivity reaction to gluten) and Crohn disease (an inflammatory bowel disorder).

Celiac sprue - foods to avoid

Click the icon to see an image of foods to avoid if you have celiac sprue.

Risk Factors

For 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 are actually more at risk for iron overload, probably because of their high meat intake and minimal iron loss.

Risk Factors 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.

Children need to absorb an average of 1 mg per day of iron to keep up with the needs of their growing bodies. Since children only absorb about 10% of the iron they eat, most children need to receive 8 to 10 mg of iron per day. Breast milk contains very little iron. Babies who are exclusively breastfed should get a daily oral iron supplement starting at age 4 months and continued until iron-rich solid foods are introduced.

In Western countries, drinking too much cow's milk (usually more than 2 cups per day) is a common cause of iron deficiency in young children. Cow's milk contains little iron and can get in the way of iron absorption. Cow's milk also can also cause irritation and problems in the intestine that lead to blood loss and increased risk of anemia. Babies should not get cow's milk before they are 12 months old.

Iron deficiency most commonly affects babies 9 to 24 months old. All babies should have a screening test for iron deficiency at around age 12 months. Babies born prematurely may need to be tested earlier. Other factors associated with iron-deficiency anemia in infants and small children include:

Risk Factors in Premenopausal Women

Up to 10% or more of adolescent and adult women under age 49 years are iron deficient. Anemia among premenopausal women typically occurs from heavy menstrual periods, which are often associated with uterine fibroids or endometriosis.

Pregnancy can also contribute to anemia by:

Poor Diet

Although most meat-eating Americans probably consume too much iron in their diets, some people may be at risk for diet-related iron deficiencies. In particular, vegans and other strict vegetarians who avoid all animal products are at risk for deficiencies in iron and some B vitamins.

Dried beans and green vegetables contain iron, but the body absorbs iron less easily from plant iron than from meat. Most commercial cereals and grain products are fortified with an easily absorbed form of vitamin B12 and with folic acid (the synthetic form of folate).

Medical Conditions

Anyone with a chronic disease that causes inflammation or bleeding is at risk for anemia. People with alcohol-use disorders are at risk for anemia both from internal bleeding as well as vitamin-deficiency-related anemias.

Complications

Most cases of anemia are mild, including those that result from chronic disease. Nevertheless, even mild anemia can reduce oxygen transport in the blood, causing fatigue and diminished physical endurance.

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. Severe anemia can lead to secondary organ dysfunction or damage, including heart arrhythmias and worse outcomes for heart failure.

Complications in Pregnant Women

Pregnant women with significant anemia may have an increased risk for poor pregnancy outcomes, particularly if they are anemic during the first two trimesters. Severe anemia increases the risk for preterm birth and infant low birth weight. Mild anemia is normal during pregnancy and does not pose any increased risk.

Complications 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 also have an increased risk for infections.

Complications in Older People

Effects of anemia in the elderly include decreased strength and increased risk for falls. Anemia can increase the severity of heart conditions. Studies suggest that anemia may also increase the risk for developing dementia, or worsen existing dementia.

Complications in People with Heart Conditions

Anemia is common in people with coronary artery disease (heart disease), heart failure, history of heart attack, and other heart problems. Anemia is associated with a poorer prognosis and an increased risk for death. It is not clear whether anemia is directly responsible for these worse outcomes or if it is a marker for severe heart disease.

Current guidelines for people with heart conditions recommend treating severe anemia with blood transfusions. Erythropoiesis-stimulating drugs should not be used to treat mild-to-moderate anemia in people with heart failure or heart disease because these medications do not seem to provide much benefit and can increase the risk for blood clots.

Complications in People with Cancer

Anemia is particularly serious in cancer and is associated with a shorter survival time.

Complications in People with Kidney Disease

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

Complications of Vitamin B12 Deficiencies and Pernicious Anemia

Vitamin B12 deficiency can cause neurologic damage, which can be irreversible if it left untreated.

