Introduction

Anemia is a condition that develops when your blood lacks enough healthy red blood cells or hemoglobin. Hemoglobin is a main part of red blood cells and binds oxygen. If you have too few or abnormal red blood cells, or your hemoglobin is abnormal or low, the cells in your body will not get enough oxygen. Symptoms of anemia like fatigue, occur because organs aren't getting what they need to function properly.

Anemia is the most common blood condition in the U.S. It affects about 3.5 million Americans. Women, young children, and people with chronic diseases are at increased risk of anemia. Important factors to remember are:

Certain forms of anemia are hereditary and infants may be affected from the time of birth.

Women in the childbearing years are particularly susceptible to iron-deficiency anemia because of the blood loss from menstruation and the increased blood supply demands during pregnancy.

Older adults also may have a greater risk of developing anemia because of poor diet and other medical conditions.

There are many types of anemia. All are very different in their causes and treatments. Iron-deficiency anemia, the most common type, is very treatable with diet changes and iron supplements. Some forms of anemia like the mild anemia that develops during pregnancy are even considered normal. However, some types of anemia may present lifelong health problems.

Human blood from a case of iron-deficiency anemia

Clinical Features

The symptoms of anemia vary according to the type of anemia, the underlying cause, the severity and any underlying health problems, such as hemorrhaging, ulcers, menstrual problems, or cancer. Specific symptoms of those problems may be noticed first.

The body also has a remarkable ability to compensate for early anemia. If your anemia is mild or has developed over a long period of time, you may not notice any symptoms.

Symptoms common to many types of anemia include the following:

• ·         Easy fatigue and loss of energy.
• ·         Unusually rapid heartbeat, particularly with exercise.
• ·         Shortness of breath and headache, particularly with exercise.
• ·         Difficulty concentrating.
• ·         Dizziness.
• ·         Pale skin.
• ·         Leg cramps.
• ·         Insomnia.

Diagnosis

Your doctor will diagnose anemia based on your medical and family histories, a physical exam, and results from tests and procedures.

Because anemia doesn't always cause symptoms, your doctor may find out you have it while checking for another condition.

Medical and Family Histories

Your doctor may ask whether you have any of the common signs or symptoms of anemia. He or she also may ask whether you've had an illness or condition that could cause anemia.

Let your doctor know about any medicines you take, what you typically eat (your diet), and whether you have family members who have anemia or a history of it.

Physical Exam

Your doctor will do a physical exam to find out how severe your anemia is and to check for possible causes. He or she may:

Listen to your heart for a rapid or irregular heartbeat

Listen to your lungs for rapid or uneven breathing

Feel your abdomen to check the size of your liver and spleen

Your doctor also may do a pelvic or rectal exam to check for common sources of blood loss.

Diagnostic Tests and Procedures

You may have various blood tests and other tests or procedures to find out what type of anemia you have and how severe it is.

Complete Blood Count

Often, the first test used to diagnose anemia is a complete blood count (CBC). The CBC measures many parts of your blood.

The test checks your hemoglobin and hematocrit (hee-MAT-oh-crit) levels. Hemoglobin is the iron-rich protein in red blood cells that carries oxygen to the body. Hematocrit is a measure of how much space red blood cells take up in your blood. A low level of hemoglobin or hematocrit is a sign of anemia.

The normal range of these levels might be lower in certain racial and ethnic populations. Your doctor can explain your test results to you.

The CBC also checks the number of red blood cells, white blood cells, and platelets in your blood. Abnormal results might be a sign of anemia, another blood disorder, an infection, or another condition.

Finally, the CBC looks at mean corpuscular (kor-PUS-kyu-lar) volume (MCV). MCV is a measure of the average size of your red blood cells and a clue as to the cause of your anemia. In iron-deficiency anemia, for example, red blood cells usually are smaller than normal.

