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Nilsson-Ehle H. The Macrocyte Secrets[evaluation] Rondellen 2001; 8. URL: http://www.rondellen.net

The Macrocyte Secrets

"Why are red cells larger in vitamin B₁₂ / folic acid deficiency?" medical students often ask. The simple answer is that cellular material accumulates due to inadequate mitosis. The megaloblastic changes affect all stages of erythroblasts, which result in a greater proportion of the cells being in S-M-phase when the nucleus is rejected and a reticulocyte is formed.

Formerly, the megaloblastic maturation block observed in vitamin B₁₂ /folic acid deficiency was thought to occur in the prophase – the erythroblasts were stuck just prior to metaphasis but the cellular membrane was not disintegrated and the chromosomes were invisible.

Recent research has shown that this maturation block also affects the S- and G2-phases of the cell cycle (1-3). The ineffective erythropoiesis, which, in combination with a slight intravascular hemolysis causes anemia, is by some (2) but not others (3) considered to be caused by increased apoptosis (programmed cell death).

Spuriously high mean cell volume (MCV) is seen in reticulocytosis. False low values in MCV are seen in concomitant iron deficiency and thalassemia. These sources of error are revealed by the cell volume distribution curves obtained by modern flow cytometers (4). Mean values are not all that matters!

The higher the MCV, the more likely is megaloblastic erythropoiesis. Vitamin B₁₂ /folic acid deficiency affects all rapidly dividing cells, i.e. bone marrow, mucosae, sperm production, fetus.

Megaloblastosis and slightly increased MCV are also seen in myelodysplastic syndromes and acute leukemia – consider a bone marrow examination in a macrocytic anemia unresponsive to appropriate vitamin(s)! The haematological response begins with decreasing serum iron and reticulocytosis – the MCV will not be normalized until several months!

S-phase-specific cytotoxic drugs such as methotrexate, hydroxyurea and cytarabine also cause megaloblastic changes and MCV often above 120 fl.

Macrocytosis (100-110 fl) without megaloblastic bone marrow may be caused by alcohol and other toxins. If the alcoholic in addition has vitamin B₁₂ / folic acid deficiency, the bone marrow is megaloblastic and MCV higher. In such cases, both long-standing abstinence and vitamin therapy are mandatory for a normalization of MCV. Thus, the old view that the erythrocyte size is central in all investigation of anemia still holds true! (4).

References

1. Fenech M. The role of folic acid and vitamin B12 in genomic stability of human cells. Mutation Res 2001; 475:57-67.
2. Koury MJ, Price JO, Hicks GG. Apoptosis in megaloblastic anemia occurs during DNA synthesis by a p53-dependent, nucleoside-reversible mechanism. Blood 2000; 96:3249-55.
3. Ingram CF, Davidoff AN, Marais E, Sherman GG, Mendelov BV. Evaluation of DNA analysis for evidence of apoptosis in megaloblastic anaemia. Br J Haematol 1997; 96:576-83.
4. Nilsson-Ehle H, Sandström H. Anemier. I: Läkemedelsboken 2001-2002:189-201, Apoteksbolaget.

Published September 11, 2001