Symptoms

Anemia may occur without symptoms and be detected only during a medical examination that includes a blood test. When symptoms do occur, they may include:

Unusual Symptoms

Pica is an odd symptom of iron-deficiency anemia that often occurs in children. Pica is the habit of eating unusual substances, such as ice (called pagophagia), clay, cardboard, foods that crunch (such as raw potatoes, carrots, or celery), or raw starch. In many cases, iron deficiency is a cause of pica. This symptom usually stops when iron supplements are given.

Symptoms of Megaloblastic Anemia

The symptoms of megaloblastic anemia from vitamin B12 or folic acid deficiencies may include not only standard anemic symptoms, but also:

Diagnosis

Anemia can be the first symptom of a serious illness, so it is very important to determine its cause.

Your health care provider will ask about:

The provider will check for certain physical signs of anemia. They include swollen lymph nodes, an enlarged spleen, and pale skin or nail color.

Complete Blood Count (CBC)

A complete blood count (CBC) is the standard diagnostic test for anemia. The CBC is a panel of tests that measures red blood cells, white blood cells, and platelets. For diagnosis of anemia, the CBC provides critical information on the size, volume, and shape of red blood cells (erythrocytes). CBC results include measurements of hemoglobin, hematocrit, and mean corpuscular volume.

Hemoglobin: Hemoglobin is the iron-bearing and oxygen-carrying component of red blood cells. The normal value for hemoglobin varies by age and gender. Anemia is generally considered when hemoglobin concentrations fall below 11 g/dL for pregnant women, 12 g/dL for non-pregnant women, and 13 g/dL for men.

Hemoglobin concentration ranges provide information on anemia severity:

Hematocrit: Hematocrit is the percentage of blood composed of red blood cells. People with a high volume of plasma (the liquid portion of blood) may be anemic even if their blood count is normal because the blood cells have become diluted. Like hemoglobin, a normal hematocrit percentage depends on age and gender. In general, anemia is diagnosed when hematocrit falls below:

Other hemoglobin measurements, such as mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) may also be calculated.

Mean Corpuscular Volume (MCV): MCV is a measurement of the average size of red blood cells. The MCV increases when red blood cells are larger than normal (macrocytic) and decreases when red blood cells are smaller than normal (microcytic). Macrocytic cells can be a sign of anemia caused by vitamin B12 deficiency, while microcytic cells are a sign of iron-deficiency anemia.

Other Iron Status Blood Tests

Serum Ferritin: Ferritin is a protein that binds to iron and helps to store iron in the body. Low levels suggest reduced iron stores. Normal values are generally 12 to 300 ng/mL for men and 12 to 150 ng/mL for women. Lower than normal levels of ferritin are a sign of iron-deficiency anemia.

Serum Iron: Serum iron measures the amount of iron in the blood. A normal serum iron is 60 to 170 mcg/dL. Lower levels may indicate iron-deficiency anemia or anemia of chronic disease.

Total Iron Binding Capacity (TIBC): TIBC measures the level of transferrin in the blood. Transferrin is a protein that carries iron in the blood. TIBC calculates how much or how little the transferrin in the body is carrying iron. A higher than normal TIBC is a sign of iron-deficiency anemia. A lower than normal level may indicate anemia of chronic disease, sickle cell, pernicious anemia, or hemolytic anemia.

Reticulocyte Count: Reticulocytes are young 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 production problems in the bone marrow. An abnormally high count indicates that red blood cells are being destroyed in high numbers and indicates hemolytic anemia.

Vitamin Deficiencies: The health care provider may order tests for vitamin B12 and folate levels. The Schilling test is used to determine whether the body absorbs vitamin B12 normally.

Other Diagnostic Tests

If internal bleeding is suspected as the cause of anemia, the gastrointestinal (digestive) tract is usually the first possible source. Telltale signs are bloody stools, which may be black and tarry or red-streaked. Often, however, bleeding may be present but not visible. If so, stool tests for this hidden (occult) fecal blood are necessary.

Additional tests may be ordered to check for gastrointestinal bleeding. Endoscopy uses a thin fiber-optic tube to view the esophagus, stomach, and other areas in the upper intestine. Colonoscopy is used to view the lower intestine and rectum and may also be recommended to rule out colorectal cancer.

Women with heavy menstrual bleeding may be referred to a gynecologist for pelvic ultrasound, endometrial biopsy, and other gynecological diagnostic exams.

If the person's diet suggests low iron intake and other causes cannot easily be established, the health care provider may recommend trying iron supplements for a few months. If red blood cell count and iron levels fail to improve, further evaluation is needed.

Dietary Factors

Iron found in foods is either in the form of heme iron (attached to hemoglobin molecule) or non-heme iron:

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:

Vitamin B9 source

Click the icon to see an image of sources of vitamin B9.

Recommended Daily Allowance (RDA)

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 for iron intake is:

Vitamin B12: The RDA for vitamin B12 for adults is 2.4 mcg a day.

Folate: The RDA of folic acid or folate for teenagers and adults is 400 mcg. Women who are pregnant need 600 mcg per day and women who are breastfeeding need 500 mcg daily.

Preventing Anemia in Infants and Small Children

The main source of iron for an infant from birth to 1 year of age is from breast milk, iron-fortified infant formula, or cereal.

Breastfeeding and Iron-Supplemented Formulas: Mothers should try to breastfeed their babies for their first year. The American Academy of Pediatrics (AAP) recommends exclusively breastfeeding for a minimum of 4 months, but preferably 6 months, then gradually adding solid foods while continuing to breastfeed until at least the baby's first birthday.

Because human breast milk contains very little iron, the AAP recommends that full-term healthy infants receive a daily oral iron supplement of 1 mg/kg beginning at age 4 months and continuing until iron-rich complementary foods, such as iron-fortified cereals, are introduced. Preterm infants who are breastfed should receive an iron supplement of 2 mg/kg by the time they are 1 month old.

Infants who are not breastfed should receive iron-fortified formulas (4 to 12 mg/L for their first year of life). Parents should discuss the best formula with their child's health care provider. The AAP does not recommend cow's milk for children under 1 year old. The baby will begin drinking less formula or breast milk once solid foods become a source of nutrition. At 8 to 12 months of age, a baby will be ready to try strained or finely chopped meats. 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. Good sources of iron include iron-fortified grains and cereals, egg yolks, red meat, potatoes (cooked with skin on), tomatoes, molasses, and raisins.

Cow's milk does not contain enough iron, interferes with iron absorption, 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. Fruits that are rich in vitamin C can help boost iron absorption. Most children will receive adequate iron from a well-balanced diet, but some toddlers may benefit from liquid supplements or chewable multivitamins.

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. Iron supplements cannot correct anemias that are not due to iron deficiency.

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.

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 people.

Oral Iron Supplements

Supplement Forms: There are two forms of supplemental iron: ferrous and ferric. Ferrous iron is better absorbed and is the preferred form of iron tablets. Ferrous iron is available in three forms: ferrous fumarate, ferrous sulfate, and ferrous gluconate.

The label of an iron supplement contains information both on the tablet size (which is typically 325 mg) and the amount of elemental iron contained in the tablet (the amount of iron that is available for absorption by the body.) When selecting an iron supplement, it is important to look at the amount of elemental iron.

A 325 mg iron supplement contains the following amounts of elemental iron depending on the type of iron:

Dosage: Depending on the severity of your anemia, as well as your age and weight, your health care provider will recommend a dosage of 60 to 200 mg of elemental iron per day. This means taking 1 iron pill 2 to 3 times during the day. Make sure your provider explains to you how many pills you should take in a day and when you should take them. Never take a double dose of iron.

Side Effects and Safety: Common side effects of iron supplements include:

Other Tips for Safety and Effectiveness: Other tips for taking iron are as follows:

The hematocrit should return to normal after 2 months of iron therapy. However, iron supplementation should be continued for another 6 to 12 months to replenish the body's iron stores in the bone marrow.

Intravenous Iron

In some cases, supplemental iron is administered intravenously. Intravenous iron is used to treat iron-deficiency anemia. It may be recommended for people who:

Intravenous iron may be given in the form of iron dextran (Dexferrum, INFeD), iron sucrose (Venofer), ferric gluconate (Ferrlecit), ferumoxytol (Feraheme), or ferric carboxymaltose (Injectafer). Your health care provider may refer you to a hematologist (a doctor who specializes in blood disorders) to oversee this treatment.

Some intravenous iron can cause an allergic reaction. It might be important to administer a test dose before you receive your first infusion. The risk for allergic reactions is higher with iron dextran than with other forms of intravenous iron. Intravenous iron should never be given at the same time as oral iron supplements.

Blood Transfusions

Transfusions are used to replace blood loss due to injuries and during certain surgeries. They are also commonly used to treat people who have thalassemia, sickle cell disease, myelodysplastic syndromes, or other severe types of anemia. In certain cases, blood transfusions may be used to treat severe anemia associated with heart disease.

Some people require frequent blood transfusions, which can cause a side effect of iron overload. 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. It uses a drug that binds to the iron in the blood. The excess iron is then removed from the body by the kidneys.

Deferasirox (Exjade) is a drug that is given as a once-daily treatment for iron overload due to blood transfusions. It does not require injections. People mix the deferasirox tablets in liquid and drink the medicine.

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.

Synthetic erythropoietin can cause serious side effects, including blood clots, and is approved only for treating select people with anemia related to certain conditions such as anemia caused by rheumatoid arthritis, chronic kidney disease, cancer chemotherapy, and HIV/AIDS treatment with zidovudine.

Erythropoiesis-Stimulating Drugs and Cancer: Erythropoietin may be used to treat anemia caused by chemotherapy. Erythropoietin treatment does not help prolong survival, but can improve quality of life during cancer treatment by improving anemia.

However, these drugs may shorten lifespan and may cause some tumors to grow faster. In general, the lowest effective dose should be used. The risks of early death and increased tumor growth are greatest when these drugs are used to boost the hemoglobin level to 10 to 12 g/dL or higher. The American Society of Clinical Oncology and the American Society of Hematology recommend starting erythropoietin only if the hemoglobin level is less than 10 g/dL.

Erythropoiesis-Stimulating Drugs and Chronic Kidney Disease: For people with chronic kidney disease or kidney failure, the FDA currently recommends that erythropoiesis-stimulating drugs be used to maintain hemoglobin levels between 10 to 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 to 14g/dL) compared to lower hemoglobin levels (10 to 11.3 g/dL).

Warning Symptoms: Contact your health care provider if you have any of the following symptoms while being treated with an erythropoiesis-stimulating drug:

Vitamin Replacement for Megaloblastic Anemia

Megaloblastic anemia is marked by abnormally large red blood cells. (Pernicious anemia is a type of megaloblastic anemia). It is caused by impaired absorption or insufficient intake of vitamin B12 or folate (vitamin B9).

If folate deficiency is responsible, treatment usually involves taking a daily oral folic acid supplement for at least several months as well as increasing intake of foods rich in folate. When vitamin B12 deficiency is responsible, vitamin B12 supplementation may be administered in tablets, injections of cyanocobalamin or hydroxocobalamin, or as a nasal spray.

Resources

References

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Review Date: 3/8/2015
Reviewed By: Todd Gersten, MD, Hematology/Oncology, Florida Cancer Specialists & Research Institute, Wellington, FL. Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, Isla Ogilvie, PhD, and the A.D.A.M. Editorial team. Author: Julia Mongo, MS.
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