Vitamin B12 and Folic Acid

Vitamin B12 and Folic Acid

1. Definition & overview — the maturation factors

• Vitamin B₁₂ (cobalamins) and folic acid (pteroylglutamic acid) are the two "maturation factors" — B-group vitamins whose deficiency produces megaloblastic anaemia, characterised by large red-cell precursors in the bone marrow and their large, short-lived progeny in peripheral blood (KDT 8e Ch.44, p.652).
• The basic defect in both deficiencies is impaired DNA synthesis; because DNA replication is needed wherever chromosomal replication and division occur, any rapidly dividing tissue suffers — but the haematopoietic system, with its very high cell-turnover rate, shows the most dramatic changes (G&G 14e Ch.45, pp.911–912; KDT 8e Ch.44, p.652).
• Because B₁₂ and folate are metabolically interlinked, the megaloblastic anaemia of either deficiency is morphologically indistinguishable — the same final lesion (a block in thymidylate/DNA synthesis) is reached by both routes (KDT 8e Ch.44, p.652; G&G 14e Ch.45, p.912).
• The cellular lesion is nucleo-cytoplasmic asynchrony: once a stem cell is committed to a programmed series of divisions, the defect in chromosomal replication leaves maturing cells unable to complete nuclear division while cytoplasmic maturation continues at a near-normal rate → morphologically abnormal cells and intramedullary cell death — ineffective haematopoiesis (G&G 14e Ch.45, p.914).
• Severe deficiency affects all cell lines, producing pronounced pancytopenia (not just anaemia); other high-turnover tissues (GI mucosa, cervical epithelium) are also affected (G&G 14e Ch.45, p.914; KDT 8e Ch.44, p.654).
• Two Nobel-Prize-winning historical threads define the field: Minot & Murphy (1926) showed dietary liver reverses pernicious anaemia; Castle (1927–32) propounded that an extrinsic factor in diet combines with an intrinsic factor produced by the stomach to give the haemopoietic principle; B₁₂ was isolated in 1948 and shown to be both the extrinsic factor and the haemopoietic principle — the intrinsic factor merely aids its absorption (KDT 8e Ch.44, pp.652–653; G&G 14e Ch.45, pp.911–912).
• Wills' factor — a macrocytic anaemia in women in India that responded to crude liver extract but not to the purified anti-pernicious-anaemia fraction — was later shown to be folic acid (named by Mitchell 1941 after its isolation from leaf/spinach, folium = leaf) (G&G 14e Ch.45, p.912; KDT 8e Ch.44, p.655).