Anemia is strictly defined as a decrease in red blood cell (RBC) mass. Methods for measuring RBC mass are time consuming, are expensive, and usually require transfusion of radiolabeled erythrocytes. Thus, in practice, anemia is usually discovered and quantified by measurement of the RBC count, hemoglobin (Hb) concentration, and hematocrit (Hct). These values should be interpreted cautiously because they are concentrations affected by changes in plasma volume. For example, dehydration elevates these values, and increased plasma volume in pregnancy can diminish them without affecting the RBC mass.
Pathophysiology
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 remain in the circulation for approximately 1 day before reticulin is excised by reticuloendothelial cells with the delivery of the mature erythrocyte into circulation. 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.

RBCs contain fluid Hb encased in a lipid membrane supported by a cytoskeleton. Abnormalities of the membrane, the chemical composition of the Hb, or certain glycolytic enzymes can reduce the lifespan of RBCs to cause anemia. Basically, only 3 causes of anemia exist: blood loss, increased RBC destruction (hemolysis), and decreased production of RBCs. Each of these 3 causes includes a number of etiologies that require specific and appropriate therapy. Often, the etiology can be determined if the RBCs are altered in either size or shape or if they contain certain inclusion bodies. For example, Plasmodium falciparum malaria is suggested by the presence of more than one ring form in an RBC and produces pan-hemolysis of RBCs of all ages.
Frequency
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 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
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.

A recent study in Iran, however, demonstrated that once-weekly low-dose iron supplementation can be effective in improving iron status and in treating iron deficiency anemia. Mozaffari-Khosravi et al randomly selected and assigned 193 adolescent girls aged 14-16 years to receive either 150 mg ferrous sulfate once weekly for 16 weeks or no iron supplementation. Both before and after intervention, the percentage of anemia, iron deficiency anemia, and iron deficiency were measured in both groups of girls.

Although the parameters measured before the intervention were not significantly different, at the end of 16 weeks, the group that received the ferrous sulfate had significant improvement in the same parameters. In addition, all cases of iron deficiency anemia were resolved in the gropu receiving the low-dose iron supplementation.
Mortality/Morbidity

• The morbidity and mortality of anemias vary greatly depending on the etiology.
  • Acute hemorrhage has variable mortality depending on the site of bleeding (80% with aortic rupture, 30-50% with bleeding esophageal varices, approximately 1% with benign peptic ulcers).
  • Anemia from gastrointestinal bleeding may be the first evidence of an intestinal malignancy.
  • Sickle cell disease may be associated with frequent painful crises and a shortened lifespan, or patients with sickle cell disease may remain relatively asymptomatic with a nearly normal lifespan.
  • Most patients with beta-0 homozygous thalassemia die during the second or third decade of life unless they undergo bone marrow transplantation.
  • Hereditary spherocytosis either may present with a severe hemolytic anemia or may be asymptomatic with compensated hemolysis.
  • Similarly, glucose-6-phosphate dehydrogenase (G-6-PD) deficiency may manifest as chronic hemolytic anemia or exist without anemia until the patient receives an oxidant medication.
  • The 2-year fatality rate for severe aplastic anemia is 70% without bone marrow transplantation or a response to immunosuppressive therapy.
• Many symptoms associated with anemia are not caused by diminished RBC mass. Patients with pernicious anemia are often asymptomatic when they are detected incidentally with an Hb of 6 g/dL. In contrast, ice chewing, calf cramps, and diminished capability to perform muscular work occur in iron-deficiency anemia with an Hb of 10-11 g/dL because of depletion of iron-containing proteins other than Hb.
• In addition, tolerance of anemia is proportional to the anemia’s rate of development. Symptoms and mortality associated with rapidly developing anemia are more profound than in slowly developing anemia.

Race

• Certain races and ethnic groups have an increased prevalence of genetic factors associated with certain anemias. Examples are hemoglobinopathies, thalassemia, and G-6-PD deficiency. Each of these disorders has 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 a greater morbidity and mortality in African Americans than among Saudi Arabians.
• Race is a factor in nutritional anemias and anemia associated with chronic untreated illnesses to the extent that socioeconomic advantages are distributed along racial lines in a given area. Socioeconomic advantages affect diet and the availability of health care and lead to a decreased prevalence of these types of anemia.For instance, iron deficiency anemia is much more prevalent in third world populations who 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, AIDS), and this is at least in part worsened by the socioeconomic status of these populations and their access to adequate health care.

