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Anemia

Description

An in-depth report on the types, diagnosis, treatment, and prevention of anemia.

Alternative Names

Iron deficiency; Pernicious anemia

Introduction

Anemia is an abnormal reduction in red blood cells.

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 requires an increase in 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 life span of a red blood cell is between 90 - 120 days. Old red blood cells are removed from the blood by the liver and spleen. There they are broken down and iron is returned to the bone marrow to make new cells.

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, and iron stores are depleted in the bone marrow. This stage generally has no symptoms.
• Second, iron deficiencies develop and begin to affect hemoglobin production. (Tests, in such cases, reflect 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.

Iron-Poor Diets. 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.

Peptic Ulcers and Their Causes. The bacteria H. pylori are known to be primary causes of peptic ulcers, and many older people with ulcers have anemia. Anemia in such cases, however, may not result from bleeding ulcers. Instead, anemia is more likely due to the presence of bacteria impairing the ability of these people to absorb iron or vitamin B12. The bacteria, in fact, may also bind to iron and reduce its availability in the intestine, causing iron deficiency anemia.

Medications (NSAIDs). Aspirin and drugs such as ibuprofen and naproxen are called nonsteroidal anti-inflammatory drugs (NSAIDs). About 70% of long-term users of these medications have some sign of gastrointestinal bleeding, although it is rarely significant enough to cause anemia.

Bleeding Due to Other Medical Conditions. Iron deficiencies most commonly occur from internal blood loss due to other conditions that range in severity from hemorrhoids toheavy menstruation to benign colon polyps to colon cancer. Very heavy periods (menorrhagia) are the most common causes of anemia in premenopausal women. Cancers of the gastrointestinal tract account for 2% of cases of iron deficiency (the rate is higher when menorrhagia is excluded).

Pica. Pica is the craving for non-food substances such as ice, starch, or clay. It is a possible cause of iron deficiency, particularly in those who eat clay or starch, which interferes with iron absorption in the stomach. To complicate matters, pica (particularly ice cravings) may also be a symptom, rather than a cause, of anemia.

Hookworm. Hookworm infects about 1 billion people worldwide and is a major cause of anemia in infested areas.

Impaired Absorption of Iron. Certain intestinal diseases (inflammatory bowel disease, celiac disease) or surgical procedures that affect the gastrointestinal tract can impair the ability of the intestine to absorb iron. (Such conditions also often impair folic acid absorption as well.)

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 urinary tract infections and osteomyelitis. Common childhood infections, such as ear infections and urinary tract infections, may even cause anemia due to inflammation. (This anemia often resolves on its own but may be confused with iron deficiency.)
• 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 person’s diet or by the body’s 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 life span. Neurologic problems are also associated with these deficiencies. Several conditions can cause these deficiencies.

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

• 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.
• H. pylori and atrophic gastritis. A 2000 study suggested that the H. pylori bacterium is a player in many cases of vitamin B12 deficiency. These bacteria are not only major culprits in peptic ulcers but also are strongly associated with atrophic gastritis. This condition is a gradual loss of the stomach lining and is a known cause of vitamin B12 deficiency. (Some researchers theorize that H. pylori-induced injuries in the stomach lining may actually be the first step in the destructive process that leads to pernicious anemia.)

• 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)
• Overexposure to nitrous oxide

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.

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
• Celiac sprue (a sensitivity reaction to 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 Dilantin, methotrexate, trimethoprim, and triamterene, may also hinder folate absorption.

