General Considerations

Adults

Anemia is defined as an abnormally low circulating red blood cell (RBC) mass, reflected by low serum hemoglobin (Hb). However, the normal range of Hb varies among different populations. For menstruating women, anemia is present if the Hb level is at or below 11.6-12.3 g/dL. In men and postmenopausal women, anemia is present if the Hb level is at or below 13.0-14.0 g/dL. Other factors, such as age, race, altitude, and exposure to tobacco smoke, can also alter Hb levels.

Anemia is usually classified by cell size (Table 31-1). Microcytic anemias, or those with mean corpuscular volume (MCV) below 80 fL, are usually due to iron deficiency, chronic inflammation, or thalassemia. Macrocytic anemias, those with MCV above 100 fL, are classified as megaloblastic or nonmegaloblastic. Megaloblasts, which are large, immature, nucleated precursors to RBCs, are seen with vitamin B12 deficiency and folic acid deficiency. Nonmegaloblastic causes of macrocytosis include alcoholism, hypothyroidism, and chronic liver disease. Normocytic anemia (MCV between 80 and 100 fL) can be due to hemolytic or nonhemolytic causes. Hemolysis can result from hereditary abnormalities of the cell contents or cell membrane. Hemolysis can also result from acquired insults caused by autoantibodies, alloantibodies (in, eg, transfusion reactions), or a nonimmune process such as malaria or hypersplenism. Important nonhemolytic causes of normocytic anemia include poor production of RBCs due to aplastic anemia, renal insufficiency, and bone marrow infiltration.

Children

Normal Hb levels vary with age. At birth, mean Hb is about 16.5 g/dL. This level increases to 18.5 g/dL during the first week of life, followed by a drop to 11.5 g/dL by 1-2 months of age. This physiologic anemia of infancy is mediated by changes in erythropoietin levels. By 1-2 years of age, the Hb level begins to rise, to 14 g/dL in adolescent girls and 15 g/dL in adolescent boys. Other relevant laboratory values also vary in children. The median MCV, for example, can be as high as 120 fL in premature infants and as low as 78 fL in 1-year-old infants. Thus, laboratory values in children should always be compared with age-appropriate norms.

Many inherited causes of anemia are discovered in infancy and childhood. It is therefore important to obtain a careful family history in an anemic child, especially if the episodes of anemia are intermittent. Sickle cell anemia, thalassemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and spherocytosis are examples of inherited forms of anemia. When only male members of a family are affected, G6PD deficiency, which is X-linked, should be particularly considered.

Other elements of the history are also important when evaluating a child for anemia. Because infants with anemia can exhibit poor feeding, irritability, and tachycardia rather than classic adult symptoms and signs, these atypical features should be explored with the family. Nutrition should be evaluated carefully, with attention to dietary sources of vitamin B12, folic acid, and iron. Potential sources of lead poisoning must also be considered. Finally, adolescents often require additional support and explanation. For instance, adolescent girls may not know what constitutes a normal menstrual period, so the specific number of tampons and pads used should be obtained.

Iron Deficiency Anemia

Essentials of Diagnosis

• Low iron and serum ferritin levels, and elevated total iron-binding capacity (TIBC).
  
• Response to therapeutic trial of iron.
  
• In adults, nearly always due to blood loss.
  
• Can also be due to poor iron intake or poor absorption.

General Considerations

Iron deficiency is the most common cause of anemia. Up to 11% of women and 4% of men have iron deficiency; however, only about 2% of women and 1% of men develop anemia due to the deficiency.

The average adult has 2-4 g of stored iron. About 65% of this reserve is located in the RBCs, with the remainder in the bone marrow, liver, spleen, and other body tissues. Iron deficiency occurs when there is a net imbalance resulting from either excessive loss or poor intake.

Toddlers aged 1-3 years are vulnerable to iron deficiency anemia. National surveys report rates as high as 15% in this age group.

Pathogenesis

Extracorporeal blood loss is the most common cause of iron deficiency anemia. When RBCs are destroyed within the body, the reticuloendothelial system usually adequately recycles iron into the next generation of RBCs. Poor iron uptake, due either to poor nutrition or inadequate absorption, is a less common cause of iron deficiency anemia.

Women develop iron deficiency more readily than men because of increased potential for iron loss. On average, women lose an additional 1 mg of iron each day due to menstruation. Pregnancy, lactation, and delivery additionally cost a woman an average of 1000 mg of iron each.

In infancy, risk factors for iron deficiency are primarily dietary and include exclusive breast-feeding beyond 6 months without iron supplementation, prolonged bottle-feeding, and excessive cow’s milk consumption. However, other risk factors for iron deficiency in childhood include Hispanic ethnicity, poverty, and being overweight.

Prevention

The US Preventive Services Task Force (USPSTF) recommends primary prevention of iron deficiency anemia by encouraging parents to breast-feed their infants and to include iron-enriched foods in the diet of infants and young children.

Although there is insufficient evidence to recommend for or against the routine use of iron supplements for healthy infants or pregnant women, the USPSTF does currently recommend screening for iron deficiency anemia—using Hb or hematocrit—for both asymptomatic pregnant women and high-risk infants (B Recommendation).