Other Tests and Procedures

If the CBC results show that you have anemia, you may need other tests, such as:

Hemoglobin electrophoresis (e-lek-tro-FOR-e-sis). This test looks at the different types of hemoglobin in your blood. The test can help diagnose the type of anemia you have.

A reticulocyte (re-TIK-u-lo-site) count. This test measures the number of young red blood cells in your blood. The test shows whether your bone marrow is making red blood cells at the correct rate.

Tests for the level of iron in your blood and body. These tests include serum iron and serum ferritin tests. Transferrin level and total iron-binding capacity tests also measure iron levels.

Because anemia has many causes, you also might be tested for conditions such as kidney failure, lead poisoning (in children), and vitamin deficiencies (lack of vitamins, such as B12 and folic acid).

If your doctor thinks that you have anemia due to internal bleeding, he or she may suggest several tests to look for the source of the bleeding. A test to check the stool for blood might be done in your doctor's office or at home. Your doctor can give you a kit to help you get a sample at home. He or she will tell you to bring the sample back to the office or send it to a laboratory.

If blood is found in the stool, you may have other tests to find the source of the bleeding. One such test is endoscopy (en-DOS-ko-pe). For this test, a tube with a tiny camera is used to view the lining of the digestive tract.

Your doctor also may want to do bone marrow tests. These tests show whether your bone marrow is healthy and making enough blood cells.

Anemia Treatment

Anemia treatment depends on the cause.

·   Iron deficiency anemia. Treatment for this form of anemia usually involves taking iron supplements and making changes to your diet.

If the underlying cause of iron deficiency is loss of blood other than from menstruation the source of the bleeding must be located and stopped. This may involve surgery.

·    Vitamin deficiency anemias. Treatment for folic acid and B-12 deficiency involves dietary supplements and increasing these nutrients in your diet.

If your digestive system has trouble absorbing vitamin B-12 from the food you eat, you may need vitamin B-12 shots. At first, you may receive the shots every other day. Eventually, you'll need shots just once a month, which may continue for life, depending on your situation.

·         Anemia of chronic disease. There's no specific treatment for this type of anemia. Doctors focus on treating the underlying disease. If symptoms become severe, a blood transfusion or injections of synthetic erythropoietin, a hormone normally produced by your kidneys, may help stimulate red blood cell production and ease fatigue.

·     Aplastic anemia. Treatment for this anemia may include blood transfusions to boost levels of red blood cells. You may need a bone marrow transplant if your bone marrow is diseased and can't make healthy blood cells.

·    Anemias associated with bone marrow disease. Treatment of these various diseases can include medication, chemotherapy or bone marrow transplantation.

·   Hemolytic anemias. Managing hemolytic anemias includes avoiding suspect medications, treating related infections and taking drugs that suppress your immune system, which may be attacking your red blood cells.

Depending on the severity of your anemia, a blood transfusion or plasmapheresis may be necessary. Plasmapheresis is a type of blood-filtering procedure. In certain cases, removal of the spleen can be helpful.

·       Sickle cell anemia. Treatment for this anemia may include the administration of oxygen, pain-relieving drugs, and oral and intravenous fluids to reduce pain and prevent complications. Doctors also may recommend blood transfusions, folic acid supplements and antibiotics.

A bone marrow transplant may be an effective treatment in some circumstances. A cancer drug called hydroxyurea (Droxia, Hydrea) also is used to treat sickle cell anemia.

·   Thalassemia. This anemia may be treated with blood transfusions, folic acid supplements, medication, removal of the spleen (splenectomy), or a blood and bone marrow stem cell transplant.

Types of Anemia

Different types of anemia and their causes include:

·      Iron deficiency anemia. This is the most common type of anemia worldwide. Iron deficiency anemia is caused by a shortage of iron in your body. Your bone marrow needs iron to make hemoglobin. Without adequate iron, your body can't produce enough hemoglobin for red blood cells.

Without iron supplementation, this type of anemia occurs in many pregnant women. It is also caused by blood loss, such as from heavy menstrual bleeding, an ulcer, cancer and regular use of some over-the-counter pain relievers, especially aspirin.

·     Vitamin deficiency anemia. In addition to iron, your body needs folate and vitamin B-12 to produce enough healthy red blood cells. A diet lacking in these and other key nutrients can cause decreased red blood cell production.

Additionally, some people may consume enough B-12, but their bodies aren't able to process the vitamin. This can lead to vitamin deficiency anemia, also known as pernicious anemia.

·     Anemia of chronic disease. Certain diseases such as cancer, HIV/AIDS, rheumatoid arthritis, kidney disease, Crohn's disease and other chronic inflammatory diseases can interfere with the production of red blood cells.

·    Aplastic anemia. This rare, life-threatening anemia occurs when your body doesn't produce enough red blood cells. Causes of aplastic anemia include infections, certain medicines, autoimmune diseases and exposure to toxic chemicals.

·      Anemias associated with bone marrow disease. A variety of diseases, such as leukemia and myelofibrosis, can cause anemia by affecting blood production in your bone marrow. The effects of these types of cancer and cancer-like disorders vary from mild to life-threatening.

·        Hemolytic anemias. This group of anemias develops when red blood cells are destroyed faster than bone marrow can replace them. Certain blood diseases increase red blood cell destruction. You can inherit a hemolytic anemia, or you can develop it later in life.

·     Sickle cell anemia. This inherited and sometimes serious condition is an inherited hemolytic anemia. It's caused by a defective form of hemoglobin that forces red blood cells to assume an abnormal crescent (sickle) shape. These irregular blood cells die prematurely, resulting in a chronic shortage of red blood cells.

·    Other anemias. There are several other forms of anemia, such as thalassemia and malarial anemia.

Pathophysiology

Erythrocyte life cycle

Erythroid precursors develop in bone marrow at rates usually determined by the requirement for sufficient circulating Hb to oxygenate tissues adequately. Erythroid precursors differentiate sequentially from stem cells to progenitor cells to erythroblasts to normoblasts in a process requiring growth factors and cytokines. This process of differentiation requires several days. Normally, erythroid precursors are released into circulation as reticulocytes.

Reticulocytes are so called because of the reticular meshwork of RNA they harbor. They remain in the circulation for approximately 1 day before they mature into erythrocytes, after the digestion of RNA by reticuloendothelial cells. The mature erythrocyte remains in circulation for about 120 days before being engulfed and destroyed by phagocytic cells of the reticuloendothelial system.

Erythrocytes are highly deformable and increase their diameter from 7 µm to 13 µm when they traverse capillaries with a 3-µm diameter. They possess a negative charge on their surface, which may serve to discourage phagocytosis. Because erythrocytes have no nucleus, they lack a Krebs cycle and rely on glycolysis via the Embden-Meyerhof and pentose pathways for energy. Many enzymes required by the aerobic and anaerobic glycolytic pathways decrease within the cell as it ages. In addition, the aging cell has a decrease in potassium concentration and an increase in sodium concentration. These factors contribute to the demise of the erythrocyte at the end of its 120-day lifespan.

Response to anemia

The physiologic response to anemia varies according to acuity and the type of insult. Gradual onset may allow for compensatory mechanisms to take place. With anemia due to acute blood loss, a reduction in oxygen-carrying capacity occurs along with a decrease in intravascular volume, with resultant hypoxia and hypovolemia. Hypovolemia leads to hypotension, which is detected by stretch receptors in the carotid bulb, aortic arch, heart, and lungs. These receptors transmit impulses along afferent fibers of the vagus and glossopharyngeal nerves to the medulla oblongata, cerebral cortex, and pituitary gland.

In the medulla, sympathetic outflow is enhanced, while parasympathetic activity is diminished. Increased sympathetic outflow leads to norepinephrine release from sympathetic nerve endings and discharge of epinephrine and norepinephrine from the adrenal medulla. Sympathetic connection to the hypothalamic nuclei increases antidiuretic hormone (ADH) secretion from the pituitary gland.  ADH increases free water reabsorption in the distal collecting tubules. In response to decreased renal perfusion, juxtaglomerular cells in the afferent arterioles release renin into the renal circulation, leading to increased angiotensin I, which is converted by angiotensin-converting enzyme (ACE) to angiotensin II.

Angiotensin II has a potent pressor effect on arteriolar smooth muscle. Angiotensin II also stimulates the zona glomerulosa of the adrenal cortex to produce aldosterone. Aldosterone increases sodium reabsorption from the proximal tubules of the kidney, thus increasing intravascular volume. The primary effect of the sympathetic nervous system is to maintain perfusion to the tissues by increasing systemic vascular resistance (SVR). The augmented venous tone increases the preload and, hence, the end-diastolic volume, which increases stroke volume. Therefore, stroke volume, heart rate, and SVR all are maximized by the sympathetic nervous system. Oxygen delivery is enhanced by the increased blood flow.

In states of hypovolemic hypoxia, the increased venous tone due to sympathetic discharge is thought to dominate the vasodilator effects of hypoxia. Counter regulatory hormones (eg, glucagon, epinephrine, cortisol) are thought to shift intracellular water to the intravascular space, perhaps because of the resultant hyperglycemia. This contribution to the intravascular volume has not been clearly elucidated.

Management

1. Preventation

Eat a vitamin-rich diet

Many types of anemia can't be prevented. But iron deficiency anemia and vitamin deficiency anemias can be avoided by having a diet that includes a variety of vitamins and nutrients, including:

·    Iron. Iron-rich foods include beef and other meats, beans, lentils, iron-fortified cereals, dark green leafy vegetables, and dried fruit.

·      Folate. This nutrient, and its synthetic form folic acid, can be found in fruits and fruit juices, dark green leafy vegetables, green peas, kidney beans, peanuts, and enriched grain products, such as bread, cereal, pasta and rice.

·         Vitamin B-12. Foods rich in vitamin B-12 include meat, dairy products, and fortified cereal and soy products.

·         Vitamin C. Foods rich in vitamin C include citrus fruits and juices, peppers, broccoli, tomatoes, melons and strawberries. These items help increase iron absorption.

Consider a multivitamin

If you're concerned about getting enough vitamins from the food you eat, ask your doctor whether a multivitamin may be right for you.

Consider genetic counseling

If you have a family history of an inherited anemia, such as sickle cell anemia or thalassemia, talk to your doctor and possibly a genetic counselor about your risk and what risks you may pass on to your children.

Prevent malaria

Anemia can be a complication of malaria. If you plan on traveling to a place where malaria is common, talk with your doctor beforehand about taking preventive drugs. In areas where malaria is common, prevention involves reducing exposure to mosquitoes, for example, by using bed nets treated with insecticide.

Complications

Left untreated, anemia can cause many health problems, such as:

·     Severe fatigue. When anemia is severe enough, you may be so tired that you can't complete everyday tasks.

·       Pregnancy complications. Pregnant women with folate deficiency anemia may be more likely to experience complications, such as premature birth.

·      Heart problems. Anemia can lead to a rapid or irregular heartbeat (arrhythmia). When you're anemic your heart must pump more blood to compensate for the lack of oxygen in the blood. This can lead to an enlarged heart or heart failure.

·    Death. Some inherited anemias, such as sickle cell anemia, can be serious and lead to life-threatening complications. Losing a lot of blood quickly results in acute, severe anemia and can be fatal.

Epidemiology

Occurrence in the United States

The prevalence of anemia in population studies of healthy, nonpregnant people depends on the Hb concentration chosen for the lower limit of normal values. The World Health Organization (WHO) chose 12.5 g/dL for both adult males and females. In the United States, limits of 13.5 g/dL for men and 12.5 g/dL for women are probably more realistic. Using these values, approximately 4% of men and 8% of women have values lower than those cited. A significantly greater prevalence is observed in patient populations. Less information is available regarding studies using RBC or Hct.

