Figure 19.1. Normal blood smear.

    The RI is the reticulocyte count corrected for the degree of anemia in an individual. It is calculated as follows:

where 40% is a normal hematocrit (Hct)

The reticulocyte index broadly divides anemias into

1. Hypoproliferative anemias: those due to inadequate production of RBCs by the bone marrow, associated with a low reticulocyte index, and

2. Hyperproliferative anemias: those due to increased clearing of RBCs by the spleen or frank blood loss, associated with a high reticulocyte index. The reticulocyte index in the normal healthy adult is between l and 2 (see Figure 19.2).

    The treatment of anemias in general is to treat the underlying cause and provide supportive care including administration of blood transfusions in unstable or high-risk patients.

HYPOPROLIFERATIVE ANEMIAS

The hypoproliferative anemias result from the inadequate production of RBCs by the bone marrow. This may be the result of a primary bone marrow pathology such as red cell aplasia, aplastic anemia, or Fanconi anemia, or from an inadequate supply of the ingredients needed by the bone marrow to produce RBCs, principally iron, vitamin B₁₂, folate, and erythropoietin, or from a dysregulation of cytokines that influence the bone marrow to make RBCs. The RI in these instances is <1. These anemias can be classified based on the average size of the cells, the mean corpuscular volume (MCV), into microcytic, macrocytic, and normocytic anemias (see Figure 19.3).

MICROCYTIC HYPOCHROMIC ANEMIAS

Microcytosis refers to the size of the RBC being small relative to the nucleus of a normal mature lymphocyte and hypochromia refers to the central pallor of the RBC being greater than one-third the diameter of the RBC. The differential diagnosis of microcytic anemia includes iron deficiency, thalassemias and other hemoglobinopathies, anemia of chronic disease, sideroblastic anemia, and lead poisoning.

IRON DEFICIENCY ANEMIA

Iron deficiency anemia is the most common hematologic problem encountered in general practice. The causes of iron deficiency include blood loss, decreased gastrointestinal absorption (after bariatric surgery or celiac disease), or increased iron requirements (during pregnancy or with exogenous erythropoietin use). In addition to the general clinical features of all anemias, iron deficiency is associated with symptoms in rapidly proliferating tissues: glossitis, angular stomatitis, gastric atrophy, koilonychia (spoon-shaped nails), and pica. The blood smear in iron deficiency shows microcytic hypochromic RBCs as well as pencil (shaped) cells and cells of all sizes and shapes (anisopoikilocytosis) (see Figure 19.4). The best single test for making a diagnosis of iron deficiency is the ferritin level (the storage form of iron). A ferritin level <30 µg/mL is generally diagnostic. Other indices that aid a diagnosis are a low serum iron and a high total iron binding capacity (TIBC). The TIBC is a reflection of transferrin, the protein that transports iron in the plasma. Iron deficiency is also associated with a high RBC distribution width (RDW) which is a quantitative measure of the variation in RBC size, and a high serum soluble transferrin receptor level. Anemia is a late feature of iron deficiency and although iron deficiency is very often a hypochromic microcytic anemia, it may present as a normocytic anemia. Figure 19.5 shows the stages of iron deficiency. Once a diagnosis of iron deficiency has been made, a thorough search for the underlying cause should be undertaken and blood loss must be ruled out.

    Treatment for iron deficiency is either with oral or intravenous replacement. Oral iron comes as iron sulfate, iron gluconate or iron lactate. Ferrous sulfate, 325 mg twice daily, is a standard dose. Intravenous formulations (in the US) include low molecular weight iron dextran, iron sucrose, ferric gluconate, and ferumoxytol. Intravenous iron should be used particularly if the patient is unable to absorb iron (malabsorption, celiac disease, etc.); unable to tolerate oral iron (severe constipation or other gastrointestinal upset); or to improve response to erythropoiesis-stimulating agents such as in patients on renal dialysis. The American Society of Hematology recommends ferric gluconate for intravenous replacement 125 mg per dose for a total dose of l to 1.5 g. Oral repletion usually takes 4–6 months to return ferritin to mid‒normal range.

NORMOCYTIC NORMOCHROMIC ANEMIAS

The differential diagnosis of normocytic anemias includes acute blood loss, anemia of chronic disease, anemia of renal failure, hypothyroidism, aplastic anemia, and hemolysis.

ANEMIA OF CHRONIC DISEASE

Anemia of chronic disease (ACD) is the second most common form of anemia. ACD is characterized by impaired absorption of iron from the GI tract and iron trapping in macrophages preventing the utilization of iron by the body. The features that define ACD are mediated by the iron regulatory hormone, hepcidin, which is a 21-peptide hormone produced by the liver that is responsible for iron homeostasis. Hepcidin production is also stimulated by inflammation and binds to and causes the degradation of ferroportin. Ferroportin is the channel through which iron transverses to go from the enterocyte into the bloodstream and from the interior to the exterior of macrophages. Hepcidin in inhibiting the function of ferroportin blocks iron transportation across these membranes. Because ACD results in iron-deficient erythropoiesis, various laboratory features are similar to those seen in iron deficiency. Table 19.1 shows the difference in laboratory values seen in ACD, iron deficiency, and thalassemia minor. ACD and iron deficiency can be differentiated by the ferritin, TIBC, and soluble transferrin receptor. Efforts are under way to develop a hepcidin assay. Medical conditions commonly associated with ACD include infective endocarditis, osteomyelitis, rheumatoid arthritis, tuberculosis, systemic lupus erythematosus, vasculitis, and cancer although no conditions are exempt. Treatment of ACD involves treating the underlying disease and exogenous erythropoietin administration (with or without intravenous iron) to a goal hemoglobin of about 11.5 g/dL.

MACROCYTIC ANEMIAS

The differential diagnoses of macrocytic anemias include vitamin B₁₂ and folate deficiency, myelodysplasia, alcoholic liver disease, reticulocytosis, hypothyroidism, and drugs that block folate metabolism (zidovudine, phenytoin, oral contraceptives, sulfasalazine, hydroxyurea).

Folate and Vitamin B₁₂ Deficiency

Folate and vitamin B₁₂ deficiency are the two most important causes of macrocytic anemia. Folate and B₁₂ deficiencies cause impaired DNA synthesis that results in macrocytic and megaloblastic RBCs as well as white blood cells (WBC) with hypersegmented (>5 lobes) nuclei.

    B₁₂ is found exclusively in animal proteins. On ingestion, B₁₂ is liberated from food (by pepsin and gastric juice) and binds to R-protein. In the duodenum, B₁₂ is released from R-protein by the action of pancreatic enzymes, and is bound to intrinsic factor (IF) produced by the parietal cells in the stomach. B₁₂–IF complex then passes to the distal ileum where it is actively absorbed. It is then transported in the blood by transcobalamin for use in erythropoiesis. Dietary deficiency is rare except in the case of a strict vegan diet. Most causes of B₁₂ deficiency are related to ineffective absorption and include pernicious anemia (autoimmune destruction of parietal cells), partial gastrectomy, blind loop syndromes, fish tapeworm, pancreatic insufficiency, ileal resection, Crohn disease, and radiation enteritis. In addition to the general features of anemia, patients with deficiency can have GI symptoms such as diarrhea and glossitis and neurological deficits ranging from paresthesias and loss of vibration and position sense, gait disturbances, to psychosis or dementia “megaloblastic madness.” Neurological deficits from B₁₂ deficiency that go untreated for long durations may cause irreversible damage.

    The Schilling test, which distinguishes among pernicious anemia, nutritional deficiency, and malabsorption, is no longer routinely used in clinical practice. The diagnosis of B₁₂ deficiency is made by the findings of low to low-normal levels of serum B₁₂ (lower limit of normal B₁₂ is 200 pg/mL) and elevated homocysteine and methylmalonic acid levels. An elevated lactate dehydrogenase (LDH) is also seen due to ineffective erythropoiesis. Vitamin B₁₂ levels are falsely low in pregnancy and oral contraceptive use. Treatment of deficiency is traditionally with a loading dose of 1000 µg intramuscularly every week for 4 weeks followed by monthly injections at 1000 µg per month. Incidentally, oral repletion is also an option even in cases of pernicious anemia at a dose of 1000 µg daily. Oral B₁₂ at this dose is absorbed by mass action.

    Folate is found exclusively in plant sources and folate bodily stores are minimal. Unlike B₁₂ deficiency which takes l–2 years to develop, in the absence of intake, folate deficiency may develop in 1–3 months. Deficiency results from poor dietary intake and increased bodily demands (pregnancy and hemolysis). Patients with folate deficiency have similar symptoms to B₁₂ deficiency besides the neurological features. Folate is not involved in myelin synthesis and so does not affect the neurological system. Likewise, folate replacement may correct anemia due to B₁₂ deficiency but will not affect the neurological abnormalities. It is therefore important to differentiate B₁₂ deficiency from folate deficiency before treating with folate supplementation (see table 19.2).

HYPERPROLIFERATIVE ANEMIAS

These are anemias caused by inappropriate loss or premature destruction (hemolysis) of RBCs with an appropriate attempt by the bone marrow to compensate. The reticulocyte count (and index) are therefore high. Hyperproliferative anemias are either of hereditary or acquired causes. The hereditary causes include:

1. Defects in the RBC membrane

2. Defects of RBC metabolism

3. Defects in hemoglobin

The acquired causes include:

1. Immune etiology

2. Nonimmune etiology (see table 19.3)

ACQUIRED HYPERPROLIFERATIVE ANEMIAS

Acquired causes of hyperproliferative anemias are distinguished from hereditary causes by the time of onset and lack of a family history. Clinically, in addition to the general signs and symptoms of anemia patients have indirect hyperbilirubinemia, an elevated LDH, low haptoglobin, and reticulocytosis. The two most important tests in the evaluation of acquired hyperproliferative anemias are (1) a direct Coombs’ test (also known as the direct antiglobulin test), which detects the presence of antibodies or complement proteins bound to the RBC surface, and (2) an examination of the peripheral smear for the morphology of the RBCs (see table 19.4). The direct Coombs’ test differentiates immune from nonimmune causes.

Stay updated, free articles. Join our Telegram channel

Join