What is anemia?
Red blood cells or erythrocytes are continuously produced in the bone marrow by a process known as hematopoiesis. This complex process requires adequate amounts of iron, vitamins such as B12 and folic acid, and hormones such as erythropoietin. Iron is required to form hemoglobin, which is the oxygen-carrying protein contained in red blood cells. Deficiency of any of the above can cause a decrease in hemoglobin or red blood cell counts, resulting clinically in anemia. Certain medications, environmental toxins, and cancers that affect the bone marrow can also cause anemia. As erythropoietin is produced in the kidneys, anemia is seen with chronic kidney disease as well.
The normal life span of a red blood cell, from its production in the bone marrow to its destruction in the liver and spleen, is about 120 days. If the life span is decreased in any way, either by increased destruction due to various reasons or through blood loss (during trauma, vaginal bleeding, gastrointestinal bleeding, or surgery), anemia can result. Increased destruction can also occur if the red blood cells are abnormal or if the liver or spleen are enlarged. Anemia is recognized by laboratory tests when the hemoglobin falls below the normal values expected for the age and sex of the patient. The normal range of hemoglobin is 13.5 to 17.5 milligrams per deciliter in males and 12 to 16 milligrams per deciliter in females.
Anemia is generally classified into three broad categories: microcytic, macrocytic, and normocytic, based on red blood cell size measured as the mean corpuscular volume (MCV) of red blood cells in blood tests. Microcytic anemia refers to decreased red blood cell size, usually with decreased hemoglobin as well. The most common cause of microcytic anemia is iron deficiency. Other causes include lead poisoning, thalassemia, sideroblastic anemia, and anemia of chronic disease.
Iron-deficiency anemia is a type of microcytic anemia with low serum iron caused by decreased intake, malabsorption, or increased loss of iron. The most common cause of iron deficiency in the United States is chronic blood loss, usually seen in women of reproductive age (menstrual loss) and the elderly (gastrointestinal blood loss due to tumors or cancers). Pregnant women may have iron deficiency as a result of inadequate intake that does not meet the requirements of the growing fetus; they require iron supplementation. Iron is absorbed in the small intestine, and any disease or procedure that causes problems with absorption, such as celiac sprue, inflammatory bowel disease (IBD), or intestinal surgery, can lead to iron-deficiency anemia. Iron-deficiency anemia is also prevalent in developing nations due to parasitic infestations such as hookworm. Iron deficiency is usually diagnosed by blood tests, but occasionally a bone marrow biopsy may be required in which absent iron stores are noted.
Chronic lead poisoning can also cause anemia by a direct toxic effect on the bone marrow. Lead is found in old house paints, pipes, bullets, batteries, and other items. Children living or playing in old houses are usually affected and may develop learning and behavioral problems in addition to anemia. The characteristic feature of lead poisoning in anemia is basophilic stippling of red blood cells.
Thalassemias are inherited disorders of the hemoglobin involving alpha or beta chains. These defective hemoglobin chains result in very small red blood cells that are fragile and destroyed in the spleen, causing hemolytic anemia. Patients with thalassemia may be revealed to suffer from anemia early in their childhood. Hydrops fetalis is a very severe form of thalassemia that results in fetal death. Thalassemia is most commonly seen in people of Mediterranean and Southeast Asian origin. Cooley’s anemia or beta thalassemia major occurs early in childhood and causes growth retardation.
Sideroblastic anemia is also caused by defective hemoglobin in red blood cells, resulting in hemolytic anemia. Certain toxins such as lead, alcohol, drugs such as chloramphenicol, and hypothermia can cause acquired sideroblastic anemia. Occasionally, sideroblastic anemia may be normocytic. A diagnosis is made when blood tests reveal an excess of iron and a characteristic bone marrow study shows ringed sideroblasts.
Macrocytic anemia is characterized by an increase in red blood cell size. Common causes of macrocytic anemia are vitamin B12 and folic acid deficiencies, alcoholism, hypothyroidism, myelodysplastic syndromes (MDS), and hemolytic anemias.
