Macrocytic Anemia

MACROCYTIC ANEMIA

Macrocytic anemias are characterized by the presence of anemia and erythrocytes of variable shapes but with diameters in excess of 9 Lm and MCVs characteristically greater than 96 fdm3 (Table 13.4). The condition may be caused by certain liver diseases, including alcoholism, that produces large rounded cells or by megaloblastic anemia, which is associated with enlarged oval cells. The latter is also indicated by the presence of the erythrocyte precursors, erythroblasts (megaloblasts) in blood. The increased proportion of immature forms of all cell lines reflects the premature death of cells in the process of development (Figure 13.17). The cells are large, although there is a substantial variation in size, and they have large, immature nuclei. The basis of the problem is the inability to synthesize deoxythymidine monophosphate from methylated deoxyuridine monophosphate. The methyl group is supplied by the folate coenzyme, methylene tetrahydrofolate polyglutamate and deficiency of folate reduces its supply. A deficiency of vitamin B12 (Figure 13.18(A)) also reduces its supply by slowing the demethylation of methyl tetrahydrofolate. Thus deficiencies of vitamins B12 or folate or other defects, for example genetic ones, that affect DNA biosynthesis in the bone marrow, produce an asynchrony between nuclear and cytoplasmic development and a delayed maturation of blood cells and result in megaloblastic anemia.

Vitamin B12, also called cobalamin, is found in animal products and is produced by certain microorganisms but not by plants. It is liberated from protein complexes by gastric enzymes and binds to a glycoprotein called intrinsicfactor. This is secreted by the gastric parietal cells alongwith H+ and carries vitamin B12 to specific receptors on the mucosal surface of the ileum. Although the vitamin enters the ileal enterocytes, the intrinsic factor remains in the lumen of the gut. Transport in the blood is by another protein, transcobalamin. Atrophy of the gastric mucosa and consequent failure to produce intrinsic factor leads to the malabsorption of the vitamin, whose deficiency results in pernicious anemia. Cytotoxic IgG antibodies directed against gastric parietal cells and/or against intrinsic factor are found in the serum in about 90% of individuals with pernicious anemia. In a majority of these individuals the antibodies are also present in the gastric juice and either prevent the binding of vitamin B12 to intrinsic factor or inhibit the absorption of the vitamin B12: intrinsic factor complex.

The onset of the disease is insidious with progressively increasing symptoms of anemia. Patients show achlorhydria, a low or absence of gastric acid secretion, and lack of secreted intrinsic factor. There may be jaundice because of excessive breakdown of Hb and because erythropoiesis in the bone marrow is deficient. The serum bilirubin may be increased and the serum vitamin B12 concentration is usually considerably below its physiological value of approximately 160 ng dm–3. However, the polyneuropathogical symptoms make it important that treatment is not delayed as they can become irreversible; patients present with symmetrical paraesthesia in the fingers and toes, an early loss of vibration sense and ataxia. Paraplegia may be the result. Pernicious anemia is predominantly a disease of the elderly with one in 8000 of the over 60 population being affected in the UK. It also seems to be associated with certain autoimmune diseases, such as thyroid and Addison’s diseases .

The causes of folate (Figure 13.18 (B)) deficiency are nutritional, for example a poor intake of green vegetables, such as broccoli and spinach and offal, alcohol excess, cancer, or excessive utilization in pregnancy and lactation and the use of antifolate drugs, such as methotrexate, phenytoin and pyrimethamine. The clinical manifestations of folate deficiency are megaloblastic anemia with a serum folate concentration that is lower than the reference value of 4 to 18 Mg dm3.

The deoxyuridine suppression test for megaloblastic anemia is performed by adding tritiated thymidine (3H-thymidine) to a sample of bone marrow. Bone marrow samples may be obtained by aspiration or by trephine. Aspiration, using a specialized needle, is usually carried out at the iliac crest with a local anesthetic. In normal marrow less than 5% of the 3H-thymidine is usually taken up, but in megaloblastic marrow up to 50% of it may be used. The microscopic picture of the bone marrow can be investigated by using the aspirate to make a smear on a microscopy slide. If a larger sample of bone marrow is required, the posterior iliac crest is used but a longer and wider needle is used to obtain a ‘core’ of bone. This core is fixed and decalcified over several days and then stained for microscopy.

It is important to distinguish pernicious anemia from other causes of megaloblastic anemia, such as folate deficiency, because this will affect treatment. However, this is usually clear from the blood concentrations of these two vitamins. Also, the ability to absorb vitamin B12 can be measured using the Schilling test in which patients are given vitamin B12 radioactively-labeled with 58Co. The urine is collected over a period of 24 h and the amount of radioactivity measured.

Vitamin B12 deficiency is treated by intramuscular injection of 1 mg of the pure vitamin, to a total of 6 mg over a period of three weeks. Oral administration is obviously unsuccessful in pernicious anemia because of the lack of intrinsic factor. A maintenance dose of 1 mg every three months is then given for the rest of the patient’s life. Clinical improvement may occur within a few days (provided that the neuropathy has not been long-standing) and a reticulocytosis is observed a few days later. Folate deficiency can be corrected by giving 5 mg of folic acid daily, and this usually produces a rapid hematological response. Prophylactic folate is recommended for all women during pregnancy and especially for women who have had a previous child with a neural tube defect.