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 nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and naproxen. Many 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 menstruating 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.

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 impaired iron utilization being a consequence.)

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. Many patients with heart failure also have anemia. Anemia is associated with a higher risk of death in patients with heart failure. 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 personâ ' s diet or by the bodyâ ' 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. There may be similarities between ACD and severe anemia in patients who are in intensive care. 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, clopidogrel, 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.

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)

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)

• 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.