Vitamin B12 and folate deficiency cause megaloblastic or macrocytic anemia. Vitamin B12 or cobalamin is essential for DNA synthesis. Cobalamin that is ingested in food is bound to the intrinsic factor that is essential for absorption of the vitamin in the small intestine. Most cobalamin deficiency is the result of chronic dietary deficiency or pernicious anemia, which is a deficiency in the intrinsic factor. Folate (folic acid) is present in green leafy vegetables and fruits such as bananas. Folate deficiency is generally attributable to dietary deficiency, increased need as in pregnancy, or decreased absorption in the small intestine. Dietary deficiency is especially common in alcoholics. Pregnant women and patients on certain medications such as methotrexate have increased folic acid needs and require folic acid supplements.
Hemolytic anemias are characterized by increased fragility of the red blood cells and hence their increased destruction in the spleen and liver. The types of hemolytic anemias are sickle cell anemia, hereditary spherocytosis, thalassemia, and autoimmune hemolytic anemias.
Sickle cell anemia is common in those with African ancestry. It is characterized by an abnormal “sickle” shape to the red blood cell that occurs when it is exposed to certain triggers. These abnormal red blood cells are unable to carry adequate oxygen to the tissues. As these fragile cells pass through the capillaries of the spleen, they rupture easily, resulting in anemia. In hereditary spherocytosis, red blood cells are spherical and rigid instead of being biconcave flexible discs. These cells are trapped in the spleen and are destroyed before completing their normal life span of 120 days. In autoimmune hemolytic anemia, antibodies are produced against the red blood cells, which enable them to be targets of destruction by the white blood cells of the immune system. This type of anemia is seen with unmatched blood transfusion or with the ingestion of certain drugs.
Normocytic anemia is characterized by a normal red blood cell size and is seen in anemia of chronic disease, acute blood loss, and anemia of chronic kidney disease.
Chronic inflammatory diseases such as rheumatoid arthritis or osteomyelitis result in the production of certain toxins that act directly on the bone marrow and decrease red blood cell production. Normocytic anemia ensues, in which there is simply an overall decrease in red blood cell production without a maturation defect. The anemia usually improves when the chronic inflammation subsides. In chronic kidney disease, a decrease in erythropoietin production results in decreased red blood cell production. Aplastic anemia is another condition characterized by a marked decrease in red blood cell production because of the effect of toxins, medications, or infections such as parvovirus B19 (fifth disease). Other blood cell types may also be affected in aplastic anemia, resulting in severe infections and bleeding problems.
The symptoms of anemia are generally the same irrespective of the cause. Patients are generally pale and fatigue easily and can experience palpitations or rapid heartbeat. Most of the symptoms are attributable to compensatory mechanisms of the body trying to overcome decreased oxygenation. These compensatory mechanisms result in an increased circulating fluid volume that can eventually cause heart failure. Patients may have symptoms of heart failure such as foot swelling, shortness of breath, palpitations, chest pain, lightheadedness, or episodes of passing out. Patients whose anemia is caused by blood loss may have these symptoms if the loss is chronic and the body has adequate time to compensate. In cases of acute blood loss or when hemoglobin falls below 5 milligrams per deciliter, however, patients may experience shock, low blood pressure, heart attack, stroke, and confusion, sometimes leading to death. On the other hand, chronic mild anemia may be asymptomatic and is detected as an incidental finding on a routine laboratory test.
Other symptoms may be specific to the cause of the anemia. Iron deficiency may sometimes manifest itself as pica (a craving for materials such as clay or ice) and flattened or spoon-shaped nails. Severe thalassemia in children is usually displayed in multiple fractures, a characteristic chipmunk face, an enlarged liver and spleen, heart failure, and gallstones. Patients with anemia caused by vitamin B12 deficiency may have neurological and psychiatric problems. There may be an associated thick red tongue and cracking at the angles of the mouth due to other associated vitamin deficiencies. Patients with hemolytic anemia can suffer from jaundice, dark urine, and gallstones because of the bilirubin released from the hemolysed red blood cells and enlarged spleen. Patients with sickle cell anemia may have acute pain crises and multiple infections. As a result of decreased oxygenation in peripheral tissues, stroke, angina, or lung clots may be the primary presentation in sickle cell disease. Patients with anemia of chronic disease usually have an obvious source of inflammation. Patients with bone marrow failure may also display symptoms of infection and bleeding.