Sex

• 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. Each gram of Hb contains 3.46 mg of iron (1 mL of blood with Hb 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 sufficient iron to avoid iron deficiency.
• Women have a markedly lower incidence of anemia from X-linked anemias, such as G-6-PD deficiency and sex-linked sideroblastic anemias.

Age

• Severe genetically acquired anemias (eg, sickle cell disease, thalassemia, Fanconi syndrome) are more commonly found in children because they do not survive to adulthood.
• During the childbearing years, women are more likely to become iron deficient.
• Neoplasia increases in prevalence with each decade of life and can produce anemia from bleeding, from the replacement of bone marrow with tumor, or from the development of anemia associated with chronic disorders. Use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and Coumadin increases with age and can produce gastrointestinal bleeding.

Clinical
History
Carefully obtain a history and perform a physical examination in every patient with anemia because the findings usually provide important clues to the etiology of the underlying disorder. From the standpoint of the investigation of the anemia, asking questions in addition to those conventionally explored during a routine examination is important. Areas of inquiry found valuable are briefly described below.

• Often, the duration of anemia can be established by obtaining a history of previous blood examination and, if necessary, by acquiring those records. Similarly, a history of rejection as a blood donor or prior prescription of hematinics provides clues that anemia was detected previously.
• Obtain a careful family history not only for anemia but also for jaundice, cholelithiasis, splenectomy, bleeding disorders, and abnormal Hbs. Carefully document the patient’s occupation, hobbies, prior medical treatment, drugs (including over-the-counter medications and vitamins), and household exposures to potentially noxious agents. Patients are unlikely to volunteer exposures to tranquilizers, insecticides, paints, solvents, and hair dyes unless specifically queried.
• In searching for blood loss, carefully document pregnancies, abortions, and menstrual loss. Estimates of menstrual losses are notoriously inaccurate if only routine inquiry is made.
• Often, patients do not appreciate the significance of tarry stools. Changes in bowel habits can be useful in uncovering neoplasms of the colon.
• Hemorrhoidal blood loss is difficult to quantify, and it may be overlooked or overestimated from one patient to another. Obviously, seek a careful history of gastrointestinal complaints that may suggest gastritis, peptic ulcers, hiatal hernias, or diverticula.
• Abnormal urine color can occur in renal and hepatic disease and in hemolytic anemia.
• A thorough dietary history is important in a patient who is anemic. This history must include foods that the patient both eats and avoids as well as an estimate of their quantity.
  • A meal-by-meal description is necessary to obtain appropriate estimates.
  • Even then, patients frequently attempt to deceive the physician because of embarrassment regarding dietary idiosyncrasies or financial restrictions. In these circumstances, a close and concerned family member participating in the dietary history can often be helpful because this person is usually more objective than the patient.
  • Specifically question patients regarding consumption of either clay or laundry starch. This history will not be provided spontaneously. These substances render iron less absorbable.
  • Changes in body weight are important with regard to dietary intake and can suggest the presence of malabsorption or an underlying wasting disease of infectious, metabolic, or neoplastic origin.
• Nutritional deficiencies may be associated with unusual symptoms that can be elicited by a history.
  • Patients with iron deficiencies frequently chew or suck ice (pagophagia). Occasionally, they complain of dysphasia, brittle fingernails, relative impotence, fatigue, and cramps in the calves on climbing stairs that are out of proportion to their anemia.
  • In vitamin B-12 deficiency, early graying of the hair, a burning sensation of the tongue, and a loss of proprioception are common.
  • Suspect a loss of proprioception if the patient stumbles in the dark or must look in order to put on pants in the morning.
  • Paresthesia or unusual sensations frequently described as pain also occur in pernicious anemia.
  • Patients with folate deficiencies may have a sore tongue, cheilosis, and symptoms associated with steatorrhea.
  • Color, bulk, frequency, and odor of stools and whether the feces float or sink can be helpful in detecting malabsorption. More sensitive questions to detect steatorrhea include whether the toilet needs to be flushed more than once to rid it of stool and whether an oily substance is floating on the water surface after the first flush.
• Obtain a history of fever or identify the presence of fever because infections, neoplasms, and collagen vascular disease can cause anemia. Similarly, the occurrence of purpura, ecchymoses, and petechiae suggest the occurrence of either thrombocytopenia or other bleeding disorders; this may be an indication either that more than one bone marrow lineage is involved or that coagulopathy is a cause of the anemia because of bleeding.
• Cold intolerance can be an important symptom of hypothyroidism or lupus erythematosus, paroxysmal cold hemoglobinuria, and certain macroglobulinemias.
• The relation of dark urine to either physical activity or time of day can be important in march hemoglobinuria and paroxysmal nocturnal hemoglobinuria.
• Explore the presence or the absence of symptoms suggesting an underlying disease, such as cardiac, hepatic, and renal disease; chronic infection; endocrinopathy; or malignancy.

