Hypoproliferative anemias

Harrison's Internal Medicine Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes: Introduction The hypoproliferative anemias are normochromic, normocytic or macrocytic and are characterized by a low reticulocyte count. Deficient production of RBCs occurs with marrow damage and dysfunction, which may be secondary to infection, inflammation, and cancer.

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Anemia of Acute and Chronic Inflammation/Infection (the Anemia of Chronic Disease) The anemia of chronic disease—which encompasses inflammation, infection, tissue injury, and conditions (such as cancer) associated with the release of proinflammatory cytokines—is one of the most common forms of anemia seen clinically and probably the most important in the differential diagnosis of iron deficiency, since many of the features of the anemia are brought about by inadequate iron delivery to the marrow, despite the presence of normal or increased iron stores.

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Table 98-6 Diagnosis of Hypoproliferative Anemias Tests Iron Deficiency tion Inflamma Renal Disease Hypometa bolic States Anemia Mild to severe Mild severe Mild to Mild MCV (fL) 90 60– 80–90 90 90 Morphol ogy mo- Nor c Normocyti ytic Normoc Normocytic microcytic SI 360

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Protein Starvation Decreased dietary intake of protein may lead to mild to moderate hypoproliferative anemia; this form of anemia may be prevalent in the elderly. The anemia can be more severe in patients with a greater degree of starvation. In marasmus, where patients are both protein- and calorie-deficient, the release of EPO is impaired in proportion to the reduction in metabolic rate; however, the degree of anemia may be masked by volume depletion and becomes apparent after refeeding.

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The second condition is the anemia of chronic inflammation with inadequate iron supply to the erythroid marrow. The distinction between true irondeficiency anemia and the anemia associated with chronic inflammation is among the most common diagnostic problems encountered by clinicians (see below). Usually the anemia of chronic inflammation is normocytic and normochromic. The iron values usually make the differential diagnosis clear, as the ferritin level is normal or increased and the percent transferrin saturation and TIBC are typically below normal.

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Of the complications of oral iron therapy, gastrointestinal distress is the most prominent and is seen in 15–20% of patients. Abdominal pain, nausea, vomiting, or constipation may lead to noncompliance. Although small doses of iron or iron preparations with delayed release may help somewhat, the gastrointestinal side effects are a major impediment to the effective treatment of a number of patients. The response to iron therapy varies, depending on the erythropoietin (EPO) stimulus and the rate of absorption.

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Table 98-3 Iron Store Measurements Iron Stores 4+ Marrow Iron Stain, 0– µg/L Serum Ferritin, 0 0 150 Iron overload — 500–1000 Red Cell Protoporphyrin Levels Protoporphyrin is an intermediate in the pathway to heme synthesis. Under conditions in which heme synthesis is impaired, protoporphyrin accumulates within the red cell.

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Harrison's Internal Medicine

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Internal iron exchange. Normally about 80% of iron passing through the plasma transferrin pool is recycled from broken-down red cells. Absorption of about 1 mg/d is required from the diet in men, 1.4 mg/d in women to maintain homeostasis. As long as transferrin saturation is maintained between 20–60% and erythropoiesis is not increased, iron stores are not required. However, in the event of blood loss, dietary iron deficiency, or inadequate iron absorption, up to 40 mg/d of iron can be mobilized from stores. RE, reticuloendothelial.

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Nutritional Iron Balance The balance of iron in humans is tightly controlled and designed to conserve iron for reutilization. There is no regulated excretory pathway for iron, and the only mechanisms by which iron is lost from the body are blood loss (via gastrointestinal bleeding, menses, or other forms of bleeding) and the loss of epithelial cells from the skin, gut, and genitourinary tract. Normally, the only route by which iron comes into the body is via absorption from food or from medicinal iron taken orally.

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Stages of Iron Deficiency Iron-deficiency anemia is the condition in which there is anemia and clear evidence of iron lack. The progression to iron deficiency can be divided into three stages (Fig. 98-2). The first stage is negative iron balance, in which the demands for (or losses of) iron exceed the body's ability to absorb iron from the diet.

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Clinical Presentation of Iron Deficiency Certain clinical conditions carry an increased likelihood of iron deficiency. Pregnancy, adolescence, periods of rapid growth, and an intermittent history of blood loss of any kind should alert the clinician to possible iron deficiency. A cardinal rule is that the appearance of iron deficiency in an adult male means gastrointestinal blood loss until proven otherwise. Signs related to iron deficiency depend on the severity and chronicity of the anemia in addition to the usual signs of anemia—fatigue, pallor, and reduced exercise capacity.

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Anemia: Treatment An overriding principle is to initiate treatment of mild to moderate anemia only when a specific diagnosis is made. Rarely, in the acute setting, anemia may be so severe that red cell transfusions are required before a specific diagnosis is made. Whether the anemia is of acute or gradual onset, the selection of the appropriate treatment is determined by the documented cause(s) of the anemia. Often, the cause of the anemia may be multifactorial.

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Cytoplasmic maturation defects result from severe iron deficiency or abnormalities in globin or heme synthesis. Iron deficiency occupies an unusual position in the classification of anemia. If the iron-deficiency anemia is mild to moderate, erythroid marrow proliferation is decreased and the anemia is classified as hypoproliferative. However, if the anemia is severe and prolonged, the erythroid marrow will become hyperplastic despite the inadequate iron supply, and the anemia will be classified as ineffective erythropoiesis with a cytoplasmic maturation defect.

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Bone Marrow Examination A bone marrow aspirate and smear or a needle biopsy may be useful in the evaluation of some patients with anemia. In patients with hypoproliferative anemia and normal iron status, a bone marrow is indicated. Marrow examination can diagnose primary marrow disorders such as myelofibrosis, a red cell maturation defect, or an infiltrative disease (Figs. 58-14, 58-15, and 58-16). The increase or decrease of one cell lineage (myeloid vs.

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