Finally, the USPSTF suggests that although there is insufficient evidence to recommend for or against routine screening for iron deficiency anemia in other asymptomatic persons, screening may be indicated based on other clinical information.

Clinical Findings

Symptoms and Signs

Iron deficiency can be asymptomatic, especially in the early stages. However, patients can present with varying degrees of any of the common symptoms associated with anemia, such as weakness, fatigue, dizziness, headaches, exercise intolerance, or palpitations. Possible signs on physical examination include tachycardia, tachypnea, and pallor, especially of the palpebral conjunctivae.

One symptom associated with iron deficiency in particular is pica—the craving for ice, clay, or other unusual substances that may or may not contain iron. Rare symptoms include koilonychia (spoon nails), blue sclerae, and atrophic glossitis. Esophageal webs, dysphagia, and iron deficiency characterize the Plummer-Vinson syndrome, a disease of unknown pathophysiology that can increase the risk of squamous cell carcinoma of the pharynx and esophagus.

In childhood, iron deficiency anemia has been associated with cognitive and motor delays.

Laboratory Findings

Hb levels can be normal in early iron deficiency. Mild deficiency yields Hb levels of 9-11 g/dL, whereas in severe deficiency levels can fall as low as 5 g/dL.

Serum iron levels below 60 μg/dL indicate iron deficiency. As iron stores are depleted, serum ferritin falls below 30 ng/dL. TIBC therefore rises above 400 μg/dL. Percent iron saturation, which is inversely proportional to TIBC, falls below about 15%.

Although serum ferritin levels are often useful in differentiating iron deficiency from other forms of microcytic anemia, it should be noted that ferritin is an acute-phase reactant that can be elevated during acute illnesses, chronic inflammatory states, or cancer.

The peripheral blood smear is also a useful test. Iron-deficient RBCs manifest varying degrees of hypochromia and microcytosis. However, the gold standard of iron deficiency is bone marrow examination, which shows absent iron reserves in affected patients. A Prussian blue stain is used to examine marrow iron stores.

Another method of diagnosis involves measuring a patient’s response to oral iron therapy. Increased reticulocytosis several days after institution of oral iron treatment can be diagnostic.

Treatment

Iron can be increased in the diet. Foods particularly rich in iron include meats (especially liver) and fish. Whole grains, green leafy vegetables, nuts, seeds, and dried fruit also contain iron. Toddlers’ multivitamins commonly contain iron. Cooking with iron pots and pans also increases iron intake.

Oral iron therapy is available in the form of iron salts. One 300-mg tablet of iron sulfate, for example, delivers 60 mg of elemental iron. One 300-mg tablet of iron gluconate delivers 34 mg of elemental iron and may be better tolerated by some patients. Up to 180 mg of elemental iron can be given each day, depending on the degree of deficiency. Absorption of oral iron is dependent on many environmental factors. An acidic environment increases absorption; thus iron tablets are often given with ascorbic acid. For this same reason, antacids should be avoided within several hours of iron ingestion. Other substances that impair the absorption of iron include calcium, soy protein, tannins (found in tea), and phytate (found in bran). Side effects of oral iron therapy include gastrointestinal distress and constipation. For this reason, some physicians routinely prescribe an as-necessary stool softener along with each iron prescription.

Iron can be given intramuscularly or intravenously to patients who cannot tolerate oral iron due to gastrointestinal upset. This route may also be convenient for patients who have concurrent gastrointestinal malabsorption or ongoing blood loss, such as those with severe inflammatory bowel disease. Phlebitis, muscle breakdown, anaphylaxis, and fever are possible side effects of parenteral iron.

Anemia of Chronic Disease

Essentials of Diagnosis

• Presence of a chronic disease or chronic inflammation.
  
• Shortened RBC survival but poor compensatory erythropoiesis.
  
• High or normal serum ferritin level and low TIBC.

General Considerations

Many chronic diseases–such as cancer, collagen vascular disease, chronic infections, diabetes mellitus, and coronary artery disease—can be associated with anemia (Table 31-2).

Pathogenesis

In spite of shortened RBC survival, bone marrow RBC production is low. This is thought to be due to (1) trapping of iron stores in the reticuloendothelial system, (2) a mild decrease in erythropoietin production, and (3) impaired response of the bone marrow to erythropoietin.

Clinical Findings

Symptoms and Signs

The anemia of chronic disease (ACD) is often mild and therefore general anemic symptoms, such as fatigue, dizziness, and palpitations, can be mild or nonexistent. Signs such as pallor of the palpebral conjunctivae are only sometimes present. The condition must therefore be suspected and investigated in patients known to have underlying conditions such as collagen vascular diseases, cancers, or chronic infections. The condition is often diagnosed incidentally on laboratory reports.

Laboratory Findings

Hb levels are generally mildly decreased (10-11 g/dL), but levels can occasionally be below 8 g/dL. RBCs are often hypochromic. MCV can be either normal (80-100 fL) or low (<80 fL). Because RBC production is poor, the absolute reticulocyte count is often low (<25,000/μL). Acute-phase reactants such as erythrocyte sedimentation rate (ESR), platelets, and fibrinogen can be elevated.

