Introduction

Anemia is an abnormal reduction in red blood cells.

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

Anemia is a great problem globally, and worse 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.

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

Click the icon to see an image of hemoglobin.

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. Lack of iron in the diet is not a common cause of iron deficiency anemia, except in infants. In fact, most Americans adults may be consuming too much iron in their diet. Most of the iron in red blood cells is recycled and reused. In general, most people need just 1 mg and menstruating women need 2 mg of extra iron each day, which a healthy diet easily provides. Iron-poor diets are only a cause of anemia 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, which, in turn, is an important cause of anemia in older people. Anemia in such cases may be less likely to result from bleeding ulcers but more to impaired iron or vitamin B12 absorption caused by the presence of the bacteria. 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. Two laboratory studies suggest that aspirin -- but not other NSAIDs -- may stimulate the production of ferritin, a blood protein that binds iron. Since low ferritin levels indicate iron deficiencies, this effect could mask the true cause of anemia. However, a clinical study found that aspirin users actually have low ferritin levels, possibly because of gastrointestinal bleeding. More research is needed.

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, heavy menstruation, or 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 one billion people worldwide. It is a major cause of anemia in areas where it occurs.

Click the icon to see an image of a hookworm.

Impaired Absorption of Iron. Certain intestinal diseases (e.g., 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.)

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 diseases associated with a persistent inflammatory process. 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, red blood cell survival is reduced, and 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 it 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 put powerful proteins known as cytokines, which are critical in the development of ACD. Cytokines are indispensable for healing. However, often in chronic and inflammatory diseases cytokines are overproduced and cause 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 as well as 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 are the following:

• 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 the 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/AIDS. In addition to ribavirin, patients with HIV/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 (e.g., phenytoin), immunosuppressive drugs (e.g., 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, 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. There are a number of conditions that 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 the following:

• 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 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. The 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.)

Click the icon to see an image of a peptic ulcer.

• 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 three-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.

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 alcohol 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)

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

• Parasitic diseases such as giardiasis
• Short bowel syndrome

Deficiencies can also be caused by 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.

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

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Review Date: 12/16/2005
Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital