Underlying basic science Biochemical basis of megaloblastic anaemia

The common feature of all megaloblastic anaemias is a defect in DNA synthesis that affects rapidly dividing cells in the bone marrow and other tissues. All conditions that give rise to mega-loblastic changes share in common a disparity in the rate of synthesis or availability of the four immediate precursors of DNA: the deoxyribonucleoside triphosphates (dNTPs), dA(adenine) TP and dG(guanine)TP (purines) and dT(thymine)TP and

Table 5.1 Causes of megaloblastic anaemia.

Cobalamin deficiency or abnormalities of cobalamin metabolism (Table 5.4)

Folate deficiency or abnormalities of folate metabolism (Table 5.8) Therapy with antifolate drugs (e.g. methotrexate) Independent of either cobalamin or folate deficiency and refractory to cobalamin and folate therapy:

Some cases of acute myeloid leukaemia, myelodysplasia* Therapy with drugs interfering with synthesis of DNA

(e.g. cytosine arabinoside, hydroxyurea, 6-mercaptopurine, azidothymidine (AZT)) Orotic aciduria (responds to uridine) Lesch-Nyhan syndrome (? responds to adenine)

*Folate deficiency also occurs frequently in these diseases.

dC(cytosine)TP (pyrimidines) required for ordered DNA replication during the S-phase of the cell cycle (Figure 5.1). In deficiencies of either folate or cobalamin, the defect in DNA synthesis is caused by a failure to convert adequate amounts of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (dTMP). This is because folate is needed as the

Figure 5.1 Deoxyuridine suppression test. The circle represents a bone marrow or other haemopoietic cell. THF, tetrahydrofolate; MP, monophosphate; TP, triphosphate; d, deoxyribose; A, adenine; T, thymine; C, cytosine; G, guanine.

Figure 5.1 Deoxyuridine suppression test. The circle represents a bone marrow or other haemopoietic cell. THF, tetrahydrofolate; MP, monophosphate; TP, triphosphate; d, deoxyribose; A, adenine; T, thymine; C, cytosine; G, guanine.

coenzyme 5,10-methylene tetrahydrofolate polyglutamate for conversion of dUMP to dTMP and the availability of this coenzyme is reduced in either cobalamin or folate deficiencies.

Synthesis of new strands of DNA during the S-phase of the cell cycle commences with separation of the two parent strands from each other at many points along the chromosome. At a number of points of origin, RNA primers are synthesized first and new DNA strands are then synthesized bidirectionally using the parent strands as templates, with A pairing with T and G with C. The RNA primer is ultimately hydrolysed and the gap filled with DNA. The small pieces of DNA (Okazaki fragments) are then joined up to make complete new chromosomal DNA.

The reduced supply of dTTP in megaloblastic anaemia owing to folate or cobalamin deficiency appears to slow elongation of newly originated replicating segments. Thus, small fragments accumulate, single-stranded areas become points of weakness, where mechanical or enzymatic breakage may occur, and the failure to form bulk DNA may impair contraction of newly replicated lengths of DNA, thus leaving the chromosomes elongated, despirillated and with random breaks. Late-replicating DNA is particularly affected, many of the gross defects in DNA appearing in late replication. Indeed, some cells become arrested and die at this stage. Apoptosis occurs particularly at the late stage of erythroblast differentiation and can be prevented by thymidine. Surprisingly, measurements of dTTP concentration in megaloblasts have not shown a deficiency. This may be because the overall cell concentration masks a localized deficiency at the multienzyme complex directly concerned with DNA replication.

An alternative theory for megaloblastic anaemia in cobalamin or folate deficiency is the misincorporation of uracil into DNA because of a build-up of deoxyuridine triphosphate (dUTP) at the replication fork in consequence of the block in conversion of dUMP to dTMP (Figure 5.1). As dUTP does not normally occur in DNA, there is a mechanism for recognition of this aberrant material for excision and repair, but as long as dTTP remains in short supply this may not be possible. Repeated cycles of futile excision and misrepair may occur with disruption of the normal programme of DNA synthesis leading to apoptotic cell death. Data on this theory are conflicting. It does not explain megaloblastic anaemia due to defects of DNA synthesis at sites other than thymidylate synthesis (e.g. with drugs such as hydroxyurea, cytosine arabinoside or 6-mercaptopurine, or with enzyme deficiencies such as orotic aciduria or thiamine-responsive megaloblastic anaemia; see below). A reduced supply of one of three other deoxyribonucleoside triphosphates or malfunction of DNA polymerase is the likely cause of these megaloblastic anaemias.

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