Because ACD is associated with decreased production of transferrin, serum iron level and TIBC are often both low. Calculated percent saturation, however, remains normal. This is to be distinguished from iron deficiency anemia, in which TIBC is often high, resulting in low-percent saturation. Serum ferritin level is high or normal in ACD but low in iron deficiency anemia.

Treatment

Treatment of ACD should be aimed at the underlying condition. Symptomatic patients or heart patients often require packed transfusions of RBCs, especially if the HBG count is below 10 mg/dL. Erythropoietin is also used to correct anemia associated with certain chronic diseases, especially cancer.

Thalassemia

Essentials of Diagnosis

• Elevated RBC count despite decreased Hb level.
  
• Exaggerated microcytosis.
  
• Positive family history.
  
• Mediterranean or African heritage.
  
• Pattern of inheritance.

General Considerations

One normal adult Hb molecule, also known as HbA, consists of a heme moiety, two α Hb chains, and two β Hb chains. The thalassemias are the diverse group of genetic diseases resulting from abnormal Hb due to defective α or β chains.

Other Hb chains exist, such as γ and δ chains. Fetal Hb consists of two α chains and two γ chains (α2γ2), and HbA2 consists of two α chains and two δ chains (α2δ2). Although ordinarily these lesser types of Hb comprise no more than 5% of the total amount of Hb, the thalassemias are characterized by increased proportions of non-A Hb because of defective α or β chains. These disorders are classified as α-thalassemias or β-thalassemias, based on the abnormal gene.

Thalassemia traits are more common in those with Mediterranean, African, and South Asian ancestry. This is at least in part because these parts of the world are inhabited by Plasmodium species, and heterozygous thalassemic traits confer survival advantage to those afflicted with malaria.

Pathogenesis

Because there are four α Hb genes per individual (two on each copy of chromosome 16), there are four major types of α-thalassemia. If only one α Hb gene is damaged, the result is called α-thalassemia minima, an essentially asymptomatic condition. Damage to two different α Hb genes results in α-thalassemia minor, which has only mild clinical significance. Three damaged α Hb genes can lead to a relative abundance of α Hb, causing an abundance of Hb β4, also known as HbH. This disorder, also called hemoglobin H disease, is characterized by severe clinical manifestations of chronic hemolysis, hospitalizations, and decreased lifespan. Absence of normal α Hb chains causes Hb Barts disease and is fatal in utero.

The two β Hb genes are found on chromosome 11. If one is damaged, β-thalassemia minor results, with few clinical effects. Infants with two damaged copies of β Hb will be phenotypically normal at birth due to the predominance of fetal Hb (α2γ2). Affected infants become severely symptomatic in the first year of life, however, and often die before age 5.

Clinical Findings

Symptoms and Signs

α-Thalassemia minima is almost always asymptomatic. α-Thalassemia minor can be accompanied by occasional mild symptoms of anemia, including headaches, fatigue, and dizziness. Patients with HbH disease, however, often exhibit severe clinical manifestations of chronic hemolytic anemia, including hepatosplenomegaly and cholelithiasis (due to bilirubin gallstones). These patients often require chronic transfusions, usually beginning in late childhood and adolescence. Patients with no normal α Hb develop tetramers of γ Hb in utero, known as Hb Barts, which are inefficient at delivering oxygen to the tissues. The accompanying hypoxia results in high-output congestive heart failure, severe edema, and hydrops fetalis.

The clinical appearance of β-thalassemia minor often mimics that of mild or moderate iron deficiency, and often laboratory findings are necessary to distinguish the two. β-Thalassemia major, however, results in a severe phenotype. Widespread hemolysis in these patients causes pallor, irritability, jaundice, and hepatosplenomegaly. Eighty percent of patients die in the first 5 years of life due to severe anemia, high-output congestive heart failure, or infection.

Laboratory Findings

As with iron deficiency, Hb levels and MCV are often low with the thalassemias. In contrast to iron deficiency, however, thalassemias are usually characterized by an elevated RBC count. Furthermore, the decrease in MCV is often more exaggerated in the thalassemias; levels as low as 50-60 fL are not unusual. The red cell distribution width (RDW) can also be used to distinguish the two conditions. With iron deficiency, the RDW is elevated due to a variety of cell sizes, whereas the RDW is usually normal in thalassemic patients because RBCs are uniformly small.

Hb electrophoresis should be conducted on any patient with suspected thalassemia. Although some patients with α-thalassemia minima or media can have normal electrophoresis patterns, abnormalities are often seen in other thalassemic patients. In β-thalassemia minor, for example, relative proportions of fetal Hb (α2γ2) and HbA2 are increased.

Treatment

Patients with α-thalassemia minor, α-thalassemia minima, and β-thalassemia minor are generally asymptomatic and should be treated only if necessary. These patients may require blood transfusions under certain conditions, such as after vaginal delivery or surgery.