Less Common Anemias
Form of Anemia	Description and Diagnosis	Causes and Risk Factors	Treatments
Aplastic Anemia	Bone marrow fails to produce all types of blood cells. Symptoms in addition to standard anemia are bleeding in mucous membranes and skin, gingivitis, higher risk for infection, and shortness of breath.	Cause is unknown in half the cases. Known causes include hereditary conditions (Fanconi's anemia), viruses (HIV, hepatitis, Epstein-Barr), autoimmune diseases (lupus, rheumatoid arthritis), medications (valproic acid, tacrolimus, azathioprine) or chemicals (benzene, pesticides).	Transfusions, antibiotics, bone marrow or stem cell transplantation, immunosuppressant drugs. (This anemia used to be nearly always fatal, but survival rates now can reach 92% with successful transplants and up to 87% with immunosuppressants.)
Thalassemia	Genetic blood disease caused by a defect in the rate of production of hemoglobin. The two major forms are thalassemia minor and thalassemia major (Cooley's anemia, beta thalassemia). Thalassemia minor is the more common and milder form, in which life span is normal. Thalassemia major can be serious but it is fortunately very rare.	Affects males and females equally. Most common in people of Mediterranean descent, especially Italians and Greeks. Both types of thalassemia are found in an area that extends from northern Africa and southern Europe to Thailand, including Iran, Iraq, Indonesia, and southern China. Thalassemia major is more common in families who intermarry.	Transfusions to supply enough red blood cells to achieve moderate anemia and avoid iron overload are standard approaches for thalassemia major. Investigation ongoing to find alternatives to transfusions. Hydroxyurea may help some patients. Bone marrow transplantation may be needed. No treatment necessary for thalassemia minor.
Hemolytic Anemias: Acquired	Anemia caused by hemolysis (premature destruction of red blood cells). Diagnosis considered when there is marked increase in RBC production by bone marrow.	Autoimmune hemolytic anemia is the primary type, in which antibodies produced by the immune system damage RBCs. Cause unknown or associated with disorders such as systemic lupus erythematosus, lymphoma, and paroxysmal nocturnal hemoglobinuria. Other causes are high exposure to certain metals or chemicals (lead, copper, benzene, naphthalene), snake and insect bites, malaria, transfusions, post-surgical complications, and drugs such as methyldopa. In infants, blood group incompatibility between mother and child or infections in the womb.	Corticosteroids for autoimmune hemolytic anemia. Transfusions beneficial in many cases. An investigational drug, eculizumab, is showing promise in studies for paroxysmal nocturnal hemoglobinuria.
Hemolytic Anemias: Inherited	Hemolysis (premature destruction of RBCs) caused by sphere-shaped RBCs, which have difficulties circulating through the spleen.	Inherited defects include membrane defects, hemoglobin abnormalities, and enzyme deficiencies. Fava beans may trigger symptoms. More likely and more serious in males than females.	Blood transfusions may be necessary for some types of hemolytic anemia. Experimental trials use immune globulin. Removal of the spleen (splenectomy) or bone marrow transplantation may help some patients.
Sideroblastic Anemias	Group of anemias caused by impaired ability of bone marrow to produce normal RBCs. Normal to high iron levels, but iron cannot be used to make hemoglobin. In addition to the standard symptoms of anemia are jaundice, enlarged liver and spleen, fever, headache, loss of appetite, vomiting, and leg sores. Symptoms can be mild. Usually appears in childhood. Infections, trauma, and pregnancy may trigger symptoms.	Inherited or acquired after excessive alcohol use, certain medications, including chloramphenicol, or other disorders, including some cancers and rheumatoid arthritis. More common in the elderly.	Deferoxamine (Desferal) is used to remove iron. Effectiveness is increased when ascorbate is added to the regimen. Folate and pyridoxine are used, but their effectiveness is under question.
Sickle Cell Anemia	Serious, life-threatening, inherited disease. The sickle-shaped, inflexible RBC has impaired ability to squeeze through vessels. Short life span of RBC (10-20 days) causes anemia. In addition to anemia symptoms, joint and bone pain, infections, and heart failure can occur.	Disease occurs in 0.6% and the trait is found in the genetic makeup of 9% of African-Americans. Also occurs in people from India and Spanish-speaking and Mediterranean regions.	Measures to avoid cycling and control pain. Including hydration, hydroxyurea, NSAIDs and narcotic analgesics. Bone marrow transplantation. [See In-Depth Report #58: Sickle-cell disease . ]

• Review Date: 1/17/2007
• Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital

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