Physical
Too often, the physician rushes into the physical examination without looking at the patient for an unusual habitus or appearance of underdevelopment, malnutrition, or chronic illness. These findings can be important clues to the underlying etiology of disease and provide information related to the duration of illness. The skin and mucous membranes are often bypassed so that pallor, abnormal pigmentation, icterus, spider nevi, petechiae, purpura, angiomas, ulcerations, palmar erythema, coarseness of hair, puffiness of the face, thinning of the lateral aspects of the eyebrows, nail defects, and a usually prominent venous pattern on the abdominal wall are missed in the rush to examine the heart and the lungs.

• Examine optic fundi carefully but not at the expense of the conjunctivae and the sclerae, which can show pallor, icterus, splinter hemorrhages, petechiae, comma signs in the conjunctival vessels, or telangiectasia that can be helpful in planning additional studies.
• Perform systematic examination for palpable enlargement of lymph nodes for evidence of infection or neoplasia. Bilateral edema is useful in disclosing underlying cardiac, renal, or hepatic disease, whereas unilateral edema may portend lymphatic obstruction due to a malignancy that cannot be observed or palpated.
• Carefully search for both hepatomegaly and splenomegaly. Their presence or absence is important, as are the size, the tenderness, the firmness, and the presence or the absence of nodules. In patients with chronic disorders, these organs are firm, nontender, and nonnodular. In patients with carcinoma, they may be hard and nodular. The patient with an acute infection usually has a palpably softer and more tender organ.
• A rectal and pelvic examination cannot be neglected because tumor or infection of these organs can be the cause of anemia.
• The neurologic examination should include tests of position sense and vibratory sense, examination of the cranial nerves, and testing for tendon reflexes. The heart should not be ignored because enlargement may provide evidence of the duration and the severity of the anemia, and murmurs may be the first evidence of a bacterial endocarditis that could explain the etiology of the anemia.

Causes
Causes of anemia are numerous and multifaceted. A family history may be useful in detecting hereditary etiology. Diet and exposure to drugs and chemicals can be useful. A geographic history and a thorough knowledge of the patient’s health can be important in establishing an etiology.

• Genetic
  • Hemoglobinopathies
  • Thalassemias
  • Enzyme abnormalities of the glycolytic pathways
  • Defects of the RBC cytoskeleton
  • Congenital dyserythropoietic anemia
  • Rh null disease
  • Hereditary xerocytosis
  • Abetalipoproteinemia
  • Fanconi anemia
• Nutritional
  • Iron deficiency
  • Vitamin B-12 deficiency
  • Folate deficiency
  • Starvation and generalized malnutrition
• Hemorrhage
• Immunologic – Antibody-mediated abnormalities
• Physical effects
  • Trauma
  • Burns
  • Frostbite
  • Prosthetic valves and surfaces
• Drugs and chemicals
  • Aplastic anemia
  • Megaloblastic anemia
• Chronic diseases and malignancies
  • Renal disease
  • Hepatic disease
  • Chronic infections
  • Neoplasia
  • Collagen vascular diseases
• Infections
  • Viral – Hepatitis, infectious mononucleosis, cytomegalovirus
  • Bacterial – Clostridia, gram-negative sepsis
  • Protozoal – Malaria, leishmaniasis, toxoplasmosis
• Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome