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Chapter 8: Folate, Cobalamin, and Megaloblastic Anemias

DEFINITION

  • These disorders are caused by impaired synthesis of DNA.

  • They most commonly result from folate or cobalamin (vitamin B12) deficiency.

  • Characteristics are megaloblastic cells, typically present in the erythroid series as large cells with immature-appearing nuclei but with increasing hemoglobinization of the cytoplasm—often referred to as nuclear-cytoplasmic asynchrony.

  • Megaloblastic granulocytic cells have large size. Giant band neutrophils are a feature in the marrow with hypersegmented neutrophils in the marrow and blood. Megakaryocytes may be abnormally large with nuclear abnormalities.

ETIOLOGY AND PATHOGENESIS

  • Table 8–1 lists causes of megaloblastic anemia.

  • By far the most common causes worldwide are folate deficiency and cobalamin deficiency.

  • The underlying defect is impaired DNA synthesis because of failure of conversion of dUMP to dTMP.

  • Intramedullary destruction of red cell precursors (ineffective erythropoiesis) is a major feature of megaloblastic anemia. Ineffective granulopoiesis and thrombopoiesis are also present and can result in neutropenia and thrombocytopenia. Ineffective hematopoiesis is characterized by marked hyperplasia of precursor cells (hypercellular marrow) with exaggerated apoptosis of late precursors, which results in blood cytopenias.

  • Mild hemolysis also occurs; the red cell life span is reduced by about 40%.

TABLE 8–1CAUSES OF MEGALOBLASTIC ANEMIAS
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TABLE 8–1 CAUSES OF MEGALOBLASTIC ANEMIAS

  1. Folate Deficiency

    1. Decreased intake

      1. Poor nutrition

      2. Old age, poverty, alcoholism

      3. Hyperalimentation

      4. Hemodialysis

      5. Premature infants

      6. Spinal cord injury

      7. Children on synthetic diets

      8. Goat’s milk anemia

    2. Impaired absorption

      1. Nontropical sprue

      2. Tropical sprue

      3. Other disease of the small intestine

    3. Increased requirements

      1. Pregnancy

      2. Increased cell turnover

      3. Chronic hemolytic anemia

      4. Exfoliative dermatitis

  2. Cobalamin Deficiency

    1. Impaired absorption

      1. Gastric causes

        1. Pernicious anemia

        2. Gastrectomy

        3. Zollinger-Ellison syndrome

      2. Intestinal causes

        1. Ileal resection or disease

        2. Blind loop syndrome

        3. Fish tapeworm

      3. Pancreatic insufficiency

    2. Decreased intake: vegans

  3. Acute Megaloblastic Anemia

    1. Nitrous oxide exposure

    2. Severe illness with

      1. Extensive transfusion

      2. Dialysis

      3. Total parenteral nutrition

  4. Drugs

    1. Dihydrofolate reductase inhibitors

    2. Antimetabolites

    3. Inhibitors of deoxynucleotide synthesis

    4. Anticonvulsants

    5. Oral contraceptives

    6. Others, such as long-term exposure to weak folate antagonists (e.g., trimethoprim or low-dose methotrexate)

  5. Inborn Errors

    1. Cobalamin deficiency

      1. Imerslund-Gräsbeck disease

      2. Congenital deficiency of intrinsic factor

      3. Transcobalamin deficiency

    2. Errors of cobalamin metabolism: “cobalamin mutant” syndromes with homocystinuria and/or methylmalonic acidemia

    3. Errors of folate metabolism

      1. Congenital folate malabsorption

      2. Dihydrofolate reductase deficiency

      3. N5-methyl FH4 homocysteine-methyltransferase deficiency

    4. Other errors

      1. Hereditary orotic aciduria

      2. Lesch-Nyhan syndrome

      3. Thiamine-responsive megaloblastic anemia

  6. Unexplained

    1. Congenital dyserythropoietic anemia

    2. Refractory megaloblastic anemia

    3. Erythroleukemia

Source: Williams Hematology, 9th ed, Chap. 41, Table 41–4.

CLINICAL FEATURES

  • Anemia develops gradually, and patients can adapt to very low hemoglobin levels. Eventually, as it progresses, the presenting symptoms are those of anemia with weakness, palpitation, fatigue, light-headedness, and shortness of breath.

  • The condition may present initially with neurologic manifestations without anemia.

  • Folic acid deficiency and cobalamin deficiency have indistinguishable blood and marrow changes (megaloblastosis), but the former deficiency is not associated with neuropathology and the latter characteristically is (see “Pernicious Anemia” below).

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