After studying this chapter you should be able to:
Draw a simple scheme outlining the key biochemical reactions involving cobalamin (vitamin B12) and folate.
Understand how cobalamin and folate are absorbed from the gut and transported in plasma.
Explain the mechanisms that cause megaloblastic morphology in the bone marrow and blood and describe these features.
List the causes of cobalamin deficiency.
List the causes of folate deficiency.
Hematopoiesis depends upon orderly cell division for the logarithmic expansion of progenitor cells into large numbers of circulating blood cells. In the megaloblastic anemias, DNA synthesis is impaired, leading to slowing or arrest of cellular division during the DNA synthesis phase of the cell cycle (S phase). A high fraction of cells suffering from such defects undergo programmed cell death (apoptosis). In the bone marrow, the decreased survival of hematopoietic progenitors leads to reduced production of circulating cells (ineffective hematopoiesis). Because RNA synthesis and cytoplasmic differentiation are relatively unaffected, progenitors and progeny that survive are enlarged (macrocytic). The main cause of megaloblastic anemias is deficiency of either cobalamin (vitamin B12) or folic acid, vitamins that are essential for DNA replication and repair. In addition, chemotherapeutic drugs that inhibit DNA synthesis can result in findings similar to those seen in cobalamin or folate deficiency. It is not surprising that the clinical phenotype extends to other tissues that rely on continuous and robust cellular proliferation and differentiation, particularly the gastrointestinal tract.
Understanding the pathophysiology of the megaloblastic anemias requires knowledge about the absorption, transport, and utilization of folate and cobalamin as well as familiarity with the key chemical reactions in which these vitamins are essential cofactors.
PHYSIOLOGY OF COBALAMIN AND FOLATE
Cobalamin is a complex organic molecule consisting of a tetrapyrole corrin ring, similar in structure to heme except that the divalent metal atom in the center of the ring is cobalt rather than iron. Like heme iron, the cobalt atom in the corrin ring binds to two axial ligands. One is a benzimidazole nucleotide, whereas the other can be either a methyl group (methylcobalamin) or an adenosyl group (adenosylcobalamin). Cobalamin is found in all foods of animal origin including meat, fish, and dairy products. Food cobalamin is tightly bound to proteins. Following ingestion, some cobalamin in food is transferred to human haptocorrin in saliva. As depicted in Figure 6-1, the acidic environment of the stomach enables efficient release and transfer of the remaining food cobalamin to haptocorrin in gastric juice. After transit to the duodenum, the increase in pH enables the transfer of cobalamin from haptocorrin to intrinsic factor, a transport protein secreted by gastric parietal cells. The cobalamin-intrinsic factor complex resists digestion and travels down the gut until it encounters epithelial cells in the distal ileum that express cubilin, a receptor with specificity for this bimolecular complex. The cobalamin that is absorbed in the ileum ...