The most important step in the management of anemia is an evaluation of the patient’s condition and the cause of anemia by a physician. A detailed history is usually elicited and should include dietary habits, occupation, associated symptoms, family history, medication history, and other medical problems. A complete physical examination is performed looking specifically for jaundice, pallor, signs of heart failure, and enlarged liver and spleen. The most helpful tool in the diagnosis of anemia is the blood test. The physician may order further tests when the diagnosis is difficult, which may include invasive tests such as a bone marrow biopsy.
The treatment of anemia is directed toward the cause and acuteness of the problem. Acute blood loss is an emergency and requires close monitoring in a hospital. It is treated with blood transfusions and fluid resuscitation. Some patients displaying signs of shock may need to be monitored in an intensive care setting. Patients with chronic anemia may be managed on an outpatient basis.
Iron deficiency is usually treated with oral iron sulfate tablets. Antacids interfere with iron absorption and hence should not be taken simultaneously. Patients who cannot tolerate oral iron may be given iron intravenously. Lead poisoning is treated with chelating agents to remove the lead from the body. Thalassemia requires multiple blood transfusions and, if severe enough, bone marrow transplantation. Iron overload may become a problem with multiple blood transfusions, and chelating treatment with desferrioxamine may be needed to remove the excess iron. Hereditary spherocytosis may be treated with pyridoxine, and acquired spherocytosis caused by alcohol and medications is treated with discontinuation of the offending agent. Megaloblastic anemia due to vitamin B12 and folic acid deficiency is treated with oral supplements of these vitamins. Vitamin B12 may also be given intramuscularly. The neurological abnormalities are reversible if treated early. Autoimmune hemolytic anemias are treated by removal of the offending agent and with steroids. Some patients may require splenectomy (surgical removal of the spleen). Sickle cell crises are treated in the hospital with intravenous fluids, oxygen, and blood transfusion. Supportive care is generally required, and patients may need antibiotics for infections and high doses of painkillers. The number of attacks may be reduced by oral hydroxyurea therapy as an outpatient.
The treatment of anemia caused by chronic kidney disease due to low erythropoietin will require supplementation with weekly subcutaneous erythropoietin and iron. In patients undergoing dialysis, hemoglobin must be maintained above 11 milligrams per deciliter. Patients with aplastic anemia will require multiple blood transfusions and immunosuppressive therapy and may benefit from bone marrow transplantation.
The earliest mention of iron therapy is in Greek mythology in the story of Iphiclus being cured of impotence by drinking a tea made from the rust of an iron blade. The use of iron for the treatment of anemia, however, occurred much later, after the discovery of blood and blood transfusion.
Jan Swammerdam first described red blood cells in 1658, and the first blood transfusion was dog-to-dog in 1665 by Oxford physician Richard Lower. The first human-to-human blood transfusion was performed successfully in 1818 by British obstetrician James Blundell for the treatment of postpartum hemorrhage. Death from hemolytic anemias caused by mismatched blood transfusions, however, was a problem until Karl Landsteiner identified the ABO blood groups in 1901, for which he received the Nobel Prize in Medicine in 1930. He subsequently discovered Rh groups in blood that further reduced the incidence of hemolytic anemias resulting from blood transfusions. The first case of sickle cell anemia was described by James Herrick in 1910, but it was Linus Pauling who postulated that the disease was the result of the presence of mutant hemoglobin HbS.
The mortality rate of anemia has improved significantly over the past century thanks to advances in blood transfusion and bone marrow transplantation. Current research is focusing on the therapeutic potential of anemia correction in cancer, rheumatoid arthritis, human immunodeficiency virus (HIV) infection, heart failure, and kidney disease. It is being shown that the correction of anemia improves quality of life significantly. Synthetic blood may become the treatment of anemia in the future.
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