International occurrence

The prevalence of anemia in Canada and northern Europe is believed to be similar to that in the United States. In underprivileged countries, limited studies of purportedly healthy subjects show the prevalence of anemia to be 2-5 times greater than that in the United States. Although geographic diseases, such as sickle cell anemia, thalassemia, malaria, hookworm, and chronic infections, are responsible for a portion of the increase, nutritional factors with iron deficiency and, to a lesser extent, folic acid deficiency play major roles in the increased prevalence of anemia. Populations with little meat in the diet have a high incidence of iron deficiency anemia, because heme iron is better absorbed from food than inorganic iron.

Sickle cell disease is common in regions of Africa, India, Saudi Arabia, and the Mediterranean basin. The thalassemias are the most common genetic blood diseases and are found in Southeast Asia and in areas where sickle cell disease is common.

Race-related demographics

Certain races and ethnic groups have an increased prevalence of genetic factors associated with certain anemias. Diseases such as the hemoglobinopathies, thalassemia, and G-6-PD deficiency have different morbidity and mortality in different populations due to differences in the genetic abnormality producing the disorder. For example, G-6-PD deficiency and thalassemia have less morbidity in African Americans than in Sicilians because of differences in the genetic fault. Conversely, sickle cell anemia has greater morbidity and mortality in African Americans than in Saudi Arabians.

Race is a factor in nutritional anemias and anemia associated with untreated chronic illnesses to the extent that socioeconomic advantages are distributed along racial lines in a given area;  socioeconomic advantages that positively affect diet and the availability of health care lead to a decreased prevalence of these types of anemia. For instance, iron deficiency anemia is much more prevalent in the populations of developing nations, who tend to have little meat in their diets, than it is in populations of the United States and northern Europe.

Similarly, anemia of chronic disorders is commonplace in populations with a high incidence of chronic infectious disease (eg, malaria, tuberculosis, acquired immunodeficiency syndrome [AIDS]), and this is at least in part worsened by the socioeconomic status of these populations and their limited access to adequate health care.

Sex-related demographics

Overall, anemia is twice as prevalent in females as in males. This difference is significantly greater during the childbearing years due to pregnancies and menses.

Approximately 65% of body iron is incorporated into circulating Hb. One gram of Hb contains 3.46 mg of iron (1 mL of blood with an Hb concentration of 15 g/dL = 0.5 mg of iron). Each healthy pregnancy depletes the mother of approximately 500 mg of iron. While a man must absorb about 1 mg of iron to maintain equilibrium, a premenopausal woman must absorb an average of 2 mg daily. Further, because women eat less food than men, they must be more than twice as efficient as men in the absorption of iron to avoid iron deficiency.

Women have a markedly lower incidence of X-linked anemias, such as G-6-PD deficiency and sex-linked sideroblastic anemias, than men do. In addition, in the younger age groups, males have a higher incidence of acute anemia from traumatic causes.

Age-related demographics

Previously, severe, genetically acquired anemias (eg, sickle cell disease, thalassemia, Fanconi syndrome) were more commonly found in children because they did not survive to adulthood. However, with improvement in medical care and breakthroughs in transfusion and iron chelation therapy, in addition to fetal hemoglobin modifiers, the life expectancy of persons with these diseases has been significantly prolonged. 

Acute anemia has a bimodal frequency distribution, affecting mostly young adults and persons in their late fifties. Causes among young adults include trauma, menstrual and ectopic bleeding, and problems of acute hemolysis. During their childbearing years, women are more likely to become iron deficient.

In people aged 50-65 years, acute anemia is usually the result of acute blood loss in addition to a chronic anemic state. This is the case in uterine and GI bleeding.

Neoplasia increases in prevalence with each decade of life and can produce anemia from bleeding, from the invasion of bone marrow with tumor, or from the development of anemia associated with chronic disorders. The use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and warfarin also increases with age and can produce GI bleeding.